I recently had both the pleasure and the challenge of attending ASCO 2014, the annual meeting of the American Society of Clinical Oncology. It was my first official ASCO meeting, and as an almost-third-year fellow in oncology, no amount of reading, research, scheduling, ASCO 2014 iPad app organizing, or even attending the day 1 early morning How to Navigate the Annual Meeting seminar could have prepared me for the experience…
 

Click on the PDF icon at the top of this introduction to read the full article.

I recently had both the pleasure and the challenge of attending ASCO 2014, the annual meeting of the American Society of Clinical Oncology. It was my first official ASCO meeting, and as an almost-third-year fellow in oncology, no amount of reading, research, scheduling, ASCO 2014 iPad app organizing, or even attending the day 1 early morning How to Navigate the Annual Meeting seminar could have prepared me for the experience…
 

Click on the PDF icon at the top of this introduction to read the full article.

I recently had both the pleasure and the challenge of attending ASCO 2014, the annual meeting of the American Society of Clinical Oncology. It was my first official ASCO meeting, and as an almost-third-year fellow in oncology, no amount of reading, research, scheduling, ASCO 2014 iPad app organizing, or even attending the day 1 early morning How to Navigate the Annual Meeting seminar could have prepared me for the experience…
 

Click on the PDF icon at the top of this introduction to read the full article.

The American Society of Clinical Oncology marked its 50th anniversary at this year’s annual conference in Chicago, where it showcased the latest scientific advances in oncology and explored the translation of research findings into practice under its umbrella theme, Science and Society.

Drug combo extends survival by more than 1 year in metastatic prostate cancer patients
Key clinical finding Adding docetaxel to hormonal therapy at the time of diagnosis of metastatic prostate cancer extends survival. Major finding Patients receiving docetaxel and androgen deprivation therapy at the time of diagnoses had median overall survival that was 13.6 months longer than men who received androgen deprivation therapy alone. Data source Randomized trial in 790 men with newly diagnosed metastatic hormone-sensitive prostate cancer...
 

Click on the PDF icon at the top of this introduction to read the full article.

The American Society of Clinical Oncology marked its 50th anniversary at this year’s annual conference in Chicago, where it showcased the latest scientific advances in oncology and explored the translation of research findings into practice under its umbrella theme, Science and Society.

Drug combo extends survival by more than 1 year in metastatic prostate cancer patients
Key clinical finding Adding docetaxel to hormonal therapy at the time of diagnosis of metastatic prostate cancer extends survival. Major finding Patients receiving docetaxel and androgen deprivation therapy at the time of diagnoses had median overall survival that was 13.6 months longer than men who received androgen deprivation therapy alone. Data source Randomized trial in 790 men with newly diagnosed metastatic hormone-sensitive prostate cancer...
 

Click on the PDF icon at the top of this introduction to read the full article.

The American Society of Clinical Oncology marked its 50th anniversary at this year’s annual conference in Chicago, where it showcased the latest scientific advances in oncology and explored the translation of research findings into practice under its umbrella theme, Science and Society.

Drug combo extends survival by more than 1 year in metastatic prostate cancer patients
Key clinical finding Adding docetaxel to hormonal therapy at the time of diagnosis of metastatic prostate cancer extends survival. Major finding Patients receiving docetaxel and androgen deprivation therapy at the time of diagnoses had median overall survival that was 13.6 months longer than men who received androgen deprivation therapy alone. Data source Randomized trial in 790 men with newly diagnosed metastatic hormone-sensitive prostate cancer...
 

Click on the PDF icon at the top of this introduction to read the full article.

Delirium has been described as a poten­tial complication of concurrent lithium and electroconvulsive therapy (ECT) for depression, in association with a range of serum lithium levels. Although debate persists about the safety of continuing pre­viously established lithium therapy during a course of ECT for mood symptoms, with­holding lithium for 24 hours before adminis­tering ECT and measuring the serum lithium level before ECT were found to decrease the risk of post-ECT neurocognitive effects.¹

We have found that the conven­tional practice of holding lithium for 24 hours before ECT might need to be re-evaluated in geriatric patients, as the fol­lowing case demonstrates. Only 24 hours of holding lithium therapy might result in a lithium level sufficient to contribute to delir­ium after ECT. 

CASE REPORT
An older woman with recurrent unipolar psychotic depression
Mrs. A, age 81, was admitted to the hospital with a 1-week history of depressed mood, anhedonia, insomnia, anergia, anorexia, and nihilistic somatic delusions that her organs were “rotting and shutting down.” Treatment included nortriptyline, 40 mg/d; lithium, 150 mg/d; and haloperidol, 0.5 mg/d. Her serum lithium level was 0.3 mEq/L (reference range, 0.6 to 1.2 mEq/L); the serum nortrip­tyline level was 68 ng/mL (reference range, 50 to 150 ng/mL). CT of the head and an electrocardiogram were unremarkable.

A twice-weekly course of ECT was initiated.

The day before Treatment 1 of ECT, the serum lithium level (drawn 12 hours after the last dose) was 0.4 mEq/L. Lithium was withheld 24 hours before ECT; nortriptyline and haloperidol were continued at prescribed dosages.

Right unilateral stimulation was used at 50%/mC energy (Thymatron DG, with metho­hexital anesthesia, and succinylcholine for mus­cle relaxation). Seizure duration, measured by EEG, was 57 seconds.

Mrs. A developed postictal delirium after the first 2 ECT sessions. The serum lithium level was unchanged. Subsequently, lithium treat­ment was discontinued and ECT was continued; once lithium was stopped, delirium resolved. ECT sessions 3 and 4 were uneventful, with no post-treatment delirium. Seizure duration for Treatment 4 was 58 seconds. She started breath­ing easily after all ECT sessions.

After Treatment 4, Mrs. A experienced full remission of depressive and psychotic symp­toms. Repeat CT of head, after Treatment 4, was unchanged from baseline.

What is the role of lithium?
Mrs. A did not exhibit typical signs of lithium intoxication (diarrhea, vomiting, tremor). Notably, lithium has an intrinsic anticholinergic activity²; concurrent nor­triptyline, a secondary amine tricyclic anti­depressant with fewer anticholinergic side effects than other tricyclics,² could pre­cipitate delirium in a vulnerable patient secondary to excessive cumulative anti­cholinergic exposure.

No prolonged time-to-respiration or time-to-awakening occurred during treat­ments in which concurrent lithium and ECT were used; seizure duration with and without concurrent lithium was rela­tively similar.

There are potential complications of con­current use of lithium and ECT:
    • prolongation of the duration of muscle paralysis and apnea induced by commonly used neuromuscular-blocking agents (eg, succinylcholine)
    • post-ECT cognitive disturbance.^1,3,4

There is debate about the safety of con­tinuing lithium during, or in close proximity to, ECT. In a case series of 12 patients who underwent combined lithium therapy and ECT, the authors concluded that this combi­nation can be safe, regardless of age, as long as appropriate clinical monitoring is pro­vided.⁴ In Mrs. A’s case, once post-ECT delir­ium was noted, lithium was discontinued for subsequent ECT sessions.

Because further ECT was uneventful with­out lithium, and no other clear acute cause of delirium could be identified, we concluded that lithium likely played a role in Mrs. A’s delirium. Notably, nortriptyline had been continued, suggesting that the degree of anticholinergic blockade provided by nortriptyline was insufficient to provoke delirium post-ECT in the absence of potentia­tion of this effect, as it had been when lithium also was used initially.

Guidelines for dosing and serum lithium concentrations in geriatric patients are not well-established; the current traditional range of 0.6 to 1.2 mEq/L, is too high for geriatric patients and can result in epi­sodes of lithium toxicity, including delirium.⁵ Although our patient’s lithium level was below the reference range for all patients, a level of 0.3 mEq/L can be considered at the low end of the reference range for geriatric patients.5 Inasmuch as the lithium-assisted post-ECT delirium could represent a clinical sign of lithium toxicity, perhaps even a sub­therapeutic level in a certain patient could be paradoxically “toxic.”

Although the serum lithium level in our patient remained below the toxic level for the general population (>1.5 mEq/L), delirium in a geriatric patient could result from:  
   • age-related changes in the pharmacokinetics of lithium, a water-soluble drug; these changes reduce renal clearance of the drug and extend plasma elimination half-life of a single dose to 36 hours, with the result that lithium remains in the body longer and necessitating a lower dosage (ie, a dosage that yields a serum level of approximately 0.5 mEq/L)  
    • the CNS tissue concentration of lith­ium, which can be high even though the serum level is not toxic  
    • an age-related increase in blood-brain barrier permeability, making the barrier more porous for drugs  
    • changes in blood-brain barrier perme­ability by post-ECT biochemical induction, with subsequent increased drug availability in the CNS.^5,6 

What we recommend
Possible interactions between lithium and ECT that lead to ECT-associated delirium need further elucidation, but discontinu­ing lithium during the course of ECT in a geriatric patient warrants your consider­ation. Following a safe interval after the last ECT session, lithium likely can be safely re-introduced 1) if there is clinical need and 2) as long as clinical surveillance for cognitive side effects is provided— especially if ECT will need to be reconsidered in the future.

Two additional considerations:
   • Actively reassess lithium dosing in all geriatric psychiatric patients, especially those with renal insufficiency and other systemic metabolic considerations.
   • Actively examine the use of all other anticholinergic agents in the course of evaluating a patient’s candidacy for ECT.


Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Delirium has been described as a poten­tial complication of concurrent lithium and electroconvulsive therapy (ECT) for depression, in association with a range of serum lithium levels. Although debate persists about the safety of continuing pre­viously established lithium therapy during a course of ECT for mood symptoms, with­holding lithium for 24 hours before adminis­tering ECT and measuring the serum lithium level before ECT were found to decrease the risk of post-ECT neurocognitive effects.¹

We have found that the conven­tional practice of holding lithium for 24 hours before ECT might need to be re-evaluated in geriatric patients, as the fol­lowing case demonstrates. Only 24 hours of holding lithium therapy might result in a lithium level sufficient to contribute to delir­ium after ECT. 

CASE REPORT
An older woman with recurrent unipolar psychotic depression
Mrs. A, age 81, was admitted to the hospital with a 1-week history of depressed mood, anhedonia, insomnia, anergia, anorexia, and nihilistic somatic delusions that her organs were “rotting and shutting down.” Treatment included nortriptyline, 40 mg/d; lithium, 150 mg/d; and haloperidol, 0.5 mg/d. Her serum lithium level was 0.3 mEq/L (reference range, 0.6 to 1.2 mEq/L); the serum nortrip­tyline level was 68 ng/mL (reference range, 50 to 150 ng/mL). CT of the head and an electrocardiogram were unremarkable.

A twice-weekly course of ECT was initiated.

The day before Treatment 1 of ECT, the serum lithium level (drawn 12 hours after the last dose) was 0.4 mEq/L. Lithium was withheld 24 hours before ECT; nortriptyline and haloperidol were continued at prescribed dosages.

Right unilateral stimulation was used at 50%/mC energy (Thymatron DG, with metho­hexital anesthesia, and succinylcholine for mus­cle relaxation). Seizure duration, measured by EEG, was 57 seconds.

Mrs. A developed postictal delirium after the first 2 ECT sessions. The serum lithium level was unchanged. Subsequently, lithium treat­ment was discontinued and ECT was continued; once lithium was stopped, delirium resolved. ECT sessions 3 and 4 were uneventful, with no post-treatment delirium. Seizure duration for Treatment 4 was 58 seconds. She started breath­ing easily after all ECT sessions.

After Treatment 4, Mrs. A experienced full remission of depressive and psychotic symp­toms. Repeat CT of head, after Treatment 4, was unchanged from baseline.

What is the role of lithium?
Mrs. A did not exhibit typical signs of lithium intoxication (diarrhea, vomiting, tremor). Notably, lithium has an intrinsic anticholinergic activity²; concurrent nor­triptyline, a secondary amine tricyclic anti­depressant with fewer anticholinergic side effects than other tricyclics,² could pre­cipitate delirium in a vulnerable patient secondary to excessive cumulative anti­cholinergic exposure.

No prolonged time-to-respiration or time-to-awakening occurred during treat­ments in which concurrent lithium and ECT were used; seizure duration with and without concurrent lithium was rela­tively similar.

There are potential complications of con­current use of lithium and ECT:
    • prolongation of the duration of muscle paralysis and apnea induced by commonly used neuromuscular-blocking agents (eg, succinylcholine)
    • post-ECT cognitive disturbance.^1,3,4

There is debate about the safety of con­tinuing lithium during, or in close proximity to, ECT. In a case series of 12 patients who underwent combined lithium therapy and ECT, the authors concluded that this combi­nation can be safe, regardless of age, as long as appropriate clinical monitoring is pro­vided.⁴ In Mrs. A’s case, once post-ECT delir­ium was noted, lithium was discontinued for subsequent ECT sessions.

Because further ECT was uneventful with­out lithium, and no other clear acute cause of delirium could be identified, we concluded that lithium likely played a role in Mrs. A’s delirium. Notably, nortriptyline had been continued, suggesting that the degree of anticholinergic blockade provided by nortriptyline was insufficient to provoke delirium post-ECT in the absence of potentia­tion of this effect, as it had been when lithium also was used initially.

Guidelines for dosing and serum lithium concentrations in geriatric patients are not well-established; the current traditional range of 0.6 to 1.2 mEq/L, is too high for geriatric patients and can result in epi­sodes of lithium toxicity, including delirium.⁵ Although our patient’s lithium level was below the reference range for all patients, a level of 0.3 mEq/L can be considered at the low end of the reference range for geriatric patients.5 Inasmuch as the lithium-assisted post-ECT delirium could represent a clinical sign of lithium toxicity, perhaps even a sub­therapeutic level in a certain patient could be paradoxically “toxic.”

Although the serum lithium level in our patient remained below the toxic level for the general population (>1.5 mEq/L), delirium in a geriatric patient could result from:  
   • age-related changes in the pharmacokinetics of lithium, a water-soluble drug; these changes reduce renal clearance of the drug and extend plasma elimination half-life of a single dose to 36 hours, with the result that lithium remains in the body longer and necessitating a lower dosage (ie, a dosage that yields a serum level of approximately 0.5 mEq/L)  
    • the CNS tissue concentration of lith­ium, which can be high even though the serum level is not toxic  
    • an age-related increase in blood-brain barrier permeability, making the barrier more porous for drugs  
    • changes in blood-brain barrier perme­ability by post-ECT biochemical induction, with subsequent increased drug availability in the CNS.^5,6 

What we recommend
Possible interactions between lithium and ECT that lead to ECT-associated delirium need further elucidation, but discontinu­ing lithium during the course of ECT in a geriatric patient warrants your consider­ation. Following a safe interval after the last ECT session, lithium likely can be safely re-introduced 1) if there is clinical need and 2) as long as clinical surveillance for cognitive side effects is provided— especially if ECT will need to be reconsidered in the future.

Two additional considerations:
   • Actively reassess lithium dosing in all geriatric psychiatric patients, especially those with renal insufficiency and other systemic metabolic considerations.
   • Actively examine the use of all other anticholinergic agents in the course of evaluating a patient’s candidacy for ECT.


Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Delirium has been described as a poten­tial complication of concurrent lithium and electroconvulsive therapy (ECT) for depression, in association with a range of serum lithium levels. Although debate persists about the safety of continuing pre­viously established lithium therapy during a course of ECT for mood symptoms, with­holding lithium for 24 hours before adminis­tering ECT and measuring the serum lithium level before ECT were found to decrease the risk of post-ECT neurocognitive effects.¹

We have found that the conven­tional practice of holding lithium for 24 hours before ECT might need to be re-evaluated in geriatric patients, as the fol­lowing case demonstrates. Only 24 hours of holding lithium therapy might result in a lithium level sufficient to contribute to delir­ium after ECT. 

CASE REPORT
An older woman with recurrent unipolar psychotic depression
Mrs. A, age 81, was admitted to the hospital with a 1-week history of depressed mood, anhedonia, insomnia, anergia, anorexia, and nihilistic somatic delusions that her organs were “rotting and shutting down.” Treatment included nortriptyline, 40 mg/d; lithium, 150 mg/d; and haloperidol, 0.5 mg/d. Her serum lithium level was 0.3 mEq/L (reference range, 0.6 to 1.2 mEq/L); the serum nortrip­tyline level was 68 ng/mL (reference range, 50 to 150 ng/mL). CT of the head and an electrocardiogram were unremarkable.

A twice-weekly course of ECT was initiated.

The day before Treatment 1 of ECT, the serum lithium level (drawn 12 hours after the last dose) was 0.4 mEq/L. Lithium was withheld 24 hours before ECT; nortriptyline and haloperidol were continued at prescribed dosages.

Right unilateral stimulation was used at 50%/mC energy (Thymatron DG, with metho­hexital anesthesia, and succinylcholine for mus­cle relaxation). Seizure duration, measured by EEG, was 57 seconds.

Mrs. A developed postictal delirium after the first 2 ECT sessions. The serum lithium level was unchanged. Subsequently, lithium treat­ment was discontinued and ECT was continued; once lithium was stopped, delirium resolved. ECT sessions 3 and 4 were uneventful, with no post-treatment delirium. Seizure duration for Treatment 4 was 58 seconds. She started breath­ing easily after all ECT sessions.

After Treatment 4, Mrs. A experienced full remission of depressive and psychotic symp­toms. Repeat CT of head, after Treatment 4, was unchanged from baseline.

What is the role of lithium?
Mrs. A did not exhibit typical signs of lithium intoxication (diarrhea, vomiting, tremor). Notably, lithium has an intrinsic anticholinergic activity²; concurrent nor­triptyline, a secondary amine tricyclic anti­depressant with fewer anticholinergic side effects than other tricyclics,² could pre­cipitate delirium in a vulnerable patient secondary to excessive cumulative anti­cholinergic exposure.

No prolonged time-to-respiration or time-to-awakening occurred during treat­ments in which concurrent lithium and ECT were used; seizure duration with and without concurrent lithium was rela­tively similar.

There are potential complications of con­current use of lithium and ECT:
    • prolongation of the duration of muscle paralysis and apnea induced by commonly used neuromuscular-blocking agents (eg, succinylcholine)
    • post-ECT cognitive disturbance.^1,3,4

There is debate about the safety of con­tinuing lithium during, or in close proximity to, ECT. In a case series of 12 patients who underwent combined lithium therapy and ECT, the authors concluded that this combi­nation can be safe, regardless of age, as long as appropriate clinical monitoring is pro­vided.⁴ In Mrs. A’s case, once post-ECT delir­ium was noted, lithium was discontinued for subsequent ECT sessions.

Because further ECT was uneventful with­out lithium, and no other clear acute cause of delirium could be identified, we concluded that lithium likely played a role in Mrs. A’s delirium. Notably, nortriptyline had been continued, suggesting that the degree of anticholinergic blockade provided by nortriptyline was insufficient to provoke delirium post-ECT in the absence of potentia­tion of this effect, as it had been when lithium also was used initially.

Guidelines for dosing and serum lithium concentrations in geriatric patients are not well-established; the current traditional range of 0.6 to 1.2 mEq/L, is too high for geriatric patients and can result in epi­sodes of lithium toxicity, including delirium.⁵ Although our patient’s lithium level was below the reference range for all patients, a level of 0.3 mEq/L can be considered at the low end of the reference range for geriatric patients.5 Inasmuch as the lithium-assisted post-ECT delirium could represent a clinical sign of lithium toxicity, perhaps even a sub­therapeutic level in a certain patient could be paradoxically “toxic.”

Although the serum lithium level in our patient remained below the toxic level for the general population (>1.5 mEq/L), delirium in a geriatric patient could result from:  
   • age-related changes in the pharmacokinetics of lithium, a water-soluble drug; these changes reduce renal clearance of the drug and extend plasma elimination half-life of a single dose to 36 hours, with the result that lithium remains in the body longer and necessitating a lower dosage (ie, a dosage that yields a serum level of approximately 0.5 mEq/L)  
    • the CNS tissue concentration of lith­ium, which can be high even though the serum level is not toxic  
    • an age-related increase in blood-brain barrier permeability, making the barrier more porous for drugs  
    • changes in blood-brain barrier perme­ability by post-ECT biochemical induction, with subsequent increased drug availability in the CNS.^5,6 

What we recommend
Possible interactions between lithium and ECT that lead to ECT-associated delirium need further elucidation, but discontinu­ing lithium during the course of ECT in a geriatric patient warrants your consider­ation. Following a safe interval after the last ECT session, lithium likely can be safely re-introduced 1) if there is clinical need and 2) as long as clinical surveillance for cognitive side effects is provided— especially if ECT will need to be reconsidered in the future.

Two additional considerations:
   • Actively reassess lithium dosing in all geriatric psychiatric patients, especially those with renal insufficiency and other systemic metabolic considerations.
   • Actively examine the use of all other anticholinergic agents in the course of evaluating a patient’s candidacy for ECT.


Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

 

 

Monoclonal antibodies

Credit: Linda Bartlett

 

KOHALA COAST, HAWAII—Early results of a small, phase 1 study suggest a novel combination treatment is active and generally well-tolerated in relapsed or refractory patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or non-Hodgkin lymphomas (NHLs).

The treatment consists of ublituximab (TG-1101), a monoclonal antibody that targets a unique epitope on the CD20 antigen, and TGR-1202, a next-generation PI3K delta inhibitor.

The combination appeared to be well tolerated overall, although infusion-related reactions were common, and nearly a quarter of patients experienced grade 3/4 neutropenia.

Four of 5 CLL/SLL patients experienced a partial response (PR), and the remaining patient had stable disease (SD). Among the 10 NHL patients, 1 had progressive disease, 7 had SD, and 2 achieved a PR.

Matthew Lunning, DO, of the University of Nebraska Medical Center in Omaha, and his colleagues presented these results in a poster at the 2014 Pan Pacific Lymphoma Conference.

The study is sponsored by TG Therapeutics, the company developing both drugs.

The researchers presented results from 8 patients with CLL/SLL, 7 patients with diffuse large B-cell lymphoma (DLBCL), 5 with follicular lymphoma (FL), and 1 patient with Richter’s syndrome (RS).

Patients had a median age of 64 years (range, 35-82), and they had received a median of 3 prior therapies (range, 1-9). Fifty-seven percent of patients had received 3 or more prior therapies, and 38% were refractory to their prior therapy.

The patients received escalating doses of TGR-1202, with a fixed dose of ublituximab—900 mg for patients with NHL and 600 mg for patients with CLL.

As of the data cutoff, all 21 patients were evaluable for safety, but only 15 were evaluable for efficacy.

Adverse events

The most common adverse event was infusion-related reactions, which occurred in 48% of patients. All of these events were manageable without dose reductions, and all but 1 event was grade 1 or 2 in severity.

Neutropenia was also common, occurring in 38% of patients. Grade 3/4 neutropenia occurred in 24% of patients. One CLL patient required a dose delay for neutropenia in cycle 1, which met the criteria for a dose-limiting toxicity.

No additional dose-limiting toxicities have been observed to date. Likewise, none of the patients has required dose reductions for either drug, and there were no drug-related AST/ALT elevations.

On the other hand, 1 patient did come off the study due to grade 1 itching that was possibly related to TGR-1202.

Other common adverse events associated with treatment included diarrhea (29%), nausea (29%), hoarseness (10%), muscle aches (10%), and fatigue (10%).

Activity in CLL/SLL

Of the 8 CLL/SLL patients enrolled to date, 5 were evaluable for efficacy. Four patients achieved a PR at the first efficacy assessment. The remaining patient, a CLL patient with both 17p and 11q del, achieved SD with a 44% nodal reduction at the first assessment.

All 5 patients achieved a greater-than-50% reduction in ALC by the first efficacy assessment. One patient achieved complete normalization of ALC (less than 4000/uL), and the other 4 patients achieved at least an 80% reduction by the first efficacy assessment.

The lymphocytosis generally observed in CLL patients treated with TGR-1202, similar to other PI3K delta and BTK inhibitors, appears to be mitigated by the addition of ublituximab.

Activity in NHL

Of the 13 patients in this group, 10 were evaluable for efficacy, including 5 with DLBCL, 4 with FL, and 1 with RS. Results were not as favorable in this group as they were among CLL/SLL patients, but, as the researchers pointed out, these patients were heavily pretreated.

Among the DLBCL patients, 2 achieved PRs with TGR-1202 and ublituximab. Both of these responses occurred at the higher dose of TGR-1202.

Two DLBCL patients had SD, and 1 patient progressed. DLBCL patients had a median of 3 prior treatment lines, and 3 patients had GCB DLBCL, with 1 patient classified as triple-hit lymphoma (overexpression of BCL2, BCL6, and MYC rearrangements).

In the FL group, all 4 patients had SD after treatment and exhibited a reduction in tumor mass at the first assessment. These patients had advanced disease and a median of 6 prior lines of therapy.

The RS patient also had SD following TGR-1202 and ublituximab.

“We have been very impressed with the safety profile and the level of activity observed to date in all patient groups with TGR-1202 in combination with ublituximab, particularly given the advanced stage of disease . . . ,” said Susan O’Brien, MD, a professor at MD Anderson Cancer Center in Houston and study chair for the CLL patient group.

“Of particular interest is the absence of observed elevations in AST/ALT with TGR-1202, which is a known adverse event associated with other PI3K delta inhibitors. We look forward to continuing enrollment at all trial centers of this exciting combination and presenting data on more patients at upcoming medical meetings.”

 

 

Monoclonal antibodies

Credit: Linda Bartlett

 

KOHALA COAST, HAWAII—Early results of a small, phase 1 study suggest a novel combination treatment is active and generally well-tolerated in relapsed or refractory patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or non-Hodgkin lymphomas (NHLs).

The treatment consists of ublituximab (TG-1101), a monoclonal antibody that targets a unique epitope on the CD20 antigen, and TGR-1202, a next-generation PI3K delta inhibitor.

The combination appeared to be well tolerated overall, although infusion-related reactions were common, and nearly a quarter of patients experienced grade 3/4 neutropenia.

Four of 5 CLL/SLL patients experienced a partial response (PR), and the remaining patient had stable disease (SD). Among the 10 NHL patients, 1 had progressive disease, 7 had SD, and 2 achieved a PR.

Matthew Lunning, DO, of the University of Nebraska Medical Center in Omaha, and his colleagues presented these results in a poster at the 2014 Pan Pacific Lymphoma Conference.

The study is sponsored by TG Therapeutics, the company developing both drugs.

The researchers presented results from 8 patients with CLL/SLL, 7 patients with diffuse large B-cell lymphoma (DLBCL), 5 with follicular lymphoma (FL), and 1 patient with Richter’s syndrome (RS).

Patients had a median age of 64 years (range, 35-82), and they had received a median of 3 prior therapies (range, 1-9). Fifty-seven percent of patients had received 3 or more prior therapies, and 38% were refractory to their prior therapy.

The patients received escalating doses of TGR-1202, with a fixed dose of ublituximab—900 mg for patients with NHL and 600 mg for patients with CLL.

As of the data cutoff, all 21 patients were evaluable for safety, but only 15 were evaluable for efficacy.

Adverse events

The most common adverse event was infusion-related reactions, which occurred in 48% of patients. All of these events were manageable without dose reductions, and all but 1 event was grade 1 or 2 in severity.

Neutropenia was also common, occurring in 38% of patients. Grade 3/4 neutropenia occurred in 24% of patients. One CLL patient required a dose delay for neutropenia in cycle 1, which met the criteria for a dose-limiting toxicity.

No additional dose-limiting toxicities have been observed to date. Likewise, none of the patients has required dose reductions for either drug, and there were no drug-related AST/ALT elevations.

On the other hand, 1 patient did come off the study due to grade 1 itching that was possibly related to TGR-1202.

Other common adverse events associated with treatment included diarrhea (29%), nausea (29%), hoarseness (10%), muscle aches (10%), and fatigue (10%).

Activity in CLL/SLL

Of the 8 CLL/SLL patients enrolled to date, 5 were evaluable for efficacy. Four patients achieved a PR at the first efficacy assessment. The remaining patient, a CLL patient with both 17p and 11q del, achieved SD with a 44% nodal reduction at the first assessment.

All 5 patients achieved a greater-than-50% reduction in ALC by the first efficacy assessment. One patient achieved complete normalization of ALC (less than 4000/uL), and the other 4 patients achieved at least an 80% reduction by the first efficacy assessment.

The lymphocytosis generally observed in CLL patients treated with TGR-1202, similar to other PI3K delta and BTK inhibitors, appears to be mitigated by the addition of ublituximab.

Activity in NHL

Of the 13 patients in this group, 10 were evaluable for efficacy, including 5 with DLBCL, 4 with FL, and 1 with RS. Results were not as favorable in this group as they were among CLL/SLL patients, but, as the researchers pointed out, these patients were heavily pretreated.

Among the DLBCL patients, 2 achieved PRs with TGR-1202 and ublituximab. Both of these responses occurred at the higher dose of TGR-1202.

Two DLBCL patients had SD, and 1 patient progressed. DLBCL patients had a median of 3 prior treatment lines, and 3 patients had GCB DLBCL, with 1 patient classified as triple-hit lymphoma (overexpression of BCL2, BCL6, and MYC rearrangements).

In the FL group, all 4 patients had SD after treatment and exhibited a reduction in tumor mass at the first assessment. These patients had advanced disease and a median of 6 prior lines of therapy.

The RS patient also had SD following TGR-1202 and ublituximab.

“We have been very impressed with the safety profile and the level of activity observed to date in all patient groups with TGR-1202 in combination with ublituximab, particularly given the advanced stage of disease . . . ,” said Susan O’Brien, MD, a professor at MD Anderson Cancer Center in Houston and study chair for the CLL patient group.

“Of particular interest is the absence of observed elevations in AST/ALT with TGR-1202, which is a known adverse event associated with other PI3K delta inhibitors. We look forward to continuing enrollment at all trial centers of this exciting combination and presenting data on more patients at upcoming medical meetings.”

 

 

Monoclonal antibodies

Credit: Linda Bartlett

 

KOHALA COAST, HAWAII—Early results of a small, phase 1 study suggest a novel combination treatment is active and generally well-tolerated in relapsed or refractory patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or non-Hodgkin lymphomas (NHLs).

The treatment consists of ublituximab (TG-1101), a monoclonal antibody that targets a unique epitope on the CD20 antigen, and TGR-1202, a next-generation PI3K delta inhibitor.

The combination appeared to be well tolerated overall, although infusion-related reactions were common, and nearly a quarter of patients experienced grade 3/4 neutropenia.

Four of 5 CLL/SLL patients experienced a partial response (PR), and the remaining patient had stable disease (SD). Among the 10 NHL patients, 1 had progressive disease, 7 had SD, and 2 achieved a PR.

Matthew Lunning, DO, of the University of Nebraska Medical Center in Omaha, and his colleagues presented these results in a poster at the 2014 Pan Pacific Lymphoma Conference.

The study is sponsored by TG Therapeutics, the company developing both drugs.

The researchers presented results from 8 patients with CLL/SLL, 7 patients with diffuse large B-cell lymphoma (DLBCL), 5 with follicular lymphoma (FL), and 1 patient with Richter’s syndrome (RS).

Patients had a median age of 64 years (range, 35-82), and they had received a median of 3 prior therapies (range, 1-9). Fifty-seven percent of patients had received 3 or more prior therapies, and 38% were refractory to their prior therapy.

The patients received escalating doses of TGR-1202, with a fixed dose of ublituximab—900 mg for patients with NHL and 600 mg for patients with CLL.

As of the data cutoff, all 21 patients were evaluable for safety, but only 15 were evaluable for efficacy.

Adverse events

The most common adverse event was infusion-related reactions, which occurred in 48% of patients. All of these events were manageable without dose reductions, and all but 1 event was grade 1 or 2 in severity.

Neutropenia was also common, occurring in 38% of patients. Grade 3/4 neutropenia occurred in 24% of patients. One CLL patient required a dose delay for neutropenia in cycle 1, which met the criteria for a dose-limiting toxicity.

No additional dose-limiting toxicities have been observed to date. Likewise, none of the patients has required dose reductions for either drug, and there were no drug-related AST/ALT elevations.

On the other hand, 1 patient did come off the study due to grade 1 itching that was possibly related to TGR-1202.

Other common adverse events associated with treatment included diarrhea (29%), nausea (29%), hoarseness (10%), muscle aches (10%), and fatigue (10%).

Activity in CLL/SLL

Of the 8 CLL/SLL patients enrolled to date, 5 were evaluable for efficacy. Four patients achieved a PR at the first efficacy assessment. The remaining patient, a CLL patient with both 17p and 11q del, achieved SD with a 44% nodal reduction at the first assessment.

All 5 patients achieved a greater-than-50% reduction in ALC by the first efficacy assessment. One patient achieved complete normalization of ALC (less than 4000/uL), and the other 4 patients achieved at least an 80% reduction by the first efficacy assessment.

The lymphocytosis generally observed in CLL patients treated with TGR-1202, similar to other PI3K delta and BTK inhibitors, appears to be mitigated by the addition of ublituximab.

Activity in NHL

Of the 13 patients in this group, 10 were evaluable for efficacy, including 5 with DLBCL, 4 with FL, and 1 with RS. Results were not as favorable in this group as they were among CLL/SLL patients, but, as the researchers pointed out, these patients were heavily pretreated.

Among the DLBCL patients, 2 achieved PRs with TGR-1202 and ublituximab. Both of these responses occurred at the higher dose of TGR-1202.

Two DLBCL patients had SD, and 1 patient progressed. DLBCL patients had a median of 3 prior treatment lines, and 3 patients had GCB DLBCL, with 1 patient classified as triple-hit lymphoma (overexpression of BCL2, BCL6, and MYC rearrangements).

In the FL group, all 4 patients had SD after treatment and exhibited a reduction in tumor mass at the first assessment. These patients had advanced disease and a median of 6 prior lines of therapy.

The RS patient also had SD following TGR-1202 and ublituximab.

“We have been very impressed with the safety profile and the level of activity observed to date in all patient groups with TGR-1202 in combination with ublituximab, particularly given the advanced stage of disease . . . ,” said Susan O’Brien, MD, a professor at MD Anderson Cancer Center in Houston and study chair for the CLL patient group.

“Of particular interest is the absence of observed elevations in AST/ALT with TGR-1202, which is a known adverse event associated with other PI3K delta inhibitors. We look forward to continuing enrollment at all trial centers of this exciting combination and presenting data on more patients at upcoming medical meetings.”

Hematopoietic stem cells

in the bone marrow

New research indicates that cycles of prolonged fasting may prevent chemotherapy-induced immunosuppressive toxicity and induce regeneration of the hematopoietic system.

Long periods of fasting reduced damage in bone marrow stem and progenitor cells and protected both mice and humans from chemotoxicity.

In mice, the fasting cycles “flipped a regenerative switch,” changing the signaling pathways for hematopoietic stem cells (HSCs).

Researchers reported these results in Cell Stem Cell.

“We could not predict that prolonged fasting would have such a remarkable effect in promoting stem cell-based regeneration of the hematopoietic system,” said study author Valter Longo, PhD, of the University of Southern California in Los Angeles.

“When you starve, the system tries to save energy, and one of the things it can do to save energy is to recycle a lot of the immune cells that are not needed, especially those that may be damaged. What we started noticing in both our human work and animal work is that the white blood cell count goes down with prolonged fasting. Then, when you re-feed, the blood cells come back. So we started thinking, well, where does it come from?”

The researchers found that prolonged fasting reduced the enzyme PKA, which regulates HSC self-renewal and pluripotency.

“PKA is the key gene that needs to shut down in order for these stem cells to switch into regenerative mode,” Dr Longo said. “It gives the ‘okay’ for stem cells to go ahead and begin proliferating and rebuild the entire system.”

Prolonged fasting also lowered levels of IGF-1, a growth-factor hormone that has been linked to aging, tumor progression, and cancer risk.

In addition to downregulating the IGF-1/PKA pathway in HSCs, prolonged fasting protected hematopoietic cells from chemotoxicity and promoted HSC self-renewal to reverse immunosuppression.

Experiments revealed that inhibiting IGF-1 or PKA signaling mimicked the effects of prolonged fasting.

The researchers also analyzed a small group of patients from a pilot study evaluating the effects of fasting before chemotherapy. Fasting for 72 hours, but not 24 hours, ensured that patients had normal lymphocyte counts and maintained a normal lineage balance in white blood cells after chemotherapy.

Dr Longo’s lab is now conducting further research on controlled dietary interventions and stem cell regeneration in both animal and clinical studies.

Hematopoietic stem cells

in the bone marrow

New research indicates that cycles of prolonged fasting may prevent chemotherapy-induced immunosuppressive toxicity and induce regeneration of the hematopoietic system.

Long periods of fasting reduced damage in bone marrow stem and progenitor cells and protected both mice and humans from chemotoxicity.

In mice, the fasting cycles “flipped a regenerative switch,” changing the signaling pathways for hematopoietic stem cells (HSCs).

Researchers reported these results in Cell Stem Cell.

“We could not predict that prolonged fasting would have such a remarkable effect in promoting stem cell-based regeneration of the hematopoietic system,” said study author Valter Longo, PhD, of the University of Southern California in Los Angeles.

“When you starve, the system tries to save energy, and one of the things it can do to save energy is to recycle a lot of the immune cells that are not needed, especially those that may be damaged. What we started noticing in both our human work and animal work is that the white blood cell count goes down with prolonged fasting. Then, when you re-feed, the blood cells come back. So we started thinking, well, where does it come from?”

The researchers found that prolonged fasting reduced the enzyme PKA, which regulates HSC self-renewal and pluripotency.

“PKA is the key gene that needs to shut down in order for these stem cells to switch into regenerative mode,” Dr Longo said. “It gives the ‘okay’ for stem cells to go ahead and begin proliferating and rebuild the entire system.”

Prolonged fasting also lowered levels of IGF-1, a growth-factor hormone that has been linked to aging, tumor progression, and cancer risk.

In addition to downregulating the IGF-1/PKA pathway in HSCs, prolonged fasting protected hematopoietic cells from chemotoxicity and promoted HSC self-renewal to reverse immunosuppression.

Experiments revealed that inhibiting IGF-1 or PKA signaling mimicked the effects of prolonged fasting.

The researchers also analyzed a small group of patients from a pilot study evaluating the effects of fasting before chemotherapy. Fasting for 72 hours, but not 24 hours, ensured that patients had normal lymphocyte counts and maintained a normal lineage balance in white blood cells after chemotherapy.

Dr Longo’s lab is now conducting further research on controlled dietary interventions and stem cell regeneration in both animal and clinical studies.

Hematopoietic stem cells

in the bone marrow

New research indicates that cycles of prolonged fasting may prevent chemotherapy-induced immunosuppressive toxicity and induce regeneration of the hematopoietic system.

Long periods of fasting reduced damage in bone marrow stem and progenitor cells and protected both mice and humans from chemotoxicity.

In mice, the fasting cycles “flipped a regenerative switch,” changing the signaling pathways for hematopoietic stem cells (HSCs).

Researchers reported these results in Cell Stem Cell.

“We could not predict that prolonged fasting would have such a remarkable effect in promoting stem cell-based regeneration of the hematopoietic system,” said study author Valter Longo, PhD, of the University of Southern California in Los Angeles.

“When you starve, the system tries to save energy, and one of the things it can do to save energy is to recycle a lot of the immune cells that are not needed, especially those that may be damaged. What we started noticing in both our human work and animal work is that the white blood cell count goes down with prolonged fasting. Then, when you re-feed, the blood cells come back. So we started thinking, well, where does it come from?”

The researchers found that prolonged fasting reduced the enzyme PKA, which regulates HSC self-renewal and pluripotency.

“PKA is the key gene that needs to shut down in order for these stem cells to switch into regenerative mode,” Dr Longo said. “It gives the ‘okay’ for stem cells to go ahead and begin proliferating and rebuild the entire system.”

Prolonged fasting also lowered levels of IGF-1, a growth-factor hormone that has been linked to aging, tumor progression, and cancer risk.

In addition to downregulating the IGF-1/PKA pathway in HSCs, prolonged fasting protected hematopoietic cells from chemotoxicity and promoted HSC self-renewal to reverse immunosuppression.

Experiments revealed that inhibiting IGF-1 or PKA signaling mimicked the effects of prolonged fasting.

The researchers also analyzed a small group of patients from a pilot study evaluating the effects of fasting before chemotherapy. Fasting for 72 hours, but not 24 hours, ensured that patients had normal lymphocyte counts and maintained a normal lineage balance in white blood cells after chemotherapy.

Dr Longo’s lab is now conducting further research on controlled dietary interventions and stem cell regeneration in both animal and clinical studies.

Diffuse large B-cell lymphoma

The Israeli Ministry of Health has granted approval for the antineoplastic agent pixantrone (Pixuvri).

The drug is now approved as monotherapy for adults with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL) who have received fewer than 4 previous courses of treatment.

The benefit of pixantrone has not been established when used as fifth-line or greater treatment in patients who were refractory to their last therapy.

Pixantrone will be distributed in Israel by the Neopharm Group.

“The approval of Pixuvri in Israel provides patients with aggressive B-cell NHL who have failed second- or third-line therapy a new approved option, where none existed before, that can effectively treat their disease with manageable side effects,” said Abraham Avigdor, MD, of Tel Aviv University.

“Patients who have relapsed after second-line therapy have a poor survival outcome. It is vital to have additional treatment options available, like Pixuvri, so we can provide these patients the best care possible and help them battle their disease.”

The main study of pixantrone, the phase 3 EXTEND PIX301 trial, compared the drug to other chemotherapeutic agents in patients with relapsed or refractory NHL. The response rate was 20% in the pixantrone arm and 6% in the comparator arm.

In addition, patients receiving pixantrone had longer progression-free survival than patients in the comparator group, with a median of 10.2 months and 7.6 months, respectively.

However, grade 3/4 adverse events—including neutropenia, leukopenia, and thrombocytopenia—were more common in the pixantrone arm.

Pixantrone is already marketed in the European Union. In 2012, the European Commission granted conditional marketing authorization for the drug as monotherapy for adults with relapsed or refractory aggressive B-cell NHL.

Under the provisions of the conditional marketing authorization, Cell Therapeutics, Inc., the company developing pixantrone, will be required to complete a post-marketing study aimed at confirming the drug’s clinical benefit.

The European Medicines Agency’s Committee for Medicinal Products for Human Use has accepted PIX306, a randomized, phase 3 trial comparing pixantrone plus rituximab to gemcitabine plus rituximab in patients who have relapsed after 1 to 3 prior regimens for aggressive B-cell NHL and who are not eligible for autologous stem cell transplant.

As a condition of approval, Cell Therapeutics has agreed to have the trial data available by June 2015.

Pixantrone is not approved for use in the US.

Diffuse large B-cell lymphoma

The Israeli Ministry of Health has granted approval for the antineoplastic agent pixantrone (Pixuvri).

The drug is now approved as monotherapy for adults with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL) who have received fewer than 4 previous courses of treatment.

The benefit of pixantrone has not been established when used as fifth-line or greater treatment in patients who were refractory to their last therapy.

Pixantrone will be distributed in Israel by the Neopharm Group.

“The approval of Pixuvri in Israel provides patients with aggressive B-cell NHL who have failed second- or third-line therapy a new approved option, where none existed before, that can effectively treat their disease with manageable side effects,” said Abraham Avigdor, MD, of Tel Aviv University.

“Patients who have relapsed after second-line therapy have a poor survival outcome. It is vital to have additional treatment options available, like Pixuvri, so we can provide these patients the best care possible and help them battle their disease.”

The main study of pixantrone, the phase 3 EXTEND PIX301 trial, compared the drug to other chemotherapeutic agents in patients with relapsed or refractory NHL. The response rate was 20% in the pixantrone arm and 6% in the comparator arm.

In addition, patients receiving pixantrone had longer progression-free survival than patients in the comparator group, with a median of 10.2 months and 7.6 months, respectively.

However, grade 3/4 adverse events—including neutropenia, leukopenia, and thrombocytopenia—were more common in the pixantrone arm.

Pixantrone is already marketed in the European Union. In 2012, the European Commission granted conditional marketing authorization for the drug as monotherapy for adults with relapsed or refractory aggressive B-cell NHL.

Under the provisions of the conditional marketing authorization, Cell Therapeutics, Inc., the company developing pixantrone, will be required to complete a post-marketing study aimed at confirming the drug’s clinical benefit.

The European Medicines Agency’s Committee for Medicinal Products for Human Use has accepted PIX306, a randomized, phase 3 trial comparing pixantrone plus rituximab to gemcitabine plus rituximab in patients who have relapsed after 1 to 3 prior regimens for aggressive B-cell NHL and who are not eligible for autologous stem cell transplant.

As a condition of approval, Cell Therapeutics has agreed to have the trial data available by June 2015.

Pixantrone is not approved for use in the US.

Diffuse large B-cell lymphoma

The Israeli Ministry of Health has granted approval for the antineoplastic agent pixantrone (Pixuvri).

The drug is now approved as monotherapy for adults with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL) who have received fewer than 4 previous courses of treatment.

The benefit of pixantrone has not been established when used as fifth-line or greater treatment in patients who were refractory to their last therapy.

Pixantrone will be distributed in Israel by the Neopharm Group.

“The approval of Pixuvri in Israel provides patients with aggressive B-cell NHL who have failed second- or third-line therapy a new approved option, where none existed before, that can effectively treat their disease with manageable side effects,” said Abraham Avigdor, MD, of Tel Aviv University.

“Patients who have relapsed after second-line therapy have a poor survival outcome. It is vital to have additional treatment options available, like Pixuvri, so we can provide these patients the best care possible and help them battle their disease.”

The main study of pixantrone, the phase 3 EXTEND PIX301 trial, compared the drug to other chemotherapeutic agents in patients with relapsed or refractory NHL. The response rate was 20% in the pixantrone arm and 6% in the comparator arm.

In addition, patients receiving pixantrone had longer progression-free survival than patients in the comparator group, with a median of 10.2 months and 7.6 months, respectively.

However, grade 3/4 adverse events—including neutropenia, leukopenia, and thrombocytopenia—were more common in the pixantrone arm.

Pixantrone is already marketed in the European Union. In 2012, the European Commission granted conditional marketing authorization for the drug as monotherapy for adults with relapsed or refractory aggressive B-cell NHL.

Under the provisions of the conditional marketing authorization, Cell Therapeutics, Inc., the company developing pixantrone, will be required to complete a post-marketing study aimed at confirming the drug’s clinical benefit.

The European Medicines Agency’s Committee for Medicinal Products for Human Use has accepted PIX306, a randomized, phase 3 trial comparing pixantrone plus rituximab to gemcitabine plus rituximab in patients who have relapsed after 1 to 3 prior regimens for aggressive B-cell NHL and who are not eligible for autologous stem cell transplant.

As a condition of approval, Cell Therapeutics has agreed to have the trial data available by June 2015.

Pixantrone is not approved for use in the US.

Malaria-infected cell bursting

Credit: Peter H. Seeberger

Researchers have used military technology to develop a test for detecting malaria parasites in the blood.

The team used a detector known as a focal plane array (FPA), which was originally developed for heat-seeking missiles.

The FPA gives highly detailed information on a sample area in minutes. The heat-seeking detector, which is coupled to an infrared imaging microscope, could detect the malaria parasite in a single red blood cell.

The infrared signature from the fatty acids of the parasites allowed the researchers to detect the parasite at its earliest stages and determine the number of parasites in a blood smear.

The team described the technology in Analyst.

“Our test detects malaria at its very early stages, so that doctors can stop the disease in its tracks before it takes hold and kills,” said study author Bayden Wood, PhD, of Monash University in Victoria, Australia. “We believe this sets the gold standard for malaria testing.”

“There are some excellent tests that diagnose malaria. However, the sensitivity is limited, and the best methods require hours of input from skilled microscopists, and that’s a problem in developing countries where malaria is most prevalent.”

The new test, on the other hand, gives an automatic diagnosis within 4 minutes and doesn’t require a specialist technician.

Study author Leann Tilley, PhD, of the University of Melbourne in Australia, said the test could make an impact in large-scale screening of malaria parasite carriers who do not present with the classic fever-type symptoms associated with the disease.

“In many countries, only people who display signs of malaria are treated,” Dr Tilley said. “But the problem with this approach is that some people don’t have typical flu-like symptoms associated with malaria, and this means a reservoir of parasites persists that can reemerge and spread very quickly within a community.”

“Our test works because it can detect the malaria parasite at the very early stages and can reliably detect it in an automated manner in a single red blood cell. No other test can do that.”

FPA detectors were originally developed for Javelin Portable anti-tank missiles in the 1990s. The heat-seeking detector is used on shoulder-fired missiles but can also be installed on tracked, wheeled, or amphibious vehicles, providing spatial and spectral information in a matter of seconds.

The FPA detector used in this project was coupled to a synchrotron source located at the InfraRed Environmental Imaging facility at the Synchrotron Radiation Center in Wisconsin.

For the next phase of this research, Dr Wood’s team is collaborating with Patcharee Jearanaikoon, PhD, of Kohn Kaen University in Thailand, to test the technology in clinics.

Malaria-infected cell bursting

Credit: Peter H. Seeberger

Researchers have used military technology to develop a test for detecting malaria parasites in the blood.

The team used a detector known as a focal plane array (FPA), which was originally developed for heat-seeking missiles.

The FPA gives highly detailed information on a sample area in minutes. The heat-seeking detector, which is coupled to an infrared imaging microscope, could detect the malaria parasite in a single red blood cell.

The infrared signature from the fatty acids of the parasites allowed the researchers to detect the parasite at its earliest stages and determine the number of parasites in a blood smear.

The team described the technology in Analyst.

“Our test detects malaria at its very early stages, so that doctors can stop the disease in its tracks before it takes hold and kills,” said study author Bayden Wood, PhD, of Monash University in Victoria, Australia. “We believe this sets the gold standard for malaria testing.”

“There are some excellent tests that diagnose malaria. However, the sensitivity is limited, and the best methods require hours of input from skilled microscopists, and that’s a problem in developing countries where malaria is most prevalent.”

The new test, on the other hand, gives an automatic diagnosis within 4 minutes and doesn’t require a specialist technician.

Study author Leann Tilley, PhD, of the University of Melbourne in Australia, said the test could make an impact in large-scale screening of malaria parasite carriers who do not present with the classic fever-type symptoms associated with the disease.

“In many countries, only people who display signs of malaria are treated,” Dr Tilley said. “But the problem with this approach is that some people don’t have typical flu-like symptoms associated with malaria, and this means a reservoir of parasites persists that can reemerge and spread very quickly within a community.”

“Our test works because it can detect the malaria parasite at the very early stages and can reliably detect it in an automated manner in a single red blood cell. No other test can do that.”

FPA detectors were originally developed for Javelin Portable anti-tank missiles in the 1990s. The heat-seeking detector is used on shoulder-fired missiles but can also be installed on tracked, wheeled, or amphibious vehicles, providing spatial and spectral information in a matter of seconds.

The FPA detector used in this project was coupled to a synchrotron source located at the InfraRed Environmental Imaging facility at the Synchrotron Radiation Center in Wisconsin.

For the next phase of this research, Dr Wood’s team is collaborating with Patcharee Jearanaikoon, PhD, of Kohn Kaen University in Thailand, to test the technology in clinics.

Malaria-infected cell bursting

Credit: Peter H. Seeberger

Researchers have used military technology to develop a test for detecting malaria parasites in the blood.

The team used a detector known as a focal plane array (FPA), which was originally developed for heat-seeking missiles.

The FPA gives highly detailed information on a sample area in minutes. The heat-seeking detector, which is coupled to an infrared imaging microscope, could detect the malaria parasite in a single red blood cell.

The infrared signature from the fatty acids of the parasites allowed the researchers to detect the parasite at its earliest stages and determine the number of parasites in a blood smear.

The team described the technology in Analyst.

“Our test detects malaria at its very early stages, so that doctors can stop the disease in its tracks before it takes hold and kills,” said study author Bayden Wood, PhD, of Monash University in Victoria, Australia. “We believe this sets the gold standard for malaria testing.”

“There are some excellent tests that diagnose malaria. However, the sensitivity is limited, and the best methods require hours of input from skilled microscopists, and that’s a problem in developing countries where malaria is most prevalent.”

The new test, on the other hand, gives an automatic diagnosis within 4 minutes and doesn’t require a specialist technician.

Study author Leann Tilley, PhD, of the University of Melbourne in Australia, said the test could make an impact in large-scale screening of malaria parasite carriers who do not present with the classic fever-type symptoms associated with the disease.

“In many countries, only people who display signs of malaria are treated,” Dr Tilley said. “But the problem with this approach is that some people don’t have typical flu-like symptoms associated with malaria, and this means a reservoir of parasites persists that can reemerge and spread very quickly within a community.”

“Our test works because it can detect the malaria parasite at the very early stages and can reliably detect it in an automated manner in a single red blood cell. No other test can do that.”

FPA detectors were originally developed for Javelin Portable anti-tank missiles in the 1990s. The heat-seeking detector is used on shoulder-fired missiles but can also be installed on tracked, wheeled, or amphibious vehicles, providing spatial and spectral information in a matter of seconds.

The FPA detector used in this project was coupled to a synchrotron source located at the InfraRed Environmental Imaging facility at the Synchrotron Radiation Center in Wisconsin.

For the next phase of this research, Dr Wood’s team is collaborating with Patcharee Jearanaikoon, PhD, of Kohn Kaen University in Thailand, to test the technology in clinics.

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic neoplasms with an annual incidence of 4.1 cases per 100,000 Americans. Patients with MDS suffer from chronic cytopenias that may lead to recurrent transfusions, infections, and increased risk for bleeding. They are also at risk for progression to acute myeloid leukemia. Allogeneic hematopoietic cell transplantation is the only potentially curative treatment for MDS, although 3 drugs have been approved by the US Food and Drug Administration for its treatment: lenalidomide, 5-azacitidine, and decitabine.
 

Click on the PDF icon at the top of this introduction to read the full article.

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic neoplasms with an annual incidence of 4.1 cases per 100,000 Americans. Patients with MDS suffer from chronic cytopenias that may lead to recurrent transfusions, infections, and increased risk for bleeding. They are also at risk for progression to acute myeloid leukemia. Allogeneic hematopoietic cell transplantation is the only potentially curative treatment for MDS, although 3 drugs have been approved by the US Food and Drug Administration for its treatment: lenalidomide, 5-azacitidine, and decitabine.
 

Click on the PDF icon at the top of this introduction to read the full article.

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic neoplasms with an annual incidence of 4.1 cases per 100,000 Americans. Patients with MDS suffer from chronic cytopenias that may lead to recurrent transfusions, infections, and increased risk for bleeding. They are also at risk for progression to acute myeloid leukemia. Allogeneic hematopoietic cell transplantation is the only potentially curative treatment for MDS, although 3 drugs have been approved by the US Food and Drug Administration for its treatment: lenalidomide, 5-azacitidine, and decitabine.
 

Click on the PDF icon at the top of this introduction to read the full article.

Although delirium has many descriptive terms (Table 1), a common unifying term is “acute global cognitive dysfunction,” now recognized as delirium; a consensus supported by DSM-5¹ and ICD-10² (Table 2). According to DSM-5, the essential feature is a disturbance of attention or awareness that is accompanied by a change in baseline cognition that cannot be explained by another preexisting, established, or evolving neurocognitive disorder (the newly named DSM-5 entity for dementia syndromes).¹ Because delirium affects the cortex diffusely, psychiatric symp­toms can include cognitive, mood, anxiety, or psychotic symp­toms. Because many systemic illnesses can induce delirium, the differential diagnosis spans all organ systems.

Three subtypes
Delirium can be classified, based on symptoms,^3,4 into 3 sub­types: hyperactive-hyperalert, hypoactive-hypoalert, and mixed delirium. Hyperactive patients present with rest­lessness and agitation. Hypoactive patients are lethargic, confused, slow to respond to questions, and often appear depressed. The differential prognostic significance of these subtypes has been examined in the literature, with conflicting results. Rabinowitz⁵ reported that hypoactive delirium has the worst prognosis, while Marcantonio et al⁶ indicated that the hyperactive subtype is associated with the highest mortality rate. Mixed delirium, with periods of both hyperactivity and hypoactivity, is the most common type of delirium.⁷

A prodromal phase, characterized by anxiety, frequent requests for nursing and medical assistance, decreased attention, rest­lessness, vivid dreams, disorientation imme­diately after awakening, and hallucinations, can occur before an episode of full-spectrum delirium; this prodromal state often is iden­tified retrospectively —after the patient is in an episode of delirium.^8,9

Evidence-based guidelines aim to improve recognition and clinical management.^10-13 Disruptive behavior is the main reason for psychiatric referral in delirium.^14,15 Delayed psychiatric consultation because of non-recognition of delirium is related to variables such as older age; history of a pre-existing, comorbid neurocognitive disorder; and the clinical appearance of hypoactive delirium.¹⁴

The case of Mr. D (Box),¹⁶ illus­trates how the emergence of antipsychotic-associated neuroleptic malignant syndrome (NMS) can complicate antipsychotic treat­ment of delirium in a geriatric medical patient, although delirium also is a common presentation in NMS.¹⁷ Delirium developed after an increase in carbidopa/levodopa, which has central dopaminergic effects that can precipitate delirium, particularly in a geriatric patient with preexisting comorbid neurocognitive disorder. Further complicat­ing Mr. D’s delirium presentation was the development of NMS, which had a multifac­torial causation, such as the use of dopamine antagonists (ie, quetiapine, metoclopramide), and an abrupt decrease of a dopaminergic agent (ie, carbidopa/levodopa), all inducing a central dopamine relative hypoactivity.

Epidemiology
Delirium is more common in older patients,¹⁵ and is seen in 30% to 40% of hospitalized geri­atric patients.¹⁸ Delirium in older patients, compared with other adults, is associated with more severe cognitive impairment.¹⁹ It is com­mon among geriatric surgical patients (15% to 62%)²⁰ with a peak 2 to 5 days postoperatively for hip fracture,²¹ and often is seen in ICU patients (70% to 87%).²⁰ However, Spronk et al²² found that delirium is significantly under-recognized in the ICU. Nearly 90% of terminally ill patients become delirious before death.²³ Terminal delirium often is unrecognized and can interfere with assessment of other clinical problems.²⁴ A preexisting history of comor­bid neurocognitive disorder was evident in as many as two-thirds of delirium cases.²⁵

Pathophysiology and risk factors
The pathophysiology of delirium has been characterized as an imbalance of CNS metab­olism, including decreased blood flow in vari­ous regions of the brain that may normalize once delirium resolves.²⁶ Studies describe the simultaneous decrease of cholinergic transmission and dopaminergic excess.^27,28 Predisposing and precipitating factors for delirium that are of particular importance in geriatric patients include:
   • advanced age
   • CNS disease
   • infection
   • cognitive impairment
   • male sex
   • poor nutrition
   • dehydration and other metabolic abnormalities
   • cardiovascular events
   • substance use
   • medication
   • sensory deprivation (eg, impaired vision or hearing)
   • sleep deprivation
   • low level of physical activity.^27,29,30

Table 3 lists the most common delirium-provocative medications.²⁷

Evaluation and psychometric scales
The EEG can be useful in evaluating delir­ium, especially in clinically ambiguous cases. EEG findings may indicate generalized slowing or dropout of the posterior domi­nant rhythm, and generalized slow theta and delta waves, findings that are more common in delirium than in other neurocognitive dis­orders and other psychiatric illnesses. The EEG must be interpreted in the context of the delirium diagnostic workup, because abnor­malities seen in other neurocognitive disor­ders can overlap with those of delirium.³¹

The EEG referral should specify the clini­cal suspicion of delirium to help interpret the results. Delirium cases in which the patient’s previous cognitive status is unknown may benefit from EEG evaluation, such as:
   • in possible status epilepticus
   • when delirium improvement has reached a plateau at a lower level of cognitive function than before onset of delirium
   • when the patient is unable or unwilling to complete a psychiatric interview.²⁷

Assessment instruments are available to diagnose and monitor delirium (Table 4). Typically, delirium assessment includes examining levels of arousal, psychomotor activity, cognition (ie, orienta­tion, attention, and memory), and percep­tual disturbances.

Psychometrically, a review of Table 4 suggests that validity appeared stable with adequate specificity (64% to 99%) but more variable sensitivity (36% to 100%). These reliability parameters also will be affected by the classification sys­tem (ie, DSM vs ICD) and the cut-off score employed.³² Most measures (eg, Confusion Assessment Method [CAM], CAM-ICU) provide an adequate sample of behavioral (ie, level of alertness), motor (ie, psychomo­tor activity), and cognitive (ie, orientation, attention, memory, and receptive language) function, with the exception of the Global Attentiveness Rating, which is a 2-minute open conversation protocol between physi­cian and patient.

Some measures are stand-alone instru­ments, such as the Memorial Delirium Assessment Scale, whereas the CAM requires administration of separate cogni­tive screens, including the Mini-Mental State Examination (MMSE) and Digit Span.³³ Instruments to detect delirium in critically ill patients are a more recent development. Wong et al³⁴ reported that the most widely studied tool was the CAM. Obtaining collat­eral information from family, caregivers, and hospital staff is essential, particularly given the fluctuating nature of delirium.

Management
Prevention. Identify patients at high risk of delirium so that preventive strategies can be employed. Multi-component, nonphar­macotherapeutic interventions are used in clinical settings but few randomized trials have been conducted. The contributing effectiveness of individual components is not well-studied, but most include staff education to increase awareness of delir­ium. Of 3 multi-component intervention randomized trials, 2 reported a signifi­cantly lower incidence of delirium in the intervention group.^35-37 Implementation of a multi-component protocol in medical/ surgical units was associated with a sig­nificant reduction in use of restraints.³⁸

As in Mr. D’s case, complex drug regimens, particularly for CNS illness, can increase the risk of delirium. Considering the medication profile for patients with complex systemic illness—in particular, minimizing the use anticholinergics and dopamine agonists— may be crucial in preventing delirium.

Prophylactic administration of antipsychotics may reduce the risk of devel­oping postoperative delirium.³⁹ Studies of the use of these agents were characterized by small sample sizes and selected groups of patient populations. Of the 4 random­ized studies evaluating prophylactic anti­psychotics (vs placebo), 3 found a lower incidence of delirium in the intervention groups.^39-41

A study of haloperidol in post-GI sur­gery patients showed a reduced occurrence of delirium,⁴⁰ whereas its prophylactic use in patients undergoing hip surgery⁴² did not reduce the incidence of delirium com­pared with placebo, but did decrease sever­ity when delirium occurred.⁴²

Risperidone³⁹ in post-cardiac sur­gery and olanzapine⁴¹ perioperatively in patients undergoing total knee or hip replacement have been shown to decrease delirium severity and duration. Targeted prophylaxis with risperidone⁴³ in post-cardiac surgery patients who showed disturbed cognition but did not meet cri­teria for delirium reduced the number of patients requiring medication, compared with placebo.⁴³

Dexmedetomidine, an α-2 adrenergic receptor agonist, compared with propofol or midazolam in post-cardiac valve surgery patients, resulted in a decreased incidence of delirium but no difference in delirium duration, hospital length of stay, or use of other medications.⁴⁴ However, other studies have shown that dexmedetomidine reduces ICU length of stay and duration of mechani­cal ventilation.⁴⁵

Treatment. Management of hospitalized medically ill geriatric patients with delirium is challenging and requires a comprehensive approach. The first step in delirium man­agement is prompt identification and man­agement of systemic medical disturbances associated with the delirium episode. First-line, nonpharmacotherapeutic strategies for patients with delirium include:
   • reorientation
   • behavioral interventions (eg, use of clear instructions and frequent eye con­tact with patients)
   • environmental interventions (eg, mini­mal noise, adequate lighting, and lim­ited room and staff changes)
   • avoidance of physical restraints.⁴⁶

Consider employing family members or hospital staff sitters to stay with the patient and to reassure, reorient, and watch for agitation and other unsafe behaviors (eg, attempted elopement). Psychoeducation for the patient and family on the phenomenol­ogy of delirium can be helpful.

The use of drug treatment strategies should be integrated into a comprehensive approach that includes the routine use of nondrug measures.⁴⁶ Using medications for treating hypoactive delirium, formerly con­troversial, now has wider acceptance.^47,48 A few high-quality randomized trials have been performed.^25,49,50

Pharmacotherapy, especially in frail patients, should be initiated at the lowest start­ing dosage and titrated cautiously to clinical effect and for the shortest period of time nec­essary. Antipsychotics are preferred agents for treating all subtypes of delirium; haloperidol is widely used.^46,51,52 However, antipsychotics, including haloperidol, can be associated with adverse neurologic effects such as extrapyra­midal symptoms (EPS) and NMS.

Although reported less frequently than with haloperidol, other agents have been implicated in development of EPS and NMS, including atypical antipsychotics and anti­emetic dopamine antagonists, particularly in parkinsonism-prone patients.⁵³ Strategies that can minimize such risks in geriatric inpatients with delirium include oral, rather than par­enteral, use of antipsychotics—preferential use of atypical over typical antipsychotics— and lowest effective dosages.⁵⁴

In controlled trials, atypical antipsychot­ics for delirium showed efficacy compared with haloperidol.^52,55 However, there is no research that demonstrates any advantage of one atypical over another.²⁵

In Mr. D’s case, the most important inter­vention for managing delirium caused by NMS is to discontinue all dopamine antag­onists and treat agitation with judicious doses of a benzodiazepine, with supportive care.¹⁷ In cases of sudden discontinuation or a dosage decrease of dopamine agonists, these medications should be resumed or optimized to minimize the risk of NMS-associated rhabdomyolysis and subse­quent renal failure.¹⁷ Antipsychotics carry an increased risk of stroke and mortality in older patients with established or evolving neurocognitive disorders^56,57 and can cause prolongation of the QTc interval.⁵⁷

Other medications that could be used for delirium include cholinesterase inhibitors^58,59 (although larger trials and a systematic review did not support this use⁶⁰), and 5-HT receptor antagonists,⁶¹ such as trazodone. Benzodiazepines, such as lorazepam, are first-line treatment for delirium associated with seizures or withdrawal from alcohol, sedatives, hypnotics, and anxiolytics and for delirium caused by NMS. Be cautious about using benzodiazepines in geriatric patients because of a risk of respiratory depression, falls, sedation, and amnesia.

Geriatric patients with alcoholism and those with malnutrition are prone to thia­mine and vitamin B₁₂ deficiencies, which can induce delirium. Laboratory assessment and consideration of supplementation is recom­mended. Despite high occurrence of delirium in hospitalized older adults with preexisting comorbid neurocognitive disorders, there is no standard care for delirium comorbid with another neurocognitive disorder.⁶² Clinical practice guidelines for older patients receiv­ing palliative care have been developed⁶³; the goal is to minimize suffering and discomfort in patients in palliative care.⁶⁴

Post-delirium prophylaxis. Medications for delirium usually can be tapered and discontinued once the episode has resolved and the patient is stable; it is common to discontinue medications when the patient has been symptom-free for 1 week.⁶⁵ Some patients (eg, with end-stage liver disease, disseminated cancer) are prone to recur­rent or to prolonged or chronic delirium. A period of post-recovery treatment with antipsychotics—even indefinite treatment in some cases—should be considered.

Post-delirium debriefing and aftercare. The psychological complications of delirium are distressing for the patient and his (her) caregivers. Psychiatric complications asso­ciated with delirium, including acute stress disorder—which might predict posttraumatic stress disorder—have been explored; early recognition and treatment may improve long-term outcomes.⁶⁶ After recovery from acute delirium, cognitive assessment (eg, MMSE⁶⁷ or Montreal Cognitive Assessment⁶⁸) is recommended to validate current cognitive status because patients may have persistent decrement in cognitive func­tion compared with pre-delirium condition, even after recovery from the acute episode.

Post-delirium debriefing may help patients who have recovered from a delirium episode. Patients may fear that their brief period of hallucinations might represent the onset of a chronic-relapsing psychotic dis­order. Allow patients to communicate their distress about the delirium episode and give them the opportunity to talk through the experience. Brief them on the possibility that delirium will recur and advise them to seek emergency medical care in case of recur­rence. Advise patients to monitor and main­tain a normal sleep-wake cycle.

Family members can watch for syndro­mal recurrence of delirium. They should be encouraged to discuss their reaction to hav­ing seen their relative in a delirious state.

Health care systems with integrated electronic medical records should list “delirium, resolved” on the patient’s illness profile or problem list and alert the patient’s primary care provider to the delirium his­tory to avoid future exposure to delirium-provocative medications, and to prompt the provider to assume an active role in post-delirium care, including delirium recur­rence surveillance, medication adjustment, risk factor management, and post-recovery cognitive assessment.

Bottom Line
Evaluation of delirium in geriatric patients includes clinical vigilance and screening, differentiating delirium from other neurocognitive disorders, and identifying and treating underlying causes. Perioperative use of antipsychotics may reduce the incidence of delirium, although hospital length of stay generally has not been reduced with prophylaxis. Management interventions include staff education, systematic screening, use of multicomponent interventions, and pharmacologic interventions.

Related Resources
• Downing LJ, Caprio TV, Lyness JM. Geriatric psychiatry review: differential diagnosis and treatment of the 3 D’s - delirium, dementia, and depression. Curr Psychiatry Rep. 2013;15(6):365.
• Brooks PB. Postoperative delirium in elderly patients. Am J Nurs. 2012;112(9):38-49.

Drug Brand Names
Carbidopa/levodopa • Sinemet                       Midazolam •  Versed
Dexmedetomidine • Precedex                        Olanzapine •  Zyprexa
Haloperidol • Haldol                                      Propofol  •  Diprivan
Lithium • Eskalith, Lithobid                            Quetiapine  •  Seroquel
Lorazepam • Ativan                                      Risperidone  •  Risperdal
Metoclopramide •  Reglan                              Trazodone  •  Desyrel

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Although delirium has many descriptive terms (Table 1), a common unifying term is “acute global cognitive dysfunction,” now recognized as delirium; a consensus supported by DSM-5¹ and ICD-10² (Table 2). According to DSM-5, the essential feature is a disturbance of attention or awareness that is accompanied by a change in baseline cognition that cannot be explained by another preexisting, established, or evolving neurocognitive disorder (the newly named DSM-5 entity for dementia syndromes).¹ Because delirium affects the cortex diffusely, psychiatric symp­toms can include cognitive, mood, anxiety, or psychotic symp­toms. Because many systemic illnesses can induce delirium, the differential diagnosis spans all organ systems.

Three subtypes
Delirium can be classified, based on symptoms,^3,4 into 3 sub­types: hyperactive-hyperalert, hypoactive-hypoalert, and mixed delirium. Hyperactive patients present with rest­lessness and agitation. Hypoactive patients are lethargic, confused, slow to respond to questions, and often appear depressed. The differential prognostic significance of these subtypes has been examined in the literature, with conflicting results. Rabinowitz⁵ reported that hypoactive delirium has the worst prognosis, while Marcantonio et al⁶ indicated that the hyperactive subtype is associated with the highest mortality rate. Mixed delirium, with periods of both hyperactivity and hypoactivity, is the most common type of delirium.⁷

A prodromal phase, characterized by anxiety, frequent requests for nursing and medical assistance, decreased attention, rest­lessness, vivid dreams, disorientation imme­diately after awakening, and hallucinations, can occur before an episode of full-spectrum delirium; this prodromal state often is iden­tified retrospectively —after the patient is in an episode of delirium.^8,9

Evidence-based guidelines aim to improve recognition and clinical management.^10-13 Disruptive behavior is the main reason for psychiatric referral in delirium.^14,15 Delayed psychiatric consultation because of non-recognition of delirium is related to variables such as older age; history of a pre-existing, comorbid neurocognitive disorder; and the clinical appearance of hypoactive delirium.¹⁴

The case of Mr. D (Box),¹⁶ illus­trates how the emergence of antipsychotic-associated neuroleptic malignant syndrome (NMS) can complicate antipsychotic treat­ment of delirium in a geriatric medical patient, although delirium also is a common presentation in NMS.¹⁷ Delirium developed after an increase in carbidopa/levodopa, which has central dopaminergic effects that can precipitate delirium, particularly in a geriatric patient with preexisting comorbid neurocognitive disorder. Further complicat­ing Mr. D’s delirium presentation was the development of NMS, which had a multifac­torial causation, such as the use of dopamine antagonists (ie, quetiapine, metoclopramide), and an abrupt decrease of a dopaminergic agent (ie, carbidopa/levodopa), all inducing a central dopamine relative hypoactivity.

Epidemiology
Delirium is more common in older patients,¹⁵ and is seen in 30% to 40% of hospitalized geri­atric patients.¹⁸ Delirium in older patients, compared with other adults, is associated with more severe cognitive impairment.¹⁹ It is com­mon among geriatric surgical patients (15% to 62%)²⁰ with a peak 2 to 5 days postoperatively for hip fracture,²¹ and often is seen in ICU patients (70% to 87%).²⁰ However, Spronk et al²² found that delirium is significantly under-recognized in the ICU. Nearly 90% of terminally ill patients become delirious before death.²³ Terminal delirium often is unrecognized and can interfere with assessment of other clinical problems.²⁴ A preexisting history of comor­bid neurocognitive disorder was evident in as many as two-thirds of delirium cases.²⁵

Pathophysiology and risk factors
The pathophysiology of delirium has been characterized as an imbalance of CNS metab­olism, including decreased blood flow in vari­ous regions of the brain that may normalize once delirium resolves.²⁶ Studies describe the simultaneous decrease of cholinergic transmission and dopaminergic excess.^27,28 Predisposing and precipitating factors for delirium that are of particular importance in geriatric patients include:
   • advanced age
   • CNS disease
   • infection
   • cognitive impairment
   • male sex
   • poor nutrition
   • dehydration and other metabolic abnormalities
   • cardiovascular events
   • substance use
   • medication
   • sensory deprivation (eg, impaired vision or hearing)
   • sleep deprivation
   • low level of physical activity.^27,29,30

Table 3 lists the most common delirium-provocative medications.²⁷

Evaluation and psychometric scales
The EEG can be useful in evaluating delir­ium, especially in clinically ambiguous cases. EEG findings may indicate generalized slowing or dropout of the posterior domi­nant rhythm, and generalized slow theta and delta waves, findings that are more common in delirium than in other neurocognitive dis­orders and other psychiatric illnesses. The EEG must be interpreted in the context of the delirium diagnostic workup, because abnor­malities seen in other neurocognitive disor­ders can overlap with those of delirium.³¹

The EEG referral should specify the clini­cal suspicion of delirium to help interpret the results. Delirium cases in which the patient’s previous cognitive status is unknown may benefit from EEG evaluation, such as:
   • in possible status epilepticus
   • when delirium improvement has reached a plateau at a lower level of cognitive function than before onset of delirium
   • when the patient is unable or unwilling to complete a psychiatric interview.²⁷

Assessment instruments are available to diagnose and monitor delirium (Table 4). Typically, delirium assessment includes examining levels of arousal, psychomotor activity, cognition (ie, orienta­tion, attention, and memory), and percep­tual disturbances.

Psychometrically, a review of Table 4 suggests that validity appeared stable with adequate specificity (64% to 99%) but more variable sensitivity (36% to 100%). These reliability parameters also will be affected by the classification sys­tem (ie, DSM vs ICD) and the cut-off score employed.³² Most measures (eg, Confusion Assessment Method [CAM], CAM-ICU) provide an adequate sample of behavioral (ie, level of alertness), motor (ie, psychomo­tor activity), and cognitive (ie, orientation, attention, memory, and receptive language) function, with the exception of the Global Attentiveness Rating, which is a 2-minute open conversation protocol between physi­cian and patient.

Some measures are stand-alone instru­ments, such as the Memorial Delirium Assessment Scale, whereas the CAM requires administration of separate cogni­tive screens, including the Mini-Mental State Examination (MMSE) and Digit Span.³³ Instruments to detect delirium in critically ill patients are a more recent development. Wong et al³⁴ reported that the most widely studied tool was the CAM. Obtaining collat­eral information from family, caregivers, and hospital staff is essential, particularly given the fluctuating nature of delirium.

Management
Prevention. Identify patients at high risk of delirium so that preventive strategies can be employed. Multi-component, nonphar­macotherapeutic interventions are used in clinical settings but few randomized trials have been conducted. The contributing effectiveness of individual components is not well-studied, but most include staff education to increase awareness of delir­ium. Of 3 multi-component intervention randomized trials, 2 reported a signifi­cantly lower incidence of delirium in the intervention group.^35-37 Implementation of a multi-component protocol in medical/ surgical units was associated with a sig­nificant reduction in use of restraints.³⁸

As in Mr. D’s case, complex drug regimens, particularly for CNS illness, can increase the risk of delirium. Considering the medication profile for patients with complex systemic illness—in particular, minimizing the use anticholinergics and dopamine agonists— may be crucial in preventing delirium.

Prophylactic administration of antipsychotics may reduce the risk of devel­oping postoperative delirium.³⁹ Studies of the use of these agents were characterized by small sample sizes and selected groups of patient populations. Of the 4 random­ized studies evaluating prophylactic anti­psychotics (vs placebo), 3 found a lower incidence of delirium in the intervention groups.^39-41

A study of haloperidol in post-GI sur­gery patients showed a reduced occurrence of delirium,⁴⁰ whereas its prophylactic use in patients undergoing hip surgery⁴² did not reduce the incidence of delirium com­pared with placebo, but did decrease sever­ity when delirium occurred.⁴²

Risperidone³⁹ in post-cardiac sur­gery and olanzapine⁴¹ perioperatively in patients undergoing total knee or hip replacement have been shown to decrease delirium severity and duration. Targeted prophylaxis with risperidone⁴³ in post-cardiac surgery patients who showed disturbed cognition but did not meet cri­teria for delirium reduced the number of patients requiring medication, compared with placebo.⁴³

Dexmedetomidine, an α-2 adrenergic receptor agonist, compared with propofol or midazolam in post-cardiac valve surgery patients, resulted in a decreased incidence of delirium but no difference in delirium duration, hospital length of stay, or use of other medications.⁴⁴ However, other studies have shown that dexmedetomidine reduces ICU length of stay and duration of mechani­cal ventilation.⁴⁵

Treatment. Management of hospitalized medically ill geriatric patients with delirium is challenging and requires a comprehensive approach. The first step in delirium man­agement is prompt identification and man­agement of systemic medical disturbances associated with the delirium episode. First-line, nonpharmacotherapeutic strategies for patients with delirium include:
   • reorientation
   • behavioral interventions (eg, use of clear instructions and frequent eye con­tact with patients)
   • environmental interventions (eg, mini­mal noise, adequate lighting, and lim­ited room and staff changes)
   • avoidance of physical restraints.⁴⁶

Consider employing family members or hospital staff sitters to stay with the patient and to reassure, reorient, and watch for agitation and other unsafe behaviors (eg, attempted elopement). Psychoeducation for the patient and family on the phenomenol­ogy of delirium can be helpful.

The use of drug treatment strategies should be integrated into a comprehensive approach that includes the routine use of nondrug measures.⁴⁶ Using medications for treating hypoactive delirium, formerly con­troversial, now has wider acceptance.^47,48 A few high-quality randomized trials have been performed.^25,49,50

Pharmacotherapy, especially in frail patients, should be initiated at the lowest start­ing dosage and titrated cautiously to clinical effect and for the shortest period of time nec­essary. Antipsychotics are preferred agents for treating all subtypes of delirium; haloperidol is widely used.^46,51,52 However, antipsychotics, including haloperidol, can be associated with adverse neurologic effects such as extrapyra­midal symptoms (EPS) and NMS.

Although reported less frequently than with haloperidol, other agents have been implicated in development of EPS and NMS, including atypical antipsychotics and anti­emetic dopamine antagonists, particularly in parkinsonism-prone patients.⁵³ Strategies that can minimize such risks in geriatric inpatients with delirium include oral, rather than par­enteral, use of antipsychotics—preferential use of atypical over typical antipsychotics— and lowest effective dosages.⁵⁴

In controlled trials, atypical antipsychot­ics for delirium showed efficacy compared with haloperidol.^52,55 However, there is no research that demonstrates any advantage of one atypical over another.²⁵

In Mr. D’s case, the most important inter­vention for managing delirium caused by NMS is to discontinue all dopamine antag­onists and treat agitation with judicious doses of a benzodiazepine, with supportive care.¹⁷ In cases of sudden discontinuation or a dosage decrease of dopamine agonists, these medications should be resumed or optimized to minimize the risk of NMS-associated rhabdomyolysis and subse­quent renal failure.¹⁷ Antipsychotics carry an increased risk of stroke and mortality in older patients with established or evolving neurocognitive disorders^56,57 and can cause prolongation of the QTc interval.⁵⁷

Other medications that could be used for delirium include cholinesterase inhibitors^58,59 (although larger trials and a systematic review did not support this use⁶⁰), and 5-HT receptor antagonists,⁶¹ such as trazodone. Benzodiazepines, such as lorazepam, are first-line treatment for delirium associated with seizures or withdrawal from alcohol, sedatives, hypnotics, and anxiolytics and for delirium caused by NMS. Be cautious about using benzodiazepines in geriatric patients because of a risk of respiratory depression, falls, sedation, and amnesia.

Geriatric patients with alcoholism and those with malnutrition are prone to thia­mine and vitamin B₁₂ deficiencies, which can induce delirium. Laboratory assessment and consideration of supplementation is recom­mended. Despite high occurrence of delirium in hospitalized older adults with preexisting comorbid neurocognitive disorders, there is no standard care for delirium comorbid with another neurocognitive disorder.⁶² Clinical practice guidelines for older patients receiv­ing palliative care have been developed⁶³; the goal is to minimize suffering and discomfort in patients in palliative care.⁶⁴

Post-delirium prophylaxis. Medications for delirium usually can be tapered and discontinued once the episode has resolved and the patient is stable; it is common to discontinue medications when the patient has been symptom-free for 1 week.⁶⁵ Some patients (eg, with end-stage liver disease, disseminated cancer) are prone to recur­rent or to prolonged or chronic delirium. A period of post-recovery treatment with antipsychotics—even indefinite treatment in some cases—should be considered.

Post-delirium debriefing and aftercare. The psychological complications of delirium are distressing for the patient and his (her) caregivers. Psychiatric complications asso­ciated with delirium, including acute stress disorder—which might predict posttraumatic stress disorder—have been explored; early recognition and treatment may improve long-term outcomes.⁶⁶ After recovery from acute delirium, cognitive assessment (eg, MMSE⁶⁷ or Montreal Cognitive Assessment⁶⁸) is recommended to validate current cognitive status because patients may have persistent decrement in cognitive func­tion compared with pre-delirium condition, even after recovery from the acute episode.

Post-delirium debriefing may help patients who have recovered from a delirium episode. Patients may fear that their brief period of hallucinations might represent the onset of a chronic-relapsing psychotic dis­order. Allow patients to communicate their distress about the delirium episode and give them the opportunity to talk through the experience. Brief them on the possibility that delirium will recur and advise them to seek emergency medical care in case of recur­rence. Advise patients to monitor and main­tain a normal sleep-wake cycle.

Family members can watch for syndro­mal recurrence of delirium. They should be encouraged to discuss their reaction to hav­ing seen their relative in a delirious state.

Health care systems with integrated electronic medical records should list “delirium, resolved” on the patient’s illness profile or problem list and alert the patient’s primary care provider to the delirium his­tory to avoid future exposure to delirium-provocative medications, and to prompt the provider to assume an active role in post-delirium care, including delirium recur­rence surveillance, medication adjustment, risk factor management, and post-recovery cognitive assessment.

Bottom Line
Evaluation of delirium in geriatric patients includes clinical vigilance and screening, differentiating delirium from other neurocognitive disorders, and identifying and treating underlying causes. Perioperative use of antipsychotics may reduce the incidence of delirium, although hospital length of stay generally has not been reduced with prophylaxis. Management interventions include staff education, systematic screening, use of multicomponent interventions, and pharmacologic interventions.

Related Resources
• Downing LJ, Caprio TV, Lyness JM. Geriatric psychiatry review: differential diagnosis and treatment of the 3 D’s - delirium, dementia, and depression. Curr Psychiatry Rep. 2013;15(6):365.
• Brooks PB. Postoperative delirium in elderly patients. Am J Nurs. 2012;112(9):38-49.

Drug Brand Names
Carbidopa/levodopa • Sinemet                       Midazolam •  Versed
Dexmedetomidine • Precedex                        Olanzapine •  Zyprexa
Haloperidol • Haldol                                      Propofol  •  Diprivan
Lithium • Eskalith, Lithobid                            Quetiapine  •  Seroquel
Lorazepam • Ativan                                      Risperidone  •  Risperdal
Metoclopramide •  Reglan                              Trazodone  •  Desyrel

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Although delirium has many descriptive terms (Table 1), a common unifying term is “acute global cognitive dysfunction,” now recognized as delirium; a consensus supported by DSM-5¹ and ICD-10² (Table 2). According to DSM-5, the essential feature is a disturbance of attention or awareness that is accompanied by a change in baseline cognition that cannot be explained by another preexisting, established, or evolving neurocognitive disorder (the newly named DSM-5 entity for dementia syndromes).¹ Because delirium affects the cortex diffusely, psychiatric symp­toms can include cognitive, mood, anxiety, or psychotic symp­toms. Because many systemic illnesses can induce delirium, the differential diagnosis spans all organ systems.

Three subtypes
Delirium can be classified, based on symptoms,^3,4 into 3 sub­types: hyperactive-hyperalert, hypoactive-hypoalert, and mixed delirium. Hyperactive patients present with rest­lessness and agitation. Hypoactive patients are lethargic, confused, slow to respond to questions, and often appear depressed. The differential prognostic significance of these subtypes has been examined in the literature, with conflicting results. Rabinowitz⁵ reported that hypoactive delirium has the worst prognosis, while Marcantonio et al⁶ indicated that the hyperactive subtype is associated with the highest mortality rate. Mixed delirium, with periods of both hyperactivity and hypoactivity, is the most common type of delirium.⁷

A prodromal phase, characterized by anxiety, frequent requests for nursing and medical assistance, decreased attention, rest­lessness, vivid dreams, disorientation imme­diately after awakening, and hallucinations, can occur before an episode of full-spectrum delirium; this prodromal state often is iden­tified retrospectively —after the patient is in an episode of delirium.^8,9

Evidence-based guidelines aim to improve recognition and clinical management.^10-13 Disruptive behavior is the main reason for psychiatric referral in delirium.^14,15 Delayed psychiatric consultation because of non-recognition of delirium is related to variables such as older age; history of a pre-existing, comorbid neurocognitive disorder; and the clinical appearance of hypoactive delirium.¹⁴

The case of Mr. D (Box),¹⁶ illus­trates how the emergence of antipsychotic-associated neuroleptic malignant syndrome (NMS) can complicate antipsychotic treat­ment of delirium in a geriatric medical patient, although delirium also is a common presentation in NMS.¹⁷ Delirium developed after an increase in carbidopa/levodopa, which has central dopaminergic effects that can precipitate delirium, particularly in a geriatric patient with preexisting comorbid neurocognitive disorder. Further complicat­ing Mr. D’s delirium presentation was the development of NMS, which had a multifac­torial causation, such as the use of dopamine antagonists (ie, quetiapine, metoclopramide), and an abrupt decrease of a dopaminergic agent (ie, carbidopa/levodopa), all inducing a central dopamine relative hypoactivity.

Epidemiology
Delirium is more common in older patients,¹⁵ and is seen in 30% to 40% of hospitalized geri­atric patients.¹⁸ Delirium in older patients, compared with other adults, is associated with more severe cognitive impairment.¹⁹ It is com­mon among geriatric surgical patients (15% to 62%)²⁰ with a peak 2 to 5 days postoperatively for hip fracture,²¹ and often is seen in ICU patients (70% to 87%).²⁰ However, Spronk et al²² found that delirium is significantly under-recognized in the ICU. Nearly 90% of terminally ill patients become delirious before death.²³ Terminal delirium often is unrecognized and can interfere with assessment of other clinical problems.²⁴ A preexisting history of comor­bid neurocognitive disorder was evident in as many as two-thirds of delirium cases.²⁵

Pathophysiology and risk factors
The pathophysiology of delirium has been characterized as an imbalance of CNS metab­olism, including decreased blood flow in vari­ous regions of the brain that may normalize once delirium resolves.²⁶ Studies describe the simultaneous decrease of cholinergic transmission and dopaminergic excess.^27,28 Predisposing and precipitating factors for delirium that are of particular importance in geriatric patients include:
   • advanced age
   • CNS disease
   • infection
   • cognitive impairment
   • male sex
   • poor nutrition
   • dehydration and other metabolic abnormalities
   • cardiovascular events
   • substance use
   • medication
   • sensory deprivation (eg, impaired vision or hearing)
   • sleep deprivation
   • low level of physical activity.^27,29,30

Table 3 lists the most common delirium-provocative medications.²⁷

Evaluation and psychometric scales
The EEG can be useful in evaluating delir­ium, especially in clinically ambiguous cases. EEG findings may indicate generalized slowing or dropout of the posterior domi­nant rhythm, and generalized slow theta and delta waves, findings that are more common in delirium than in other neurocognitive dis­orders and other psychiatric illnesses. The EEG must be interpreted in the context of the delirium diagnostic workup, because abnor­malities seen in other neurocognitive disor­ders can overlap with those of delirium.³¹

The EEG referral should specify the clini­cal suspicion of delirium to help interpret the results. Delirium cases in which the patient’s previous cognitive status is unknown may benefit from EEG evaluation, such as:
   • in possible status epilepticus
   • when delirium improvement has reached a plateau at a lower level of cognitive function than before onset of delirium
   • when the patient is unable or unwilling to complete a psychiatric interview.²⁷

Assessment instruments are available to diagnose and monitor delirium (Table 4). Typically, delirium assessment includes examining levels of arousal, psychomotor activity, cognition (ie, orienta­tion, attention, and memory), and percep­tual disturbances.

Psychometrically, a review of Table 4 suggests that validity appeared stable with adequate specificity (64% to 99%) but more variable sensitivity (36% to 100%). These reliability parameters also will be affected by the classification sys­tem (ie, DSM vs ICD) and the cut-off score employed.³² Most measures (eg, Confusion Assessment Method [CAM], CAM-ICU) provide an adequate sample of behavioral (ie, level of alertness), motor (ie, psychomo­tor activity), and cognitive (ie, orientation, attention, memory, and receptive language) function, with the exception of the Global Attentiveness Rating, which is a 2-minute open conversation protocol between physi­cian and patient.

Some measures are stand-alone instru­ments, such as the Memorial Delirium Assessment Scale, whereas the CAM requires administration of separate cogni­tive screens, including the Mini-Mental State Examination (MMSE) and Digit Span.³³ Instruments to detect delirium in critically ill patients are a more recent development. Wong et al³⁴ reported that the most widely studied tool was the CAM. Obtaining collat­eral information from family, caregivers, and hospital staff is essential, particularly given the fluctuating nature of delirium.

Management
Prevention. Identify patients at high risk of delirium so that preventive strategies can be employed. Multi-component, nonphar­macotherapeutic interventions are used in clinical settings but few randomized trials have been conducted. The contributing effectiveness of individual components is not well-studied, but most include staff education to increase awareness of delir­ium. Of 3 multi-component intervention randomized trials, 2 reported a signifi­cantly lower incidence of delirium in the intervention group.^35-37 Implementation of a multi-component protocol in medical/ surgical units was associated with a sig­nificant reduction in use of restraints.³⁸

As in Mr. D’s case, complex drug regimens, particularly for CNS illness, can increase the risk of delirium. Considering the medication profile for patients with complex systemic illness—in particular, minimizing the use anticholinergics and dopamine agonists— may be crucial in preventing delirium.

Prophylactic administration of antipsychotics may reduce the risk of devel­oping postoperative delirium.³⁹ Studies of the use of these agents were characterized by small sample sizes and selected groups of patient populations. Of the 4 random­ized studies evaluating prophylactic anti­psychotics (vs placebo), 3 found a lower incidence of delirium in the intervention groups.^39-41

A study of haloperidol in post-GI sur­gery patients showed a reduced occurrence of delirium,⁴⁰ whereas its prophylactic use in patients undergoing hip surgery⁴² did not reduce the incidence of delirium com­pared with placebo, but did decrease sever­ity when delirium occurred.⁴²

Risperidone³⁹ in post-cardiac sur­gery and olanzapine⁴¹ perioperatively in patients undergoing total knee or hip replacement have been shown to decrease delirium severity and duration. Targeted prophylaxis with risperidone⁴³ in post-cardiac surgery patients who showed disturbed cognition but did not meet cri­teria for delirium reduced the number of patients requiring medication, compared with placebo.⁴³

Dexmedetomidine, an α-2 adrenergic receptor agonist, compared with propofol or midazolam in post-cardiac valve surgery patients, resulted in a decreased incidence of delirium but no difference in delirium duration, hospital length of stay, or use of other medications.⁴⁴ However, other studies have shown that dexmedetomidine reduces ICU length of stay and duration of mechani­cal ventilation.⁴⁵

Treatment. Management of hospitalized medically ill geriatric patients with delirium is challenging and requires a comprehensive approach. The first step in delirium man­agement is prompt identification and man­agement of systemic medical disturbances associated with the delirium episode. First-line, nonpharmacotherapeutic strategies for patients with delirium include:
   • reorientation
   • behavioral interventions (eg, use of clear instructions and frequent eye con­tact with patients)
   • environmental interventions (eg, mini­mal noise, adequate lighting, and lim­ited room and staff changes)
   • avoidance of physical restraints.⁴⁶

Consider employing family members or hospital staff sitters to stay with the patient and to reassure, reorient, and watch for agitation and other unsafe behaviors (eg, attempted elopement). Psychoeducation for the patient and family on the phenomenol­ogy of delirium can be helpful.

The use of drug treatment strategies should be integrated into a comprehensive approach that includes the routine use of nondrug measures.⁴⁶ Using medications for treating hypoactive delirium, formerly con­troversial, now has wider acceptance.^47,48 A few high-quality randomized trials have been performed.^25,49,50

Pharmacotherapy, especially in frail patients, should be initiated at the lowest start­ing dosage and titrated cautiously to clinical effect and for the shortest period of time nec­essary. Antipsychotics are preferred agents for treating all subtypes of delirium; haloperidol is widely used.^46,51,52 However, antipsychotics, including haloperidol, can be associated with adverse neurologic effects such as extrapyra­midal symptoms (EPS) and NMS.

Although reported less frequently than with haloperidol, other agents have been implicated in development of EPS and NMS, including atypical antipsychotics and anti­emetic dopamine antagonists, particularly in parkinsonism-prone patients.⁵³ Strategies that can minimize such risks in geriatric inpatients with delirium include oral, rather than par­enteral, use of antipsychotics—preferential use of atypical over typical antipsychotics— and lowest effective dosages.⁵⁴

In controlled trials, atypical antipsychot­ics for delirium showed efficacy compared with haloperidol.^52,55 However, there is no research that demonstrates any advantage of one atypical over another.²⁵

In Mr. D’s case, the most important inter­vention for managing delirium caused by NMS is to discontinue all dopamine antag­onists and treat agitation with judicious doses of a benzodiazepine, with supportive care.¹⁷ In cases of sudden discontinuation or a dosage decrease of dopamine agonists, these medications should be resumed or optimized to minimize the risk of NMS-associated rhabdomyolysis and subse­quent renal failure.¹⁷ Antipsychotics carry an increased risk of stroke and mortality in older patients with established or evolving neurocognitive disorders^56,57 and can cause prolongation of the QTc interval.⁵⁷

Other medications that could be used for delirium include cholinesterase inhibitors^58,59 (although larger trials and a systematic review did not support this use⁶⁰), and 5-HT receptor antagonists,⁶¹ such as trazodone. Benzodiazepines, such as lorazepam, are first-line treatment for delirium associated with seizures or withdrawal from alcohol, sedatives, hypnotics, and anxiolytics and for delirium caused by NMS. Be cautious about using benzodiazepines in geriatric patients because of a risk of respiratory depression, falls, sedation, and amnesia.

Geriatric patients with alcoholism and those with malnutrition are prone to thia­mine and vitamin B₁₂ deficiencies, which can induce delirium. Laboratory assessment and consideration of supplementation is recom­mended. Despite high occurrence of delirium in hospitalized older adults with preexisting comorbid neurocognitive disorders, there is no standard care for delirium comorbid with another neurocognitive disorder.⁶² Clinical practice guidelines for older patients receiv­ing palliative care have been developed⁶³; the goal is to minimize suffering and discomfort in patients in palliative care.⁶⁴

Post-delirium prophylaxis. Medications for delirium usually can be tapered and discontinued once the episode has resolved and the patient is stable; it is common to discontinue medications when the patient has been symptom-free for 1 week.⁶⁵ Some patients (eg, with end-stage liver disease, disseminated cancer) are prone to recur­rent or to prolonged or chronic delirium. A period of post-recovery treatment with antipsychotics—even indefinite treatment in some cases—should be considered.

Post-delirium debriefing and aftercare. The psychological complications of delirium are distressing for the patient and his (her) caregivers. Psychiatric complications asso­ciated with delirium, including acute stress disorder—which might predict posttraumatic stress disorder—have been explored; early recognition and treatment may improve long-term outcomes.⁶⁶ After recovery from acute delirium, cognitive assessment (eg, MMSE⁶⁷ or Montreal Cognitive Assessment⁶⁸) is recommended to validate current cognitive status because patients may have persistent decrement in cognitive func­tion compared with pre-delirium condition, even after recovery from the acute episode.

Post-delirium debriefing may help patients who have recovered from a delirium episode. Patients may fear that their brief period of hallucinations might represent the onset of a chronic-relapsing psychotic dis­order. Allow patients to communicate their distress about the delirium episode and give them the opportunity to talk through the experience. Brief them on the possibility that delirium will recur and advise them to seek emergency medical care in case of recur­rence. Advise patients to monitor and main­tain a normal sleep-wake cycle.

Family members can watch for syndro­mal recurrence of delirium. They should be encouraged to discuss their reaction to hav­ing seen their relative in a delirious state.

Health care systems with integrated electronic medical records should list “delirium, resolved” on the patient’s illness profile or problem list and alert the patient’s primary care provider to the delirium his­tory to avoid future exposure to delirium-provocative medications, and to prompt the provider to assume an active role in post-delirium care, including delirium recur­rence surveillance, medication adjustment, risk factor management, and post-recovery cognitive assessment.

Bottom Line
Evaluation of delirium in geriatric patients includes clinical vigilance and screening, differentiating delirium from other neurocognitive disorders, and identifying and treating underlying causes. Perioperative use of antipsychotics may reduce the incidence of delirium, although hospital length of stay generally has not been reduced with prophylaxis. Management interventions include staff education, systematic screening, use of multicomponent interventions, and pharmacologic interventions.

Related Resources
• Downing LJ, Caprio TV, Lyness JM. Geriatric psychiatry review: differential diagnosis and treatment of the 3 D’s - delirium, dementia, and depression. Curr Psychiatry Rep. 2013;15(6):365.
• Brooks PB. Postoperative delirium in elderly patients. Am J Nurs. 2012;112(9):38-49.

Drug Brand Names
Carbidopa/levodopa • Sinemet                       Midazolam •  Versed
Dexmedetomidine • Precedex                        Olanzapine •  Zyprexa
Haloperidol • Haldol                                      Propofol  •  Diprivan
Lithium • Eskalith, Lithobid                            Quetiapine  •  Seroquel
Lorazepam • Ativan                                      Risperidone  •  Risperdal
Metoclopramide •  Reglan                              Trazodone  •  Desyrel

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.