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Study supports sequential MRD monitoring in certain patients
Photo by Chad McNeeley
Based on results of a prospective study, investigators are advocating sequential minimal residual disease (MRD) monitoring in pediatric patients with acute lymphoblastic leukemia (ALL) who have detectable MRD after remission induction therapy.
The researchers said their findings show that MRD levels during remission induction treatment have important therapeutic indications, even in the context of MRD-guided therapy, as patients with higher MRD levels have worse outcomes.
Ching-Hon Pui, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues described the findings in The Lancet Oncology.
The team analyzed 498 pediatric patients newly diagnosed with ALL, 492 of whom (99%) attained a complete remission following induction therapy and 491 of whom were monitored for MRD.
The researchers first estimated patients’ risk of relapse according to baseline clinical and laboratory features, provisionally classifying them as having a low, standard, or high risk of relapse.
But the investigators also took MRD levels into consideration. They measured MRD on days 19 and 46 of remission induction, on week 7 of maintenance treatment, and on weeks 17, 48, and 120 (the end of treatment).
The team found that 10-year event-free survival (EFS) was significantly worse for patients with 1% or greater MRD levels on day 19, regardless of their initial risk assessment. Ten-year EFS was 64.1% in these patients, compared to 90.7% in patients with lower or no detectable MRD (P<0.001).
Thirteen percent of patients who were deemed low-risk initially and 28% of patients deemed standard-risk initially had 1% or higher MRD levels on day 19. And these levels were associated with worse 10-year EFS.
In the provisional low-risk group, EFS was 69.2% in the high-MRD patients and 95.5% in the low-MRD patients (P<0.001). And in the provisional standard-risk group, 10-year EFS was 65.1% and 82.9%, respectively (P=0.01).
MRD levels at day 46 also appeared to have a bearing on EFS. For patients in the provisional low-risk group who had 1% or higher MRD on day 19 but became MRD-negative on day 46, 10-year EFS was 88.9%, compared to 59.2% for other provisionally low-risk patients who had detectable MRD on day 46 (P=0.02).
MRD levels on days 19 and 46 led to the reclassification of 50 patients from low-risk to a higher risk group that warranted more intensive therapy. The researchers credited the change with boosting survival.
“This analysis shows that MRD-directed therapy clearly contributed to the unprecedented high rates of long-term survival that patients in this study achieved,” Dr Pui said. “MRD proved to be a powerful way to identify high-risk patients who needed more intensive therapy and helped us avoid over-treatment of low-risk patients by reducing their exposure to chemotherapy.”
Still, MRD assessments at days 19 and 46 were not perfect predictors of patient outcomes. Of the patients who were MRD negative after remission induction, MRD re-emerged in 6 patients—4 of the 382 patients studied on week 7, 1 of the 448 studied at week 17, and 1 of the 437 studied at week 48. All but 1 of these patients died despite additional treatment.
On the other hand, relapse occurred in 2 of the 11 patients who had decreasing MRD levels between the end of induction and week 7 of maintenance therapy and were treated with chemotherapy alone.
Taking these results together, the investigators concluded that measuring MRD at days 19 and 46 was sufficient to guide the treatment of most pediatric ALL patients. However, MRD measurements should continue to guide treatment for patients with detectable MRD on day 46. 
Photo by Chad McNeeley
Based on results of a prospective study, investigators are advocating sequential minimal residual disease (MRD) monitoring in pediatric patients with acute lymphoblastic leukemia (ALL) who have detectable MRD after remission induction therapy.
The researchers said their findings show that MRD levels during remission induction treatment have important therapeutic indications, even in the context of MRD-guided therapy, as patients with higher MRD levels have worse outcomes.
Ching-Hon Pui, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues described the findings in The Lancet Oncology.
The team analyzed 498 pediatric patients newly diagnosed with ALL, 492 of whom (99%) attained a complete remission following induction therapy and 491 of whom were monitored for MRD.
The researchers first estimated patients’ risk of relapse according to baseline clinical and laboratory features, provisionally classifying them as having a low, standard, or high risk of relapse.
But the investigators also took MRD levels into consideration. They measured MRD on days 19 and 46 of remission induction, on week 7 of maintenance treatment, and on weeks 17, 48, and 120 (the end of treatment).
The team found that 10-year event-free survival (EFS) was significantly worse for patients with 1% or greater MRD levels on day 19, regardless of their initial risk assessment. Ten-year EFS was 64.1% in these patients, compared to 90.7% in patients with lower or no detectable MRD (P<0.001).
Thirteen percent of patients who were deemed low-risk initially and 28% of patients deemed standard-risk initially had 1% or higher MRD levels on day 19. And these levels were associated with worse 10-year EFS.
In the provisional low-risk group, EFS was 69.2% in the high-MRD patients and 95.5% in the low-MRD patients (P<0.001). And in the provisional standard-risk group, 10-year EFS was 65.1% and 82.9%, respectively (P=0.01).
MRD levels at day 46 also appeared to have a bearing on EFS. For patients in the provisional low-risk group who had 1% or higher MRD on day 19 but became MRD-negative on day 46, 10-year EFS was 88.9%, compared to 59.2% for other provisionally low-risk patients who had detectable MRD on day 46 (P=0.02).
MRD levels on days 19 and 46 led to the reclassification of 50 patients from low-risk to a higher risk group that warranted more intensive therapy. The researchers credited the change with boosting survival.
“This analysis shows that MRD-directed therapy clearly contributed to the unprecedented high rates of long-term survival that patients in this study achieved,” Dr Pui said. “MRD proved to be a powerful way to identify high-risk patients who needed more intensive therapy and helped us avoid over-treatment of low-risk patients by reducing their exposure to chemotherapy.”
Still, MRD assessments at days 19 and 46 were not perfect predictors of patient outcomes. Of the patients who were MRD negative after remission induction, MRD re-emerged in 6 patients—4 of the 382 patients studied on week 7, 1 of the 448 studied at week 17, and 1 of the 437 studied at week 48. All but 1 of these patients died despite additional treatment.
On the other hand, relapse occurred in 2 of the 11 patients who had decreasing MRD levels between the end of induction and week 7 of maintenance therapy and were treated with chemotherapy alone.
Taking these results together, the investigators concluded that measuring MRD at days 19 and 46 was sufficient to guide the treatment of most pediatric ALL patients. However, MRD measurements should continue to guide treatment for patients with detectable MRD on day 46.
Photo by Chad McNeeley
Based on results of a prospective study, investigators are advocating sequential minimal residual disease (MRD) monitoring in pediatric patients with acute lymphoblastic leukemia (ALL) who have detectable MRD after remission induction therapy.
The researchers said their findings show that MRD levels during remission induction treatment have important therapeutic indications, even in the context of MRD-guided therapy, as patients with higher MRD levels have worse outcomes.
Ching-Hon Pui, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues described the findings in The Lancet Oncology.
The team analyzed 498 pediatric patients newly diagnosed with ALL, 492 of whom (99%) attained a complete remission following induction therapy and 491 of whom were monitored for MRD.
The researchers first estimated patients’ risk of relapse according to baseline clinical and laboratory features, provisionally classifying them as having a low, standard, or high risk of relapse.
But the investigators also took MRD levels into consideration. They measured MRD on days 19 and 46 of remission induction, on week 7 of maintenance treatment, and on weeks 17, 48, and 120 (the end of treatment).
The team found that 10-year event-free survival (EFS) was significantly worse for patients with 1% or greater MRD levels on day 19, regardless of their initial risk assessment. Ten-year EFS was 64.1% in these patients, compared to 90.7% in patients with lower or no detectable MRD (P<0.001).
Thirteen percent of patients who were deemed low-risk initially and 28% of patients deemed standard-risk initially had 1% or higher MRD levels on day 19. And these levels were associated with worse 10-year EFS.
In the provisional low-risk group, EFS was 69.2% in the high-MRD patients and 95.5% in the low-MRD patients (P<0.001). And in the provisional standard-risk group, 10-year EFS was 65.1% and 82.9%, respectively (P=0.01).
MRD levels at day 46 also appeared to have a bearing on EFS. For patients in the provisional low-risk group who had 1% or higher MRD on day 19 but became MRD-negative on day 46, 10-year EFS was 88.9%, compared to 59.2% for other provisionally low-risk patients who had detectable MRD on day 46 (P=0.02).
MRD levels on days 19 and 46 led to the reclassification of 50 patients from low-risk to a higher risk group that warranted more intensive therapy. The researchers credited the change with boosting survival.
“This analysis shows that MRD-directed therapy clearly contributed to the unprecedented high rates of long-term survival that patients in this study achieved,” Dr Pui said. “MRD proved to be a powerful way to identify high-risk patients who needed more intensive therapy and helped us avoid over-treatment of low-risk patients by reducing their exposure to chemotherapy.”
Still, MRD assessments at days 19 and 46 were not perfect predictors of patient outcomes. Of the patients who were MRD negative after remission induction, MRD re-emerged in 6 patients—4 of the 382 patients studied on week 7, 1 of the 448 studied at week 17, and 1 of the 437 studied at week 48. All but 1 of these patients died despite additional treatment.
On the other hand, relapse occurred in 2 of the 11 patients who had decreasing MRD levels between the end of induction and week 7 of maintenance therapy and were treated with chemotherapy alone.
Taking these results together, the investigators concluded that measuring MRD at days 19 and 46 was sufficient to guide the treatment of most pediatric ALL patients. However, MRD measurements should continue to guide treatment for patients with detectable MRD on day 46.
Discovery may aid malaria vaccine development
a red blood cell
Image courtesy of St. Jude
Children’s Research Hospital
Researchers say they have made a major advance in the quest toward a viable malaria vaccine—by uncovering a strategy the immune system employs to protect against malaria infection.
The team discovered how antibodies work in partnership with complement proteins to block Plasmodium falciparum infection.
And they believe this finding will aid the development of vaccine candidates that are already under investigation.
“We have known that antibodies on their own are not highly effective at blocking malaria, so they must be getting help from other parts of the immune system,” said James Beeson, MBBS, PhD, of the Burnet Institute in Melbourne, Victoria, Australia.
“This new research provides evidence that complement plays a key role in antibody-mediated immunity to blood-stage replication of Plasmodium falciparum malaria in humans.”
Dr Beeson and his colleagues described their research in Immunity.
The team found that acquired and vaccine-induced human antibodies recruited complement to block red blood cell infection and blood-stage replication of P falciparum.
Without complement, many of the antibodies were not functional, and P falciparum merozoites invaded red blood cells. But when the antibodies interacted with complement factors, they were able to prevent invasion and lyse merozoites.
Further investigation revealed that inhibitory activity was mediated predominately by C1q fixation, and merozoite surface proteins (MSPs) 1 and 2 were major targets of antibody-mediated complement-dependent (Ab-C’) inhibition.
To examine the importance of antibody-mediated complement fixation in acquired immunity to malaria, the researchers tested antibodies for C1q fixation in 206 children (ages 5 to 14) living in a malaria-endemic region.
This revealed that complement fixation was strongly associated with protection from clinical malaria and high-density parasitemia.
The researchers also investigated whether Ab-C′ inhibitory activity could be induced by human immunization with a candidate MSP vaccine. They studied 10 immunoglobulin G (IgG) samples from a phase 1 trial of the MSP2-C1 vaccine.
Eight of the IgG samples showed substantial inhibition in normal serum, but not in heat-inactivated serum, which suggests vaccination induced Ab-C’ inhibition. The researchers did not observe inhibition in IgG from pre-vaccinated individuals or placebo-vaccinated samples.
The team said this suggests that MSP2 antibodies induced by vaccination can inhibit P falciparum invasion via Ab-C’ inhibition.
“We have shown that it is possible to effectively generate this protective immune response by immunizing humans with a candidate vaccine,” Dr Beeson said, noting that this “may prove a valuable strategy to prevent the devastating effects of malaria.”
a red blood cell
Image courtesy of St. Jude
Children’s Research Hospital
Researchers say they have made a major advance in the quest toward a viable malaria vaccine—by uncovering a strategy the immune system employs to protect against malaria infection.
The team discovered how antibodies work in partnership with complement proteins to block Plasmodium falciparum infection.
And they believe this finding will aid the development of vaccine candidates that are already under investigation.
“We have known that antibodies on their own are not highly effective at blocking malaria, so they must be getting help from other parts of the immune system,” said James Beeson, MBBS, PhD, of the Burnet Institute in Melbourne, Victoria, Australia.
“This new research provides evidence that complement plays a key role in antibody-mediated immunity to blood-stage replication of Plasmodium falciparum malaria in humans.”
Dr Beeson and his colleagues described their research in Immunity.
The team found that acquired and vaccine-induced human antibodies recruited complement to block red blood cell infection and blood-stage replication of P falciparum.
Without complement, many of the antibodies were not functional, and P falciparum merozoites invaded red blood cells. But when the antibodies interacted with complement factors, they were able to prevent invasion and lyse merozoites.
Further investigation revealed that inhibitory activity was mediated predominately by C1q fixation, and merozoite surface proteins (MSPs) 1 and 2 were major targets of antibody-mediated complement-dependent (Ab-C’) inhibition.
To examine the importance of antibody-mediated complement fixation in acquired immunity to malaria, the researchers tested antibodies for C1q fixation in 206 children (ages 5 to 14) living in a malaria-endemic region.
This revealed that complement fixation was strongly associated with protection from clinical malaria and high-density parasitemia.
The researchers also investigated whether Ab-C′ inhibitory activity could be induced by human immunization with a candidate MSP vaccine. They studied 10 immunoglobulin G (IgG) samples from a phase 1 trial of the MSP2-C1 vaccine.
Eight of the IgG samples showed substantial inhibition in normal serum, but not in heat-inactivated serum, which suggests vaccination induced Ab-C’ inhibition. The researchers did not observe inhibition in IgG from pre-vaccinated individuals or placebo-vaccinated samples.
The team said this suggests that MSP2 antibodies induced by vaccination can inhibit P falciparum invasion via Ab-C’ inhibition.
“We have shown that it is possible to effectively generate this protective immune response by immunizing humans with a candidate vaccine,” Dr Beeson said, noting that this “may prove a valuable strategy to prevent the devastating effects of malaria.”
a red blood cell
Image courtesy of St. Jude
Children’s Research Hospital
Researchers say they have made a major advance in the quest toward a viable malaria vaccine—by uncovering a strategy the immune system employs to protect against malaria infection.
The team discovered how antibodies work in partnership with complement proteins to block Plasmodium falciparum infection.
And they believe this finding will aid the development of vaccine candidates that are already under investigation.
“We have known that antibodies on their own are not highly effective at blocking malaria, so they must be getting help from other parts of the immune system,” said James Beeson, MBBS, PhD, of the Burnet Institute in Melbourne, Victoria, Australia.
“This new research provides evidence that complement plays a key role in antibody-mediated immunity to blood-stage replication of Plasmodium falciparum malaria in humans.”
Dr Beeson and his colleagues described their research in Immunity.
The team found that acquired and vaccine-induced human antibodies recruited complement to block red blood cell infection and blood-stage replication of P falciparum.
Without complement, many of the antibodies were not functional, and P falciparum merozoites invaded red blood cells. But when the antibodies interacted with complement factors, they were able to prevent invasion and lyse merozoites.
Further investigation revealed that inhibitory activity was mediated predominately by C1q fixation, and merozoite surface proteins (MSPs) 1 and 2 were major targets of antibody-mediated complement-dependent (Ab-C’) inhibition.
To examine the importance of antibody-mediated complement fixation in acquired immunity to malaria, the researchers tested antibodies for C1q fixation in 206 children (ages 5 to 14) living in a malaria-endemic region.
This revealed that complement fixation was strongly associated with protection from clinical malaria and high-density parasitemia.
The researchers also investigated whether Ab-C′ inhibitory activity could be induced by human immunization with a candidate MSP vaccine. They studied 10 immunoglobulin G (IgG) samples from a phase 1 trial of the MSP2-C1 vaccine.
Eight of the IgG samples showed substantial inhibition in normal serum, but not in heat-inactivated serum, which suggests vaccination induced Ab-C’ inhibition. The researchers did not observe inhibition in IgG from pre-vaccinated individuals or placebo-vaccinated samples.
The team said this suggests that MSP2 antibodies induced by vaccination can inhibit P falciparum invasion via Ab-C’ inhibition.
“We have shown that it is possible to effectively generate this protective immune response by immunizing humans with a candidate vaccine,” Dr Beeson said, noting that this “may prove a valuable strategy to prevent the devastating effects of malaria.”
Clozapine Management for Internists
Clozapine is a second‐generation antipsychotic (SGA) medication that was developed in 1959, introduced to Europe in 1971, and withdrawn from the market in 1975 due to associated concerns for potentially fatal agranulocytosis. In 1989, the US Food and Drug Administration (FDA) approved use of clozapine for the management of treatment‐resistant schizophrenia, under strict parameters for complete blood count (CBC) monitoring. Clozapine has since gained an additional FDA indication for reducing suicidal behavior in patients with schizophrenia and schizoaffective disorder,[1, 2, 3] and displayed superiority to both first generation antipsychotics and other SGA agents in reducing symptom burden.[2, 4, 5]
Clozapine's clinical benefits include lowering mortality in schizophrenia,[6] reducing deaths from ischemic heart disease,[7] curtailing substance use in individuals with psychotic disorders,[8] increasing rates of independent living and meaningful occupational activity, and reducing psychiatric hospitalizations and need for involuntary treatment.[9] Because schizophrenia, itself, is associated with a 15‐ to 20‐year decrease in average lifespan,[10] these benefits of clozapine are particularly salient. Yet the mechanism by which clozapine mitigates otherwise‐refractory psychotic symptoms is a conundrum. Structurally a tricyclic dibenzodiazepine, clozapine has relatively little effect on the dopamine D2 receptor, which has classically been thought to mediate the treatment effect of antipsychotics.[11, 12]
The unique nature of clozapine extends to its adverse effect profile. A significant percentage of patients who discontinue clozapine (17%35.4%) cite medical complications, the most common being seizures, constipation, sedation, and neutropenia.[13, 14] Yet several studies, including the landmark Clinical Antipsychotic Trials for Interventions Effectiveness (CATIE) study, have found that patients were more likely to adhere to clozapine therapy than to other antipsychotics.[2, 15] In the CATIE study, 44% of subjects taking clozapine continued the medication for 18 months, compared to 29% of individuals on olanzapine, 14% on risperidone, and 7% on quetiapine. Median time until discontinuation of clozapine was 10.5 months, significantly longer than for quetiapine (2.8 months) and olanzapine (2.7 months).[2] Because patients who experience clozapine‐related medical complications are likely to present first to the primary care or general hospital setting, internists must be aware of potential iatrogenic effects, and of their implications for psychiatric and medical care. Using case examples, we will examine both common and serious complications associated with clozapine, and discuss recommendations for management, including indications for clozapine discontinuation.
NEUROLOGICAL
Case Vignette 1
Mr. A is a 29‐year‐old man with asthma and schizophrenia who experienced a generalized tonic‐clonic seizure during treatment at a psychiatric facility. The patient started clozapine therapy 5 weeks prior, with gradual titration to 425 mg daily. Mr. A's previous medication trials included olanzapine and chlorpromazine, which rendered little improvement to his chronic auditory hallucinations. Clozapine was temporarily withheld during further neurologic workup, in which both electroencephalogram (EEG) and brain magnetic resonance imaging were unremarkable. After 60 hours, clozapine titration was reinitiated, and valproic acid was started for mood stabilization and seizure prophylaxis. Mr. A was discharged 6 weeks later on clozapine, 600 mg at bedtime, and extended‐release divalproate, 2500 mg at bedtime. The patient suffered no further seizure activity throughout hospitalization and for at least 1 year postdischarge.
Seizures complicate clozapine use in up to 5% of cases, with a dose‐dependent risk pattern.[16] Seizures are most commonly associated with serum clozapine levels above 500 g/L), but have also been reported with lower levels of clozapine and its metabolite norclozapine.[17] Though nonspecific EEG changes (ie, focal or generalized spikes, spike‐wave and polyspike discharges) have been associated with clozapine administration, they do not reliably predict seizure tendency.[17] Prophylaxis with antiepileptic drugs (AEDs) is not recommended, though AED treatment may be undertaken for patients who experience a seizure while on clozapine. When seizures occur in the context of elevated serum levels, reducing clozapine to the lowest effective dose is preferred over initiating an AED. Although this reduces the potential for exposure to anticonvulsant‐associated adverse effects, it may also introduce the risk of relapsed psychotic symptoms, and therefore requires close monitoring by a psychiatrist. For those who opt to initiate AED therapy, we recommend consideration of each medication's therapeutic and side‐effect profiles based on the patient's medical history and active symptoms. For example, in the case of Mr. A, valproate was used to target concomitant mood symptoms; likewise, patients who experience troublesome weight gain, as well as seizures, may benefit from topiramate. The occurrence of seizures does not preclude continuation of clozapine therapy, in conjunction with an AED[18] and after consideration of potential risks and benefits of use. Clozapine is not contraindicated in patients with well‐controlled epilepsy.[19]
Sedation, the most common neurologic side effect of clozapine, is also dose dependent and often abates during titration.[20] Though clozapine may induce extrapyramidal symptoms, including rigidity, tremor, and dystonia, the risk is considerably lower with clozapine than other antipsychotics, owing to a lesser affinity for D2 receptors. Associated parkinsonism should prompt consideration of dose reduction, in discussion with a psychiatrist, with concurrent monitoring of serum clozapine levels and close follow‐up for emergence of psychotic symptoms. If dose reduction is ineffective, not indicated, or not preferred by the patient, the addition of an anticholinergic medication may be considered (eg, diphenhydramine 2550 mg, benztropine 12 mg). Neuroleptic malignant syndrome, although rare, is life‐threatening and warrants immediate discontinuation of clozapine, though successful rechallenge after has been reported in case reports.[21]
CARDIAC
Case Vignette 2
Mr. B is a 34‐year‐old man with sinus tachycardia, a benign adrenal tumor, and chronic paranoid schizophrenia that had been poorly responsive to numerous antipsychotic trials. During a psychiatric hospitalization for paranoid delusions with aggressive threats toward family, Mr. B was started on clozapine and titrated to 250 mg daily. On day 16 of clozapine therapy, the patient began to experience cough, and several days later, diffuse rhonchi were noted on examination. Complete blood count revealed WBC 20.3 * 103/L, with 37% eosinophils and absolute eosinophil count of 7.51 (increased from 12%/1.90 the week before), and an electrocardiogram showed sinus tachycardia with ST‐segment changes. Mr. B was transferred to the general medical hospital for workup of presumed myocarditis.
Approximately one‐quarter of patients who take clozapine experience sinus tachycardia, which may be related to clozapine's anticholinergic effects causing rebound noradrenergic elevations[22]; persistent or problematic tachycardia may be treated using a cardio‐selective ‐blocker. Clozapine has also been linked to significant increases in systolic and diastolic blood pressure in 4% of patients (monitoring data); the risk of hypertension increases with the duration of clozapine treatment, and appears to be independent of the patient's weight.[23] Orthostatic hypotension has been reported in 9% of patients on clozapine therapy, though effects can be mitigated with gradual titration, adequate hydration, compression stockings, and patient education. Sinus tachycardia, hypertension, and orthostatic hypotension are not absolute indications to discontinue clozapine; rather, we advocate for treating these side effects while continuing clozapine treatment.[24]
Myocarditis represents the most serious cardiac side effect of clozapine.[25, 26] Although the absolute risk appears to be lower than 0.1%,[24] Kilian et al. calculated a 1000‐to‐2000fold increase in relative risk of myocarditis among patients who take clozapine, compared to the general population.[26] Most cases occur within the first month of treatment, with median time to onset of 15 days. This time course is consistent with an acute immunoglobulin Emediated hypersensitivity (type 1) reaction, and eosinophilic infiltrates have been found on autopsy, consistent with an acute drug reaction.[20]
Because of this early onset, the physician should maintain a particularly high index of suspicion in the first months of treatment, rigorously questioning patients and families about signs and symptoms of cardiac disease. If patients on clozapine present with flu‐like symptoms, fever, myalgia, dizziness, chest pain, dyspnea, tachycardia, palpitations, or other signs or symptoms of heart failure, evaluation for myocarditis should be undertaken.[25] Several centers have utilized cardiac enzymes (e.g., troponin I, troponin T, creatine kinase‐myocardial band) as a universal screen for myocarditis, though this is not a universal practice.[24] Both tachycardia and flu‐like symptoms may be associated with clozapine, particularly during the titration period, and these are normally benign symptoms requiring no intervention. If the diagnosis of myocarditis is made, however, clozapine should be stopped immediately. Myocarditis is often considered to be a contraindication to restarting clozapine, though cases have been reported of successful clozapine rechallenge in patients who had previously experienced myocarditis.[21]
Recommendations for clozapine‐associated electrocardiography (ECG) monitoring have not been standardized. Based on common clinical practice and the time course of serious cardiac complications, we recommend baseline ECG prior to the start of clozapine, with follow‐up ECG 2 to 4 weeks after clozapine initiation, and every 6 months thereafter.
GASTROINTESTINAL
Case Vignette 3
Mr. C is a 61‐year‐old man with chronic paranoid schizophrenia and a history of multiple‐state hospital admissions. He had been maintained on clozapine for 15 years, allowing him to live independently and avoid psychiatric hospitalization. Mr. C was admitted to the general medical hospital with nausea, vomiting, and an inability to tolerate oral intake. He was found to have a high‐grade small‐bowel obstruction, and all oral medications were initially discontinued. After successful management of his acute gastrointestinal presentation and discussion of potential risks and benefits of various treatment options, clozapine was reinitiated along with bulk laxative and stool softening agents.
Affecting 14% to 60% of individuals who are prescribed clozapine, constipation represents the most common associated gastrointestinal complaint.[27] For most patients, this condition is uncomfortable but nonlethal, though it has been implicated in several deaths by aspiration pneumonia and small‐bowel perforation.[28, 29] Providers must screen regularly for constipation and treat aggressively with stimulant laxatives and stool softeners,[18] while reviewing medication lists and, when possible, streamlining extraneous anticholinergic contributors. Clozapine‐prescribed individuals also frequently suffer from gastrointestinal reflux disease (GERD), for which behavioral interventions (eg, smoking cessation or remaining upright for 3 hours after meals) should be considered in addition to pharmacologic treatment with proton pump inhibitors. Clozapine therapy may be continued while constipation and GERD are managed medically.
Potentially fatal gastrointestinal hypomotility and small‐bowel obstruction are rare but well‐described complications that occur in up to 0.3% of patients who take clozapine.[27] This effect appears to be dose dependent, and higher blood levels are associated with greater severity of constipation and risk for serious hypomotility.[27] Clozapine should be withheld during treatment for such serious adverse events as ileus or small‐bowel perforation; however, once these conditions have stabilized, clozapine therapy may be reconsidered based on an analysis of potential benefits and risks. If clozapine is withheld, the internist must monitor for acute worsening of mental status, inattention, and disorientation, as clozapine withdrawal‐related delirium has been reported.[30] Ultimately, aggressive treatment of constipation in conjunction with continued clozapine therapy is the recommended course of action.[28]
Given the increased risk of ileus in the postoperative period, it is particularly important for physicians to inquire about preoperative bowel habits and assess for any existing constipation. Careful monitoring of postoperative bowel motility, along with early and aggressive management of constipation, is recommended. Concurrent administration of other constipating agents (eg, opiates, anticholinergics) should be limited to the lowest effective dose.[27] Although transaminitis, hepatitis, and pancreatitis have all been associated with clozapine in case reports, these are rare,[31] and the approach to management should be considered on a case‐by‐case basis.
HEMATOLOGIC
Case Vignette 4
Ms. D is a 38‐year‐old woman with a schizoaffective disorder who was started on clozapine after 3 other agents had failed to control her psychotic symptoms and alleviate chronic suicidal thoughts. Baseline CBC revealed serum white blood cell count (WBC) of 7800/mm3 and absolute neutrophil count (ANC) of 4700/mm3. In Ms. D's third week of clozapine use, WBC dropped to 4400/mm3 and ANC to 2200/mm3. Repeat lab draw confirmed this, prompting the treatment team to initiate twice‐weekly CBC monitoring. Ms. D's counts continued to fall, and 10 days after the initial drop, WBC was calculated at 1400/mm3 and ANC at 790/mm3. Clozapine was discontinued, and though the patient was asymptomatic, broad‐spectrum antibiotics were initiated. She received daily CBC monitoring until WBC >3000/mm3 and ANC >1500/mm3. An alternate psychotropic medication was initiated several weeks thereafter.
Neutropenia (white blood cell count <3000/mm3) is a common complication that affects approximately 3% of patients who take clozapine.[32] This may be mediated by clozapine's selective impact on the precursors of polymorphonuclear leukocytes, though the mechanism remains unknown.[33] Although neutropenia is not an absolute contraindication for clozapine therapy, guidelines recommend cessation of clozapine when the ANC drops below 1000/mm3.[34] A meta‐analysis of 112 patients who were rechallenged following neutropenia found that 69% tolerated a rechallenge without development of a subsequent dyscrasia.[21]
In the case of chemotherapy‐induced neutropenia, several case reports support the continued use of clozapine during cancer treatment[35]; this requires a written request to the pharmaceutical company that manufactures clozapine and documentation of the expected time course and contribution of chemotherapy to neutropenia.[36] Clozapine's association with neutropenia warrants close monitoring in individuals with human immunodeficiency virus (HIV) and other causes of immune compromise. Reports of clozapine continuation in HIV‐positive individuals underscore the importance of close collaboration between infectious disease and psychiatry, with specific focus on potential interactions between clozapine and antiretroviral agents and close monitoring of viral load and ANC.[37]
The most feared complication of clozapine remains agranulocytosis, defined as ANC<500/mm3,[33] which occurs in up to 1% of monitored patients. In 1975, clozapine was banned worldwide after 8 fatal cases of agranulocytosis were reported in Finland.[38] The drug was reintroduced for treatment‐resistant schizophrenia with strict monitoring parameters, which has sharply reduced the death rate. One study found 12 actual deaths between 1990 and 1994, compared to the 149 predicted deaths without monitoring.[39]
The risk of agranulocytosis appears to be higher in older adults and in patients with a lower baseline WBC count. Although there are reports of delayed agranulocytosis occurring in patients after up to 19 years of treatment,[40] the incidence of leukopenia is greatest in the first year. Given this high‐risk period, mandatory monitoring is as follows: weekly WBC and neutrophil counts for the first 26 weeks, biweekly counts for the second 26 weeks, and every 4 weeks thereafter. Of note, many of the later cases of agranulocytosis appear to be related to medication coadministration, particularly with valproic acid, though no definitive link has been established.[40]
Treatment of clozapine‐induced agranulocytosis consists of immediate clozapine cessation, and consideration of initiation of prophylactic broad‐spectrum antibiotics and granulocyte colony‐stimulating factor (such as filgrastim) until the granulocyte count normalizes.[41, 42] Although few case reports describe successful clozapine rechallenge in patients with a history of agranulocytosis, the data are sparse, and current practice is to permanently discontinue clozapine if ANC falls below 1000/mm3.[21, 41]
ADDITIONAL COMPLICATIONS (METABOLIC, RENAL, URINARY)
Moderate to marked weight gain occurs in over 50% of patients treated with clozapine, with average gains of nearly 10% body weight.[43] In a 10‐year follow‐up study of patients treated with clozapine, Henderson et al. reported an average weight gain of 13 kg, with 34% percent of studied patients developing diabetes mellitus. Metabolic side effects of second‐generation antipsychotics, including clozapine, are a well‐documented and troubling phenomenon.[44] Limited evidence supports use of metformin, alongside behavioral therapy, for concerns related to glucose dysregulation.[45] Some patients have also experienced weight loss with adjunctive topiramate use, particularly if they have also suffered seizures.[46]
Urinary incontinence and nocturnal enuresis are both associated with clozapine, but are likely under‐reported because of patient and provider embarrassment; providers also may not think to ask about these specific symptoms. First‐line treatment for nocturnal enuresis is to limit fluids in the evening. Desmopressin has a controversial role in treating nocturnal enuresis owing to its risk of hyponatremia; appropriate monitoring should be implemented if this agent is used.[18]
Clozapine has been associated with acute interstitial nephritis (AIN), although this is thought to be a relatively rare side effect. Drug‐induced AIN typically appears soon after initiation and presents with the clinical triad of rash, fever, and eosinophilia. Given that weekly CBC is mandatory in the initiation phase, eosinophilia is easily detectible and may serve as a marker for potential AIN.[47]
Sialorrhea, particularly during sleep, is a bothersome condition affecting up to one‐third of patients who take clozapine.[48] Although clozapine is strongly anticholinergic, its agonist activity at the M4 muscarinic receptor and antagonism of the alpha‐2 adrenergic receptor are postulated as the mechanisms underlying hypersalivation. Sialorrhea is frequently seen early in treatment and does not appear to be dose dependent.[48] Excessive salivation is typically managed with behavioral interventions (eg, utilizing towels or other absorbent materials on top of bedding). If hypersalivation occurs during the day, chewing sugar‐free gum may increase the rate of swallowing and make symptoms less bothersome. If this does not provide adequate relief, practitioners may consider use of atropine 1% solution administered directly to the oral cavity.[49]
DRUG‐DRUG INTERACTIONS
For hospitalists, who must frequently alter existing medications or add new ones, awareness of potential drug‐drug interactions is crucial. Clozapine is metabolized by the cytochrome p450 system, with predominant metabolism through the isoenzymes 1A2, 3A4, and 2D6.[50] Common medications that induce clozapine metabolism (thereby decreasing clozapine levels) include phenytoin, phenobarbital, carbamazepine, oxcarbazepine, and corticosteroids. Conversely, stopping these medications after long‐term therapy will raise clozapine levels. Substances that inhibit clozapine metabolism (thereby increasing clozapine levels) include ciprofloxacin, erythromycin, clarithromycin, fluvoxamine, fluoxetine, paroxetine, protease inhibitors, verapamil, and grapefruit juice. We recommend caution when concurrently administering other agents that increase risk for agranulocytosis, including carbamazepine, trimethoprim‐sulfamethoxazole, sulfasalazine, and tricyclic antidepressants.
Cigarette smoking decreases clozapine blood levels by induction of CYP1A2. Patients require a 10% to 30% reduction to clozapine dose during periods of smoking cessation, including when smoking is stopped during inpatient hospitalization.[51] Nicotine replacement therapy does not induce CYP1A2 and therefore does not have a compensatory effect on clozapine levels. On discharge or resumption of smoking, patients may require an increase of their dose of clozapine to maintain adequate antipsychotic effect.
SUMMARY OF RECOMMENDATIONS
Medical complications are cited as the cause in 20% of clozapine discontinuations; most commonly, these include seizures, severe constipation, somnolence, and neutropenia. Given the high risk of psychiatric morbidity posed by discontinuation, we recommend managing mild‐moderate symptoms and side effects while continuing the drug, when possible (Table 1). We encourage hospitalists to confer with the patient's psychiatrist or the inpatient psychiatry consultation service when making changes to clozapine therapy. Specific recommendations are as follows:
- We advocate withholding clozapine administration pending medical optimization for several conditions, including: small‐bowel obstruction, neuroleptic malignant syndrome, venous thromboembolism, diabetic ketoacidosis, or hyperosmolar coma.
- Clinical scenarios requiring acute discontinuation of clozapine include agranulocytosis and myocarditis. Successful rechallenge with clozapine has been described after both conditions; at the same time, given the high morbidity and mortality of myocarditis and agranulocytosis, re‐initiation of clozapine requires an extensive risk‐benefit discussion with the patient and family, informed consent, and, in the case of agranulocytosis, approval from the national clozapine registry (Table 2).
- Although adjunctive therapy with filgrastim was initially thought to permit a clozapine rechallenge in patients with a history of agranulocytosis, case reports on this strategy have been equivocal, and further research is necessary to determine the most effective strategy for management.
| Clinical Lab/Study | Frequency of Monitoring | |
|---|---|---|
| Cardiac | Electrocardiogram | Baseline, 24 weeks after initiation, every 6 months thereafter |
| Cardiac enzymes (eg, troponin I) echocardiogram | No standard guidelines, unless clinically indicated | |
| Hematologic | Complete blood count with differential | Baseline, then weekly 26 weeks, then every 2 weeks 26 weeks, then every 4 weeks thereafter |
| Metabolic | Body mass index; circumference of waist | Baseline, then every 3 to 6 months |
| Fasting glucose | Baseline, then every 6 months | |
| Fasting lipid panel | Baseline, then yearly | |
| Neurologic | Electroencephalogram | No standard guidelines, unless clinically indicated |
| Vital signs | Heart rate, blood pressure, temperature | Baseline and at each follow‐up visit |
| Requires Acute Clozapine Discontinuation* | Clozapine Interruption During Management | Does Not Typically Require Clozapine Discontinuation |
|---|---|---|
| ||
| Agranulocytosis (ANC<1.0 109/mm3) | Diabetic complications (eg, ketoacidosis, hyperosmolar coma) | Constipation |
| Cardiomyopathy (severe) | Gastrointestinal obstruction, ileus | Diabetes mellitus |
| Myocarditis | Neuroleptic malignant syndrome | Gastroesophageal Reflux |
| Venous thromboembolism | Hyperlipidemia | |
| Hypertension | ||
| Orthostatic hypotension | ||
| Sedation | ||
| Seizures | ||
| Sialorrhea | ||
| Sinus tachycardia | ||
| Urinary changes (eg, enuresis, incontinence) | ||
| Weight gain | ||
CONCLUSION
Clozapine has been a very successful treatment for patients with schizophrenia who have failed other antipsychotic therapies. However, fears of potential side effects and frequent monitoring have limited its use and led to unnecessary discontinuation. To mitigate risk for serious complications, we hope to increase hospitalists' awareness of prevention, monitoring, and treatment of side effects, and to promote comfort with circumstances that warrant continuation or discontinuation of clozapine (Table 3). The hospitalist plays a crucial role in managing these complications as well as conveying information and recommendations to primary care providers; as such, their familiarity with the medication is essential for proper management of individuals who take clozapine.
| Take‐Home Points |
|---|
| 1. Clozapine is the gold standard for treatment‐resistant schizophrenia; however, its use is limited by side effects, many of which can be successfully treated by internists. |
| 2. There are few indications for discontinuing clozapine (myocarditis, small‐bowel obstruction, agranulocytosis). The psychiatry service should be consulted in the event that clozapine is discontinued. |
| 3. Seizures are not an indication for discontinuing clozapine; instead, we recommend adding an antiepileptic drug. |
| 4. All second‐generation antipsychotics are associated with diabetes mellitus and significant weight gain. Clozapine is more highly associated with metabolic side effects than many other medications in this class. |
| 5. Sedation, sialorrhea, and constipation are common and can be managed pharmacologically and with behavioral interventions. |
Disclosure: Nothing to report.
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Clozapine is a second‐generation antipsychotic (SGA) medication that was developed in 1959, introduced to Europe in 1971, and withdrawn from the market in 1975 due to associated concerns for potentially fatal agranulocytosis. In 1989, the US Food and Drug Administration (FDA) approved use of clozapine for the management of treatment‐resistant schizophrenia, under strict parameters for complete blood count (CBC) monitoring. Clozapine has since gained an additional FDA indication for reducing suicidal behavior in patients with schizophrenia and schizoaffective disorder,[1, 2, 3] and displayed superiority to both first generation antipsychotics and other SGA agents in reducing symptom burden.[2, 4, 5]
Clozapine's clinical benefits include lowering mortality in schizophrenia,[6] reducing deaths from ischemic heart disease,[7] curtailing substance use in individuals with psychotic disorders,[8] increasing rates of independent living and meaningful occupational activity, and reducing psychiatric hospitalizations and need for involuntary treatment.[9] Because schizophrenia, itself, is associated with a 15‐ to 20‐year decrease in average lifespan,[10] these benefits of clozapine are particularly salient. Yet the mechanism by which clozapine mitigates otherwise‐refractory psychotic symptoms is a conundrum. Structurally a tricyclic dibenzodiazepine, clozapine has relatively little effect on the dopamine D2 receptor, which has classically been thought to mediate the treatment effect of antipsychotics.[11, 12]
The unique nature of clozapine extends to its adverse effect profile. A significant percentage of patients who discontinue clozapine (17%35.4%) cite medical complications, the most common being seizures, constipation, sedation, and neutropenia.[13, 14] Yet several studies, including the landmark Clinical Antipsychotic Trials for Interventions Effectiveness (CATIE) study, have found that patients were more likely to adhere to clozapine therapy than to other antipsychotics.[2, 15] In the CATIE study, 44% of subjects taking clozapine continued the medication for 18 months, compared to 29% of individuals on olanzapine, 14% on risperidone, and 7% on quetiapine. Median time until discontinuation of clozapine was 10.5 months, significantly longer than for quetiapine (2.8 months) and olanzapine (2.7 months).[2] Because patients who experience clozapine‐related medical complications are likely to present first to the primary care or general hospital setting, internists must be aware of potential iatrogenic effects, and of their implications for psychiatric and medical care. Using case examples, we will examine both common and serious complications associated with clozapine, and discuss recommendations for management, including indications for clozapine discontinuation.
NEUROLOGICAL
Case Vignette 1
Mr. A is a 29‐year‐old man with asthma and schizophrenia who experienced a generalized tonic‐clonic seizure during treatment at a psychiatric facility. The patient started clozapine therapy 5 weeks prior, with gradual titration to 425 mg daily. Mr. A's previous medication trials included olanzapine and chlorpromazine, which rendered little improvement to his chronic auditory hallucinations. Clozapine was temporarily withheld during further neurologic workup, in which both electroencephalogram (EEG) and brain magnetic resonance imaging were unremarkable. After 60 hours, clozapine titration was reinitiated, and valproic acid was started for mood stabilization and seizure prophylaxis. Mr. A was discharged 6 weeks later on clozapine, 600 mg at bedtime, and extended‐release divalproate, 2500 mg at bedtime. The patient suffered no further seizure activity throughout hospitalization and for at least 1 year postdischarge.
Seizures complicate clozapine use in up to 5% of cases, with a dose‐dependent risk pattern.[16] Seizures are most commonly associated with serum clozapine levels above 500 g/L), but have also been reported with lower levels of clozapine and its metabolite norclozapine.[17] Though nonspecific EEG changes (ie, focal or generalized spikes, spike‐wave and polyspike discharges) have been associated with clozapine administration, they do not reliably predict seizure tendency.[17] Prophylaxis with antiepileptic drugs (AEDs) is not recommended, though AED treatment may be undertaken for patients who experience a seizure while on clozapine. When seizures occur in the context of elevated serum levels, reducing clozapine to the lowest effective dose is preferred over initiating an AED. Although this reduces the potential for exposure to anticonvulsant‐associated adverse effects, it may also introduce the risk of relapsed psychotic symptoms, and therefore requires close monitoring by a psychiatrist. For those who opt to initiate AED therapy, we recommend consideration of each medication's therapeutic and side‐effect profiles based on the patient's medical history and active symptoms. For example, in the case of Mr. A, valproate was used to target concomitant mood symptoms; likewise, patients who experience troublesome weight gain, as well as seizures, may benefit from topiramate. The occurrence of seizures does not preclude continuation of clozapine therapy, in conjunction with an AED[18] and after consideration of potential risks and benefits of use. Clozapine is not contraindicated in patients with well‐controlled epilepsy.[19]
Sedation, the most common neurologic side effect of clozapine, is also dose dependent and often abates during titration.[20] Though clozapine may induce extrapyramidal symptoms, including rigidity, tremor, and dystonia, the risk is considerably lower with clozapine than other antipsychotics, owing to a lesser affinity for D2 receptors. Associated parkinsonism should prompt consideration of dose reduction, in discussion with a psychiatrist, with concurrent monitoring of serum clozapine levels and close follow‐up for emergence of psychotic symptoms. If dose reduction is ineffective, not indicated, or not preferred by the patient, the addition of an anticholinergic medication may be considered (eg, diphenhydramine 2550 mg, benztropine 12 mg). Neuroleptic malignant syndrome, although rare, is life‐threatening and warrants immediate discontinuation of clozapine, though successful rechallenge after has been reported in case reports.[21]
CARDIAC
Case Vignette 2
Mr. B is a 34‐year‐old man with sinus tachycardia, a benign adrenal tumor, and chronic paranoid schizophrenia that had been poorly responsive to numerous antipsychotic trials. During a psychiatric hospitalization for paranoid delusions with aggressive threats toward family, Mr. B was started on clozapine and titrated to 250 mg daily. On day 16 of clozapine therapy, the patient began to experience cough, and several days later, diffuse rhonchi were noted on examination. Complete blood count revealed WBC 20.3 * 103/L, with 37% eosinophils and absolute eosinophil count of 7.51 (increased from 12%/1.90 the week before), and an electrocardiogram showed sinus tachycardia with ST‐segment changes. Mr. B was transferred to the general medical hospital for workup of presumed myocarditis.
Approximately one‐quarter of patients who take clozapine experience sinus tachycardia, which may be related to clozapine's anticholinergic effects causing rebound noradrenergic elevations[22]; persistent or problematic tachycardia may be treated using a cardio‐selective ‐blocker. Clozapine has also been linked to significant increases in systolic and diastolic blood pressure in 4% of patients (monitoring data); the risk of hypertension increases with the duration of clozapine treatment, and appears to be independent of the patient's weight.[23] Orthostatic hypotension has been reported in 9% of patients on clozapine therapy, though effects can be mitigated with gradual titration, adequate hydration, compression stockings, and patient education. Sinus tachycardia, hypertension, and orthostatic hypotension are not absolute indications to discontinue clozapine; rather, we advocate for treating these side effects while continuing clozapine treatment.[24]
Myocarditis represents the most serious cardiac side effect of clozapine.[25, 26] Although the absolute risk appears to be lower than 0.1%,[24] Kilian et al. calculated a 1000‐to‐2000fold increase in relative risk of myocarditis among patients who take clozapine, compared to the general population.[26] Most cases occur within the first month of treatment, with median time to onset of 15 days. This time course is consistent with an acute immunoglobulin Emediated hypersensitivity (type 1) reaction, and eosinophilic infiltrates have been found on autopsy, consistent with an acute drug reaction.[20]
Because of this early onset, the physician should maintain a particularly high index of suspicion in the first months of treatment, rigorously questioning patients and families about signs and symptoms of cardiac disease. If patients on clozapine present with flu‐like symptoms, fever, myalgia, dizziness, chest pain, dyspnea, tachycardia, palpitations, or other signs or symptoms of heart failure, evaluation for myocarditis should be undertaken.[25] Several centers have utilized cardiac enzymes (e.g., troponin I, troponin T, creatine kinase‐myocardial band) as a universal screen for myocarditis, though this is not a universal practice.[24] Both tachycardia and flu‐like symptoms may be associated with clozapine, particularly during the titration period, and these are normally benign symptoms requiring no intervention. If the diagnosis of myocarditis is made, however, clozapine should be stopped immediately. Myocarditis is often considered to be a contraindication to restarting clozapine, though cases have been reported of successful clozapine rechallenge in patients who had previously experienced myocarditis.[21]
Recommendations for clozapine‐associated electrocardiography (ECG) monitoring have not been standardized. Based on common clinical practice and the time course of serious cardiac complications, we recommend baseline ECG prior to the start of clozapine, with follow‐up ECG 2 to 4 weeks after clozapine initiation, and every 6 months thereafter.
GASTROINTESTINAL
Case Vignette 3
Mr. C is a 61‐year‐old man with chronic paranoid schizophrenia and a history of multiple‐state hospital admissions. He had been maintained on clozapine for 15 years, allowing him to live independently and avoid psychiatric hospitalization. Mr. C was admitted to the general medical hospital with nausea, vomiting, and an inability to tolerate oral intake. He was found to have a high‐grade small‐bowel obstruction, and all oral medications were initially discontinued. After successful management of his acute gastrointestinal presentation and discussion of potential risks and benefits of various treatment options, clozapine was reinitiated along with bulk laxative and stool softening agents.
Affecting 14% to 60% of individuals who are prescribed clozapine, constipation represents the most common associated gastrointestinal complaint.[27] For most patients, this condition is uncomfortable but nonlethal, though it has been implicated in several deaths by aspiration pneumonia and small‐bowel perforation.[28, 29] Providers must screen regularly for constipation and treat aggressively with stimulant laxatives and stool softeners,[18] while reviewing medication lists and, when possible, streamlining extraneous anticholinergic contributors. Clozapine‐prescribed individuals also frequently suffer from gastrointestinal reflux disease (GERD), for which behavioral interventions (eg, smoking cessation or remaining upright for 3 hours after meals) should be considered in addition to pharmacologic treatment with proton pump inhibitors. Clozapine therapy may be continued while constipation and GERD are managed medically.
Potentially fatal gastrointestinal hypomotility and small‐bowel obstruction are rare but well‐described complications that occur in up to 0.3% of patients who take clozapine.[27] This effect appears to be dose dependent, and higher blood levels are associated with greater severity of constipation and risk for serious hypomotility.[27] Clozapine should be withheld during treatment for such serious adverse events as ileus or small‐bowel perforation; however, once these conditions have stabilized, clozapine therapy may be reconsidered based on an analysis of potential benefits and risks. If clozapine is withheld, the internist must monitor for acute worsening of mental status, inattention, and disorientation, as clozapine withdrawal‐related delirium has been reported.[30] Ultimately, aggressive treatment of constipation in conjunction with continued clozapine therapy is the recommended course of action.[28]
Given the increased risk of ileus in the postoperative period, it is particularly important for physicians to inquire about preoperative bowel habits and assess for any existing constipation. Careful monitoring of postoperative bowel motility, along with early and aggressive management of constipation, is recommended. Concurrent administration of other constipating agents (eg, opiates, anticholinergics) should be limited to the lowest effective dose.[27] Although transaminitis, hepatitis, and pancreatitis have all been associated with clozapine in case reports, these are rare,[31] and the approach to management should be considered on a case‐by‐case basis.
HEMATOLOGIC
Case Vignette 4
Ms. D is a 38‐year‐old woman with a schizoaffective disorder who was started on clozapine after 3 other agents had failed to control her psychotic symptoms and alleviate chronic suicidal thoughts. Baseline CBC revealed serum white blood cell count (WBC) of 7800/mm3 and absolute neutrophil count (ANC) of 4700/mm3. In Ms. D's third week of clozapine use, WBC dropped to 4400/mm3 and ANC to 2200/mm3. Repeat lab draw confirmed this, prompting the treatment team to initiate twice‐weekly CBC monitoring. Ms. D's counts continued to fall, and 10 days after the initial drop, WBC was calculated at 1400/mm3 and ANC at 790/mm3. Clozapine was discontinued, and though the patient was asymptomatic, broad‐spectrum antibiotics were initiated. She received daily CBC monitoring until WBC >3000/mm3 and ANC >1500/mm3. An alternate psychotropic medication was initiated several weeks thereafter.
Neutropenia (white blood cell count <3000/mm3) is a common complication that affects approximately 3% of patients who take clozapine.[32] This may be mediated by clozapine's selective impact on the precursors of polymorphonuclear leukocytes, though the mechanism remains unknown.[33] Although neutropenia is not an absolute contraindication for clozapine therapy, guidelines recommend cessation of clozapine when the ANC drops below 1000/mm3.[34] A meta‐analysis of 112 patients who were rechallenged following neutropenia found that 69% tolerated a rechallenge without development of a subsequent dyscrasia.[21]
In the case of chemotherapy‐induced neutropenia, several case reports support the continued use of clozapine during cancer treatment[35]; this requires a written request to the pharmaceutical company that manufactures clozapine and documentation of the expected time course and contribution of chemotherapy to neutropenia.[36] Clozapine's association with neutropenia warrants close monitoring in individuals with human immunodeficiency virus (HIV) and other causes of immune compromise. Reports of clozapine continuation in HIV‐positive individuals underscore the importance of close collaboration between infectious disease and psychiatry, with specific focus on potential interactions between clozapine and antiretroviral agents and close monitoring of viral load and ANC.[37]
The most feared complication of clozapine remains agranulocytosis, defined as ANC<500/mm3,[33] which occurs in up to 1% of monitored patients. In 1975, clozapine was banned worldwide after 8 fatal cases of agranulocytosis were reported in Finland.[38] The drug was reintroduced for treatment‐resistant schizophrenia with strict monitoring parameters, which has sharply reduced the death rate. One study found 12 actual deaths between 1990 and 1994, compared to the 149 predicted deaths without monitoring.[39]
The risk of agranulocytosis appears to be higher in older adults and in patients with a lower baseline WBC count. Although there are reports of delayed agranulocytosis occurring in patients after up to 19 years of treatment,[40] the incidence of leukopenia is greatest in the first year. Given this high‐risk period, mandatory monitoring is as follows: weekly WBC and neutrophil counts for the first 26 weeks, biweekly counts for the second 26 weeks, and every 4 weeks thereafter. Of note, many of the later cases of agranulocytosis appear to be related to medication coadministration, particularly with valproic acid, though no definitive link has been established.[40]
Treatment of clozapine‐induced agranulocytosis consists of immediate clozapine cessation, and consideration of initiation of prophylactic broad‐spectrum antibiotics and granulocyte colony‐stimulating factor (such as filgrastim) until the granulocyte count normalizes.[41, 42] Although few case reports describe successful clozapine rechallenge in patients with a history of agranulocytosis, the data are sparse, and current practice is to permanently discontinue clozapine if ANC falls below 1000/mm3.[21, 41]
ADDITIONAL COMPLICATIONS (METABOLIC, RENAL, URINARY)
Moderate to marked weight gain occurs in over 50% of patients treated with clozapine, with average gains of nearly 10% body weight.[43] In a 10‐year follow‐up study of patients treated with clozapine, Henderson et al. reported an average weight gain of 13 kg, with 34% percent of studied patients developing diabetes mellitus. Metabolic side effects of second‐generation antipsychotics, including clozapine, are a well‐documented and troubling phenomenon.[44] Limited evidence supports use of metformin, alongside behavioral therapy, for concerns related to glucose dysregulation.[45] Some patients have also experienced weight loss with adjunctive topiramate use, particularly if they have also suffered seizures.[46]
Urinary incontinence and nocturnal enuresis are both associated with clozapine, but are likely under‐reported because of patient and provider embarrassment; providers also may not think to ask about these specific symptoms. First‐line treatment for nocturnal enuresis is to limit fluids in the evening. Desmopressin has a controversial role in treating nocturnal enuresis owing to its risk of hyponatremia; appropriate monitoring should be implemented if this agent is used.[18]
Clozapine has been associated with acute interstitial nephritis (AIN), although this is thought to be a relatively rare side effect. Drug‐induced AIN typically appears soon after initiation and presents with the clinical triad of rash, fever, and eosinophilia. Given that weekly CBC is mandatory in the initiation phase, eosinophilia is easily detectible and may serve as a marker for potential AIN.[47]
Sialorrhea, particularly during sleep, is a bothersome condition affecting up to one‐third of patients who take clozapine.[48] Although clozapine is strongly anticholinergic, its agonist activity at the M4 muscarinic receptor and antagonism of the alpha‐2 adrenergic receptor are postulated as the mechanisms underlying hypersalivation. Sialorrhea is frequently seen early in treatment and does not appear to be dose dependent.[48] Excessive salivation is typically managed with behavioral interventions (eg, utilizing towels or other absorbent materials on top of bedding). If hypersalivation occurs during the day, chewing sugar‐free gum may increase the rate of swallowing and make symptoms less bothersome. If this does not provide adequate relief, practitioners may consider use of atropine 1% solution administered directly to the oral cavity.[49]
DRUG‐DRUG INTERACTIONS
For hospitalists, who must frequently alter existing medications or add new ones, awareness of potential drug‐drug interactions is crucial. Clozapine is metabolized by the cytochrome p450 system, with predominant metabolism through the isoenzymes 1A2, 3A4, and 2D6.[50] Common medications that induce clozapine metabolism (thereby decreasing clozapine levels) include phenytoin, phenobarbital, carbamazepine, oxcarbazepine, and corticosteroids. Conversely, stopping these medications after long‐term therapy will raise clozapine levels. Substances that inhibit clozapine metabolism (thereby increasing clozapine levels) include ciprofloxacin, erythromycin, clarithromycin, fluvoxamine, fluoxetine, paroxetine, protease inhibitors, verapamil, and grapefruit juice. We recommend caution when concurrently administering other agents that increase risk for agranulocytosis, including carbamazepine, trimethoprim‐sulfamethoxazole, sulfasalazine, and tricyclic antidepressants.
Cigarette smoking decreases clozapine blood levels by induction of CYP1A2. Patients require a 10% to 30% reduction to clozapine dose during periods of smoking cessation, including when smoking is stopped during inpatient hospitalization.[51] Nicotine replacement therapy does not induce CYP1A2 and therefore does not have a compensatory effect on clozapine levels. On discharge or resumption of smoking, patients may require an increase of their dose of clozapine to maintain adequate antipsychotic effect.
SUMMARY OF RECOMMENDATIONS
Medical complications are cited as the cause in 20% of clozapine discontinuations; most commonly, these include seizures, severe constipation, somnolence, and neutropenia. Given the high risk of psychiatric morbidity posed by discontinuation, we recommend managing mild‐moderate symptoms and side effects while continuing the drug, when possible (Table 1). We encourage hospitalists to confer with the patient's psychiatrist or the inpatient psychiatry consultation service when making changes to clozapine therapy. Specific recommendations are as follows:
- We advocate withholding clozapine administration pending medical optimization for several conditions, including: small‐bowel obstruction, neuroleptic malignant syndrome, venous thromboembolism, diabetic ketoacidosis, or hyperosmolar coma.
- Clinical scenarios requiring acute discontinuation of clozapine include agranulocytosis and myocarditis. Successful rechallenge with clozapine has been described after both conditions; at the same time, given the high morbidity and mortality of myocarditis and agranulocytosis, re‐initiation of clozapine requires an extensive risk‐benefit discussion with the patient and family, informed consent, and, in the case of agranulocytosis, approval from the national clozapine registry (Table 2).
- Although adjunctive therapy with filgrastim was initially thought to permit a clozapine rechallenge in patients with a history of agranulocytosis, case reports on this strategy have been equivocal, and further research is necessary to determine the most effective strategy for management.
| Clinical Lab/Study | Frequency of Monitoring | |
|---|---|---|
| Cardiac | Electrocardiogram | Baseline, 24 weeks after initiation, every 6 months thereafter |
| Cardiac enzymes (eg, troponin I) echocardiogram | No standard guidelines, unless clinically indicated | |
| Hematologic | Complete blood count with differential | Baseline, then weekly 26 weeks, then every 2 weeks 26 weeks, then every 4 weeks thereafter |
| Metabolic | Body mass index; circumference of waist | Baseline, then every 3 to 6 months |
| Fasting glucose | Baseline, then every 6 months | |
| Fasting lipid panel | Baseline, then yearly | |
| Neurologic | Electroencephalogram | No standard guidelines, unless clinically indicated |
| Vital signs | Heart rate, blood pressure, temperature | Baseline and at each follow‐up visit |
| Requires Acute Clozapine Discontinuation* | Clozapine Interruption During Management | Does Not Typically Require Clozapine Discontinuation |
|---|---|---|
| ||
| Agranulocytosis (ANC<1.0 109/mm3) | Diabetic complications (eg, ketoacidosis, hyperosmolar coma) | Constipation |
| Cardiomyopathy (severe) | Gastrointestinal obstruction, ileus | Diabetes mellitus |
| Myocarditis | Neuroleptic malignant syndrome | Gastroesophageal Reflux |
| Venous thromboembolism | Hyperlipidemia | |
| Hypertension | ||
| Orthostatic hypotension | ||
| Sedation | ||
| Seizures | ||
| Sialorrhea | ||
| Sinus tachycardia | ||
| Urinary changes (eg, enuresis, incontinence) | ||
| Weight gain | ||
CONCLUSION
Clozapine has been a very successful treatment for patients with schizophrenia who have failed other antipsychotic therapies. However, fears of potential side effects and frequent monitoring have limited its use and led to unnecessary discontinuation. To mitigate risk for serious complications, we hope to increase hospitalists' awareness of prevention, monitoring, and treatment of side effects, and to promote comfort with circumstances that warrant continuation or discontinuation of clozapine (Table 3). The hospitalist plays a crucial role in managing these complications as well as conveying information and recommendations to primary care providers; as such, their familiarity with the medication is essential for proper management of individuals who take clozapine.
| Take‐Home Points |
|---|
| 1. Clozapine is the gold standard for treatment‐resistant schizophrenia; however, its use is limited by side effects, many of which can be successfully treated by internists. |
| 2. There are few indications for discontinuing clozapine (myocarditis, small‐bowel obstruction, agranulocytosis). The psychiatry service should be consulted in the event that clozapine is discontinued. |
| 3. Seizures are not an indication for discontinuing clozapine; instead, we recommend adding an antiepileptic drug. |
| 4. All second‐generation antipsychotics are associated with diabetes mellitus and significant weight gain. Clozapine is more highly associated with metabolic side effects than many other medications in this class. |
| 5. Sedation, sialorrhea, and constipation are common and can be managed pharmacologically and with behavioral interventions. |
Disclosure: Nothing to report.
Clozapine is a second‐generation antipsychotic (SGA) medication that was developed in 1959, introduced to Europe in 1971, and withdrawn from the market in 1975 due to associated concerns for potentially fatal agranulocytosis. In 1989, the US Food and Drug Administration (FDA) approved use of clozapine for the management of treatment‐resistant schizophrenia, under strict parameters for complete blood count (CBC) monitoring. Clozapine has since gained an additional FDA indication for reducing suicidal behavior in patients with schizophrenia and schizoaffective disorder,[1, 2, 3] and displayed superiority to both first generation antipsychotics and other SGA agents in reducing symptom burden.[2, 4, 5]
Clozapine's clinical benefits include lowering mortality in schizophrenia,[6] reducing deaths from ischemic heart disease,[7] curtailing substance use in individuals with psychotic disorders,[8] increasing rates of independent living and meaningful occupational activity, and reducing psychiatric hospitalizations and need for involuntary treatment.[9] Because schizophrenia, itself, is associated with a 15‐ to 20‐year decrease in average lifespan,[10] these benefits of clozapine are particularly salient. Yet the mechanism by which clozapine mitigates otherwise‐refractory psychotic symptoms is a conundrum. Structurally a tricyclic dibenzodiazepine, clozapine has relatively little effect on the dopamine D2 receptor, which has classically been thought to mediate the treatment effect of antipsychotics.[11, 12]
The unique nature of clozapine extends to its adverse effect profile. A significant percentage of patients who discontinue clozapine (17%35.4%) cite medical complications, the most common being seizures, constipation, sedation, and neutropenia.[13, 14] Yet several studies, including the landmark Clinical Antipsychotic Trials for Interventions Effectiveness (CATIE) study, have found that patients were more likely to adhere to clozapine therapy than to other antipsychotics.[2, 15] In the CATIE study, 44% of subjects taking clozapine continued the medication for 18 months, compared to 29% of individuals on olanzapine, 14% on risperidone, and 7% on quetiapine. Median time until discontinuation of clozapine was 10.5 months, significantly longer than for quetiapine (2.8 months) and olanzapine (2.7 months).[2] Because patients who experience clozapine‐related medical complications are likely to present first to the primary care or general hospital setting, internists must be aware of potential iatrogenic effects, and of their implications for psychiatric and medical care. Using case examples, we will examine both common and serious complications associated with clozapine, and discuss recommendations for management, including indications for clozapine discontinuation.
NEUROLOGICAL
Case Vignette 1
Mr. A is a 29‐year‐old man with asthma and schizophrenia who experienced a generalized tonic‐clonic seizure during treatment at a psychiatric facility. The patient started clozapine therapy 5 weeks prior, with gradual titration to 425 mg daily. Mr. A's previous medication trials included olanzapine and chlorpromazine, which rendered little improvement to his chronic auditory hallucinations. Clozapine was temporarily withheld during further neurologic workup, in which both electroencephalogram (EEG) and brain magnetic resonance imaging were unremarkable. After 60 hours, clozapine titration was reinitiated, and valproic acid was started for mood stabilization and seizure prophylaxis. Mr. A was discharged 6 weeks later on clozapine, 600 mg at bedtime, and extended‐release divalproate, 2500 mg at bedtime. The patient suffered no further seizure activity throughout hospitalization and for at least 1 year postdischarge.
Seizures complicate clozapine use in up to 5% of cases, with a dose‐dependent risk pattern.[16] Seizures are most commonly associated with serum clozapine levels above 500 g/L), but have also been reported with lower levels of clozapine and its metabolite norclozapine.[17] Though nonspecific EEG changes (ie, focal or generalized spikes, spike‐wave and polyspike discharges) have been associated with clozapine administration, they do not reliably predict seizure tendency.[17] Prophylaxis with antiepileptic drugs (AEDs) is not recommended, though AED treatment may be undertaken for patients who experience a seizure while on clozapine. When seizures occur in the context of elevated serum levels, reducing clozapine to the lowest effective dose is preferred over initiating an AED. Although this reduces the potential for exposure to anticonvulsant‐associated adverse effects, it may also introduce the risk of relapsed psychotic symptoms, and therefore requires close monitoring by a psychiatrist. For those who opt to initiate AED therapy, we recommend consideration of each medication's therapeutic and side‐effect profiles based on the patient's medical history and active symptoms. For example, in the case of Mr. A, valproate was used to target concomitant mood symptoms; likewise, patients who experience troublesome weight gain, as well as seizures, may benefit from topiramate. The occurrence of seizures does not preclude continuation of clozapine therapy, in conjunction with an AED[18] and after consideration of potential risks and benefits of use. Clozapine is not contraindicated in patients with well‐controlled epilepsy.[19]
Sedation, the most common neurologic side effect of clozapine, is also dose dependent and often abates during titration.[20] Though clozapine may induce extrapyramidal symptoms, including rigidity, tremor, and dystonia, the risk is considerably lower with clozapine than other antipsychotics, owing to a lesser affinity for D2 receptors. Associated parkinsonism should prompt consideration of dose reduction, in discussion with a psychiatrist, with concurrent monitoring of serum clozapine levels and close follow‐up for emergence of psychotic symptoms. If dose reduction is ineffective, not indicated, or not preferred by the patient, the addition of an anticholinergic medication may be considered (eg, diphenhydramine 2550 mg, benztropine 12 mg). Neuroleptic malignant syndrome, although rare, is life‐threatening and warrants immediate discontinuation of clozapine, though successful rechallenge after has been reported in case reports.[21]
CARDIAC
Case Vignette 2
Mr. B is a 34‐year‐old man with sinus tachycardia, a benign adrenal tumor, and chronic paranoid schizophrenia that had been poorly responsive to numerous antipsychotic trials. During a psychiatric hospitalization for paranoid delusions with aggressive threats toward family, Mr. B was started on clozapine and titrated to 250 mg daily. On day 16 of clozapine therapy, the patient began to experience cough, and several days later, diffuse rhonchi were noted on examination. Complete blood count revealed WBC 20.3 * 103/L, with 37% eosinophils and absolute eosinophil count of 7.51 (increased from 12%/1.90 the week before), and an electrocardiogram showed sinus tachycardia with ST‐segment changes. Mr. B was transferred to the general medical hospital for workup of presumed myocarditis.
Approximately one‐quarter of patients who take clozapine experience sinus tachycardia, which may be related to clozapine's anticholinergic effects causing rebound noradrenergic elevations[22]; persistent or problematic tachycardia may be treated using a cardio‐selective ‐blocker. Clozapine has also been linked to significant increases in systolic and diastolic blood pressure in 4% of patients (monitoring data); the risk of hypertension increases with the duration of clozapine treatment, and appears to be independent of the patient's weight.[23] Orthostatic hypotension has been reported in 9% of patients on clozapine therapy, though effects can be mitigated with gradual titration, adequate hydration, compression stockings, and patient education. Sinus tachycardia, hypertension, and orthostatic hypotension are not absolute indications to discontinue clozapine; rather, we advocate for treating these side effects while continuing clozapine treatment.[24]
Myocarditis represents the most serious cardiac side effect of clozapine.[25, 26] Although the absolute risk appears to be lower than 0.1%,[24] Kilian et al. calculated a 1000‐to‐2000fold increase in relative risk of myocarditis among patients who take clozapine, compared to the general population.[26] Most cases occur within the first month of treatment, with median time to onset of 15 days. This time course is consistent with an acute immunoglobulin Emediated hypersensitivity (type 1) reaction, and eosinophilic infiltrates have been found on autopsy, consistent with an acute drug reaction.[20]
Because of this early onset, the physician should maintain a particularly high index of suspicion in the first months of treatment, rigorously questioning patients and families about signs and symptoms of cardiac disease. If patients on clozapine present with flu‐like symptoms, fever, myalgia, dizziness, chest pain, dyspnea, tachycardia, palpitations, or other signs or symptoms of heart failure, evaluation for myocarditis should be undertaken.[25] Several centers have utilized cardiac enzymes (e.g., troponin I, troponin T, creatine kinase‐myocardial band) as a universal screen for myocarditis, though this is not a universal practice.[24] Both tachycardia and flu‐like symptoms may be associated with clozapine, particularly during the titration period, and these are normally benign symptoms requiring no intervention. If the diagnosis of myocarditis is made, however, clozapine should be stopped immediately. Myocarditis is often considered to be a contraindication to restarting clozapine, though cases have been reported of successful clozapine rechallenge in patients who had previously experienced myocarditis.[21]
Recommendations for clozapine‐associated electrocardiography (ECG) monitoring have not been standardized. Based on common clinical practice and the time course of serious cardiac complications, we recommend baseline ECG prior to the start of clozapine, with follow‐up ECG 2 to 4 weeks after clozapine initiation, and every 6 months thereafter.
GASTROINTESTINAL
Case Vignette 3
Mr. C is a 61‐year‐old man with chronic paranoid schizophrenia and a history of multiple‐state hospital admissions. He had been maintained on clozapine for 15 years, allowing him to live independently and avoid psychiatric hospitalization. Mr. C was admitted to the general medical hospital with nausea, vomiting, and an inability to tolerate oral intake. He was found to have a high‐grade small‐bowel obstruction, and all oral medications were initially discontinued. After successful management of his acute gastrointestinal presentation and discussion of potential risks and benefits of various treatment options, clozapine was reinitiated along with bulk laxative and stool softening agents.
Affecting 14% to 60% of individuals who are prescribed clozapine, constipation represents the most common associated gastrointestinal complaint.[27] For most patients, this condition is uncomfortable but nonlethal, though it has been implicated in several deaths by aspiration pneumonia and small‐bowel perforation.[28, 29] Providers must screen regularly for constipation and treat aggressively with stimulant laxatives and stool softeners,[18] while reviewing medication lists and, when possible, streamlining extraneous anticholinergic contributors. Clozapine‐prescribed individuals also frequently suffer from gastrointestinal reflux disease (GERD), for which behavioral interventions (eg, smoking cessation or remaining upright for 3 hours after meals) should be considered in addition to pharmacologic treatment with proton pump inhibitors. Clozapine therapy may be continued while constipation and GERD are managed medically.
Potentially fatal gastrointestinal hypomotility and small‐bowel obstruction are rare but well‐described complications that occur in up to 0.3% of patients who take clozapine.[27] This effect appears to be dose dependent, and higher blood levels are associated with greater severity of constipation and risk for serious hypomotility.[27] Clozapine should be withheld during treatment for such serious adverse events as ileus or small‐bowel perforation; however, once these conditions have stabilized, clozapine therapy may be reconsidered based on an analysis of potential benefits and risks. If clozapine is withheld, the internist must monitor for acute worsening of mental status, inattention, and disorientation, as clozapine withdrawal‐related delirium has been reported.[30] Ultimately, aggressive treatment of constipation in conjunction with continued clozapine therapy is the recommended course of action.[28]
Given the increased risk of ileus in the postoperative period, it is particularly important for physicians to inquire about preoperative bowel habits and assess for any existing constipation. Careful monitoring of postoperative bowel motility, along with early and aggressive management of constipation, is recommended. Concurrent administration of other constipating agents (eg, opiates, anticholinergics) should be limited to the lowest effective dose.[27] Although transaminitis, hepatitis, and pancreatitis have all been associated with clozapine in case reports, these are rare,[31] and the approach to management should be considered on a case‐by‐case basis.
HEMATOLOGIC
Case Vignette 4
Ms. D is a 38‐year‐old woman with a schizoaffective disorder who was started on clozapine after 3 other agents had failed to control her psychotic symptoms and alleviate chronic suicidal thoughts. Baseline CBC revealed serum white blood cell count (WBC) of 7800/mm3 and absolute neutrophil count (ANC) of 4700/mm3. In Ms. D's third week of clozapine use, WBC dropped to 4400/mm3 and ANC to 2200/mm3. Repeat lab draw confirmed this, prompting the treatment team to initiate twice‐weekly CBC monitoring. Ms. D's counts continued to fall, and 10 days after the initial drop, WBC was calculated at 1400/mm3 and ANC at 790/mm3. Clozapine was discontinued, and though the patient was asymptomatic, broad‐spectrum antibiotics were initiated. She received daily CBC monitoring until WBC >3000/mm3 and ANC >1500/mm3. An alternate psychotropic medication was initiated several weeks thereafter.
Neutropenia (white blood cell count <3000/mm3) is a common complication that affects approximately 3% of patients who take clozapine.[32] This may be mediated by clozapine's selective impact on the precursors of polymorphonuclear leukocytes, though the mechanism remains unknown.[33] Although neutropenia is not an absolute contraindication for clozapine therapy, guidelines recommend cessation of clozapine when the ANC drops below 1000/mm3.[34] A meta‐analysis of 112 patients who were rechallenged following neutropenia found that 69% tolerated a rechallenge without development of a subsequent dyscrasia.[21]
In the case of chemotherapy‐induced neutropenia, several case reports support the continued use of clozapine during cancer treatment[35]; this requires a written request to the pharmaceutical company that manufactures clozapine and documentation of the expected time course and contribution of chemotherapy to neutropenia.[36] Clozapine's association with neutropenia warrants close monitoring in individuals with human immunodeficiency virus (HIV) and other causes of immune compromise. Reports of clozapine continuation in HIV‐positive individuals underscore the importance of close collaboration between infectious disease and psychiatry, with specific focus on potential interactions between clozapine and antiretroviral agents and close monitoring of viral load and ANC.[37]
The most feared complication of clozapine remains agranulocytosis, defined as ANC<500/mm3,[33] which occurs in up to 1% of monitored patients. In 1975, clozapine was banned worldwide after 8 fatal cases of agranulocytosis were reported in Finland.[38] The drug was reintroduced for treatment‐resistant schizophrenia with strict monitoring parameters, which has sharply reduced the death rate. One study found 12 actual deaths between 1990 and 1994, compared to the 149 predicted deaths without monitoring.[39]
The risk of agranulocytosis appears to be higher in older adults and in patients with a lower baseline WBC count. Although there are reports of delayed agranulocytosis occurring in patients after up to 19 years of treatment,[40] the incidence of leukopenia is greatest in the first year. Given this high‐risk period, mandatory monitoring is as follows: weekly WBC and neutrophil counts for the first 26 weeks, biweekly counts for the second 26 weeks, and every 4 weeks thereafter. Of note, many of the later cases of agranulocytosis appear to be related to medication coadministration, particularly with valproic acid, though no definitive link has been established.[40]
Treatment of clozapine‐induced agranulocytosis consists of immediate clozapine cessation, and consideration of initiation of prophylactic broad‐spectrum antibiotics and granulocyte colony‐stimulating factor (such as filgrastim) until the granulocyte count normalizes.[41, 42] Although few case reports describe successful clozapine rechallenge in patients with a history of agranulocytosis, the data are sparse, and current practice is to permanently discontinue clozapine if ANC falls below 1000/mm3.[21, 41]
ADDITIONAL COMPLICATIONS (METABOLIC, RENAL, URINARY)
Moderate to marked weight gain occurs in over 50% of patients treated with clozapine, with average gains of nearly 10% body weight.[43] In a 10‐year follow‐up study of patients treated with clozapine, Henderson et al. reported an average weight gain of 13 kg, with 34% percent of studied patients developing diabetes mellitus. Metabolic side effects of second‐generation antipsychotics, including clozapine, are a well‐documented and troubling phenomenon.[44] Limited evidence supports use of metformin, alongside behavioral therapy, for concerns related to glucose dysregulation.[45] Some patients have also experienced weight loss with adjunctive topiramate use, particularly if they have also suffered seizures.[46]
Urinary incontinence and nocturnal enuresis are both associated with clozapine, but are likely under‐reported because of patient and provider embarrassment; providers also may not think to ask about these specific symptoms. First‐line treatment for nocturnal enuresis is to limit fluids in the evening. Desmopressin has a controversial role in treating nocturnal enuresis owing to its risk of hyponatremia; appropriate monitoring should be implemented if this agent is used.[18]
Clozapine has been associated with acute interstitial nephritis (AIN), although this is thought to be a relatively rare side effect. Drug‐induced AIN typically appears soon after initiation and presents with the clinical triad of rash, fever, and eosinophilia. Given that weekly CBC is mandatory in the initiation phase, eosinophilia is easily detectible and may serve as a marker for potential AIN.[47]
Sialorrhea, particularly during sleep, is a bothersome condition affecting up to one‐third of patients who take clozapine.[48] Although clozapine is strongly anticholinergic, its agonist activity at the M4 muscarinic receptor and antagonism of the alpha‐2 adrenergic receptor are postulated as the mechanisms underlying hypersalivation. Sialorrhea is frequently seen early in treatment and does not appear to be dose dependent.[48] Excessive salivation is typically managed with behavioral interventions (eg, utilizing towels or other absorbent materials on top of bedding). If hypersalivation occurs during the day, chewing sugar‐free gum may increase the rate of swallowing and make symptoms less bothersome. If this does not provide adequate relief, practitioners may consider use of atropine 1% solution administered directly to the oral cavity.[49]
DRUG‐DRUG INTERACTIONS
For hospitalists, who must frequently alter existing medications or add new ones, awareness of potential drug‐drug interactions is crucial. Clozapine is metabolized by the cytochrome p450 system, with predominant metabolism through the isoenzymes 1A2, 3A4, and 2D6.[50] Common medications that induce clozapine metabolism (thereby decreasing clozapine levels) include phenytoin, phenobarbital, carbamazepine, oxcarbazepine, and corticosteroids. Conversely, stopping these medications after long‐term therapy will raise clozapine levels. Substances that inhibit clozapine metabolism (thereby increasing clozapine levels) include ciprofloxacin, erythromycin, clarithromycin, fluvoxamine, fluoxetine, paroxetine, protease inhibitors, verapamil, and grapefruit juice. We recommend caution when concurrently administering other agents that increase risk for agranulocytosis, including carbamazepine, trimethoprim‐sulfamethoxazole, sulfasalazine, and tricyclic antidepressants.
Cigarette smoking decreases clozapine blood levels by induction of CYP1A2. Patients require a 10% to 30% reduction to clozapine dose during periods of smoking cessation, including when smoking is stopped during inpatient hospitalization.[51] Nicotine replacement therapy does not induce CYP1A2 and therefore does not have a compensatory effect on clozapine levels. On discharge or resumption of smoking, patients may require an increase of their dose of clozapine to maintain adequate antipsychotic effect.
SUMMARY OF RECOMMENDATIONS
Medical complications are cited as the cause in 20% of clozapine discontinuations; most commonly, these include seizures, severe constipation, somnolence, and neutropenia. Given the high risk of psychiatric morbidity posed by discontinuation, we recommend managing mild‐moderate symptoms and side effects while continuing the drug, when possible (Table 1). We encourage hospitalists to confer with the patient's psychiatrist or the inpatient psychiatry consultation service when making changes to clozapine therapy. Specific recommendations are as follows:
- We advocate withholding clozapine administration pending medical optimization for several conditions, including: small‐bowel obstruction, neuroleptic malignant syndrome, venous thromboembolism, diabetic ketoacidosis, or hyperosmolar coma.
- Clinical scenarios requiring acute discontinuation of clozapine include agranulocytosis and myocarditis. Successful rechallenge with clozapine has been described after both conditions; at the same time, given the high morbidity and mortality of myocarditis and agranulocytosis, re‐initiation of clozapine requires an extensive risk‐benefit discussion with the patient and family, informed consent, and, in the case of agranulocytosis, approval from the national clozapine registry (Table 2).
- Although adjunctive therapy with filgrastim was initially thought to permit a clozapine rechallenge in patients with a history of agranulocytosis, case reports on this strategy have been equivocal, and further research is necessary to determine the most effective strategy for management.
| Clinical Lab/Study | Frequency of Monitoring | |
|---|---|---|
| Cardiac | Electrocardiogram | Baseline, 24 weeks after initiation, every 6 months thereafter |
| Cardiac enzymes (eg, troponin I) echocardiogram | No standard guidelines, unless clinically indicated | |
| Hematologic | Complete blood count with differential | Baseline, then weekly 26 weeks, then every 2 weeks 26 weeks, then every 4 weeks thereafter |
| Metabolic | Body mass index; circumference of waist | Baseline, then every 3 to 6 months |
| Fasting glucose | Baseline, then every 6 months | |
| Fasting lipid panel | Baseline, then yearly | |
| Neurologic | Electroencephalogram | No standard guidelines, unless clinically indicated |
| Vital signs | Heart rate, blood pressure, temperature | Baseline and at each follow‐up visit |
| Requires Acute Clozapine Discontinuation* | Clozapine Interruption During Management | Does Not Typically Require Clozapine Discontinuation |
|---|---|---|
| ||
| Agranulocytosis (ANC<1.0 109/mm3) | Diabetic complications (eg, ketoacidosis, hyperosmolar coma) | Constipation |
| Cardiomyopathy (severe) | Gastrointestinal obstruction, ileus | Diabetes mellitus |
| Myocarditis | Neuroleptic malignant syndrome | Gastroesophageal Reflux |
| Venous thromboembolism | Hyperlipidemia | |
| Hypertension | ||
| Orthostatic hypotension | ||
| Sedation | ||
| Seizures | ||
| Sialorrhea | ||
| Sinus tachycardia | ||
| Urinary changes (eg, enuresis, incontinence) | ||
| Weight gain | ||
CONCLUSION
Clozapine has been a very successful treatment for patients with schizophrenia who have failed other antipsychotic therapies. However, fears of potential side effects and frequent monitoring have limited its use and led to unnecessary discontinuation. To mitigate risk for serious complications, we hope to increase hospitalists' awareness of prevention, monitoring, and treatment of side effects, and to promote comfort with circumstances that warrant continuation or discontinuation of clozapine (Table 3). The hospitalist plays a crucial role in managing these complications as well as conveying information and recommendations to primary care providers; as such, their familiarity with the medication is essential for proper management of individuals who take clozapine.
| Take‐Home Points |
|---|
| 1. Clozapine is the gold standard for treatment‐resistant schizophrenia; however, its use is limited by side effects, many of which can be successfully treated by internists. |
| 2. There are few indications for discontinuing clozapine (myocarditis, small‐bowel obstruction, agranulocytosis). The psychiatry service should be consulted in the event that clozapine is discontinued. |
| 3. Seizures are not an indication for discontinuing clozapine; instead, we recommend adding an antiepileptic drug. |
| 4. All second‐generation antipsychotics are associated with diabetes mellitus and significant weight gain. Clozapine is more highly associated with metabolic side effects than many other medications in this class. |
| 5. Sedation, sialorrhea, and constipation are common and can be managed pharmacologically and with behavioral interventions. |
Disclosure: Nothing to report.
- , , , . Clozapine versus typical neuroleptic medication for schizophrenia. Cochrane Database Syst Rev. 2009(1):CD000059.
- , , , et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry. 2006;163(4):600–610.
- , , , et al. Randomized controlled trial of effect of prescription of clozapine versus other second‐generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull. 2006;32(4):715–723.
- , , , et al. Effects of clozapine on positive and negative symptoms in outpatients with schizophrenia. Am J Psychiatry. 1994;151(1):20–26.
- , , , . Clozapine for the treatment‐resistant schizophrenic. A double‐blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45(9):789–796.
- , , , , , . Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. 2003;60(1):82–91.
- , , , et al. 11‐year follow‐up of mortality in patients with schizophrenia: a population‐based cohort study (FIN11 study). Lancet. 2009;374(9690):620–627.
- , , , , . Clozapine use and relapses of substance use disorder among patients with co‐occurring schizophrenia and substance use disorders. Schizophr Bull. 2006;32(4):637–643.
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- , , , . Morbidity and mortality in people with serious mental illness. National Association of State Mental Health Program Directors (NASMHPD) Medical Directors Council. Available at: http://www.nasmhpd.org/docs/publications/MDCdocs/Mortality%20and%20Morbidity%20Final%20Report%208.18.08.pdf. Accessed February 3, 2015.
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- , . Clozapine. A novel antipsychotic agent. N Engl J Med. 1991;324(11):746–754.
- , . Reason for clozapine cessation. Acta Psychiatr Scand. 2012;125(1):39–44.
- , , , . Termination of clozapine treatment due to medical reasons: when is it warranted and how can it be avoided? J Clin Psychiatry. 2013;74(6):603–613.
- , , , , , . Time to discontinuation of antipsychotic drugs in a schizophrenia cohort: influence of current treatment strategies. Ther Adv Psychopharmacol. 2014;4(6):228–239.
- , , . Clozapine‐related seizures. Neurology. 1991;41(3):369–371.
- , , , . Clozapine‐related EEG changes and seizures: dose and plasma‐level relationships. Ther Adv Psychopharmacol. 2011;1(2):47–66.
- . Review and management of clozapine side effects. J Clin Psychiatry. 2000;61(suppl 8):14–17; discussion 18–19.
- , . Epilepsy, psychosis and clozapine. Human Psychopharmacol Clin Exp. 2002;17:115–119.
- , , , , , . Response of patients with treatment‐refractory schizophrenia to clozapine within three serum level ranges. Am J Psychiatry. 1996;153(12):1579–1584.
- , , , , . When can patients with potentially life‐threatening adverse effects be rechallenged with clozapine? A systematic review of the published literature. Schizophr Res. 2012;134(2–3):180–186.
- , . Clinical profile of clozapine: adverse reactions and agranulocytosis. Psychiatr Q. 1992;63(1):51–70.
- , , , , , . Clozapine and hypertension: a chart review of 82 patients. J Clin Psychiatry. 2004;65(5):686–689.
- , , . Adverse cardiac effects associated with clozapine. J Clin Psychopharmacol. 2005;25(1):32–41.
- , , , , . Clozapine induced myocarditis: a rare but fatal complication. Int J Cardiol. 2006;112(2):e5–e6.
- , , , . Myocarditis and cardiomyopathy associated with clozapine. Lancet. 1999;354(9193):1841–1845.
- , , , . Life‐threatening clozapine‐induced gastrointestinal hypomotility: an analysis of 102 cases. J Clin Psychiatry. 2008;69(5):759–768.
- , , , . Fatalities associated with clozapine‐related constipation and bowel obstruction: a literature review and two case reports. Psychosomatics. 2009;50(4):416–419.
- , , . Death from clozapine‐induced constipation: case report and literature review. Psychosomatics. 2002;43(1):71–73.
- , , , , , . Clozapine: a clinical review of adverse effects and management. Ann Clin Psychiatry. 2003;15(1):33–48.
- , , , , . Beyond white blood cell monitoring: screening in the initial phase of clozapine therapy. J Clin Psychiatry. 2012;73(10):1307–1312.
- Clozapine [package insert]. Sellersville, PA: TEVA Pharmaceuticals USA; 2013. Available at: https://www.clozapineregistry.com/insert.pdf.ashx. Accessed October 27, 2014.
- , , , , . Clozapine‐induced agranulocytosis. Incidence and risk factors in the United States. N Engl J Med. 1993;329(3):162–167.
- Clozaril (clozapine) prescribing information. Washington, DC: U.S. Food and Drug Administration; 2013. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019758s069s071lbl.pdf. Accessed February 4, 2015.
- . Clozapine therapy during cancer treatment. Am J Psychiatry. 2004;161(1):175.
- , , , , . Continuation of clozapine during chemotherapy: a case report and review of literature. Psychosomatics. 2014;55(6):673–679.
- , , . Clozapine use in HIV‐infected schizophrenia patients: a case‐based discussion and review. Psychosomatics. 2009;50(6):626–632.
- , , , . Letter: clozapine and agranulocytosis. Lancet. 1975;2(7935):611.
- . Effects of the clozapine national registry system on incidence of deaths related to agranulocytosis. Psychiatr Serv. 1996;47(1):52–56.
- , . White blood cell monitoring during long‐term clozapine treatment. Am J Psychiatry. 2013;170(4):366–369.
- , , . Add‐on filgrastim during clozapine rechallenge in patients with a history of clozapine‐related granulocytopenia/agranulocytosis. Am J Psychiatry. 2009;166(2):236.
- , , . Add‐on filgrastim during clozapine rechallenge unsuccessful in preventing agranulocytosis. Gen Hosp Psychiatry. 2013;35(5):576.e11–12.
- , , , , , . Clozapine‐induced weight gain: prevalence and clinical relevance. Am J Psychiatry. 1992;149(1):68–72.
- , , , et al. Clozapine, diabetes mellitus, hyperlipidemia, and cardiovascular risks and mortality: results of a 10‐year naturalistic study. J Clin Psychiatry. 2005;66(9):1116–1121.
- , , , et al. Effects of adjunctive metformin on metabolic traits in nondiabetic clozapine‐treated patients with schizophrenia and the effect of metformin discontinuation on body weight: a 24‐week, randomized, double‐blind, placebo‐controlled study. J Clin Psychiatry. 2013;74(5):e424–e430.
- , , , . Topiramate for clozapine‐induced seizures. Am J Psychiatry. 2001;158(6):968–969.
- , , , , . Clozapine‐induced acute interstitial nephritis. Lancet. 1999;354(9185):1180–1181.
- , , , , . Update on the clinical efficacy and side effects of clozapine. Schizophr Bull. 1991;17(2):247–261.
- , , . Clozapine‐induced sialorrhea: pathophysiology and management strategies. Psychopharmacology. 2006;185(3):265–273.
- , , . Clozapine drug‐drug interactions: a review of the literature. Hum Psychopharm Clin. 1997;12(1):5–20.
- , , . The effect of smoking and cytochrome P450 CYP1A2 genetic polymorphism on clozapine clearance and dose requirement. Pharmacogenetics. 2003;13(3):169–172.
- , , , . Clozapine versus typical neuroleptic medication for schizophrenia. Cochrane Database Syst Rev. 2009(1):CD000059.
- , , , et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry. 2006;163(4):600–610.
- , , , et al. Randomized controlled trial of effect of prescription of clozapine versus other second‐generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull. 2006;32(4):715–723.
- , , , et al. Effects of clozapine on positive and negative symptoms in outpatients with schizophrenia. Am J Psychiatry. 1994;151(1):20–26.
- , , , . Clozapine for the treatment‐resistant schizophrenic. A double‐blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45(9):789–796.
- , , , , , . Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. 2003;60(1):82–91.
- , , , et al. 11‐year follow‐up of mortality in patients with schizophrenia: a population‐based cohort study (FIN11 study). Lancet. 2009;374(9690):620–627.
- , , , , . Clozapine use and relapses of substance use disorder among patients with co‐occurring schizophrenia and substance use disorders. Schizophr Bull. 2006;32(4):637–643.
- , , . Outcomes for schizophrenia patients with clozapine treatment: how good does it get? J Psychopharmacol. 2009;23(8):957–965.
- , , , . Morbidity and mortality in people with serious mental illness. National Association of State Mental Health Program Directors (NASMHPD) Medical Directors Council. Available at: http://www.nasmhpd.org/docs/publications/MDCdocs/Mortality%20and%20Morbidity%20Final%20Report%208.18.08.pdf. Accessed February 3, 2015.
- , . Pharmacological actions of the atypical antipsychotic drug clozapine: a review. Synapse. 1996;24(4):349–394.
- , . Clozapine. A novel antipsychotic agent. N Engl J Med. 1991;324(11):746–754.
- , . Reason for clozapine cessation. Acta Psychiatr Scand. 2012;125(1):39–44.
- , , , . Termination of clozapine treatment due to medical reasons: when is it warranted and how can it be avoided? J Clin Psychiatry. 2013;74(6):603–613.
- , , , , , . Time to discontinuation of antipsychotic drugs in a schizophrenia cohort: influence of current treatment strategies. Ther Adv Psychopharmacol. 2014;4(6):228–239.
- , , . Clozapine‐related seizures. Neurology. 1991;41(3):369–371.
- , , , . Clozapine‐related EEG changes and seizures: dose and plasma‐level relationships. Ther Adv Psychopharmacol. 2011;1(2):47–66.
- . Review and management of clozapine side effects. J Clin Psychiatry. 2000;61(suppl 8):14–17; discussion 18–19.
- , . Epilepsy, psychosis and clozapine. Human Psychopharmacol Clin Exp. 2002;17:115–119.
- , , , , , . Response of patients with treatment‐refractory schizophrenia to clozapine within three serum level ranges. Am J Psychiatry. 1996;153(12):1579–1584.
- , , , , . When can patients with potentially life‐threatening adverse effects be rechallenged with clozapine? A systematic review of the published literature. Schizophr Res. 2012;134(2–3):180–186.
- , . Clinical profile of clozapine: adverse reactions and agranulocytosis. Psychiatr Q. 1992;63(1):51–70.
- , , , , , . Clozapine and hypertension: a chart review of 82 patients. J Clin Psychiatry. 2004;65(5):686–689.
- , , . Adverse cardiac effects associated with clozapine. J Clin Psychopharmacol. 2005;25(1):32–41.
- , , , , . Clozapine induced myocarditis: a rare but fatal complication. Int J Cardiol. 2006;112(2):e5–e6.
- , , , . Myocarditis and cardiomyopathy associated with clozapine. Lancet. 1999;354(9193):1841–1845.
- , , , . Life‐threatening clozapine‐induced gastrointestinal hypomotility: an analysis of 102 cases. J Clin Psychiatry. 2008;69(5):759–768.
- , , , . Fatalities associated with clozapine‐related constipation and bowel obstruction: a literature review and two case reports. Psychosomatics. 2009;50(4):416–419.
- , , . Death from clozapine‐induced constipation: case report and literature review. Psychosomatics. 2002;43(1):71–73.
- , , , , , . Clozapine: a clinical review of adverse effects and management. Ann Clin Psychiatry. 2003;15(1):33–48.
- , , , , . Beyond white blood cell monitoring: screening in the initial phase of clozapine therapy. J Clin Psychiatry. 2012;73(10):1307–1312.
- Clozapine [package insert]. Sellersville, PA: TEVA Pharmaceuticals USA; 2013. Available at: https://www.clozapineregistry.com/insert.pdf.ashx. Accessed October 27, 2014.
- , , , , . Clozapine‐induced agranulocytosis. Incidence and risk factors in the United States. N Engl J Med. 1993;329(3):162–167.
- Clozaril (clozapine) prescribing information. Washington, DC: U.S. Food and Drug Administration; 2013. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019758s069s071lbl.pdf. Accessed February 4, 2015.
- . Clozapine therapy during cancer treatment. Am J Psychiatry. 2004;161(1):175.
- , , , , . Continuation of clozapine during chemotherapy: a case report and review of literature. Psychosomatics. 2014;55(6):673–679.
- , , . Clozapine use in HIV‐infected schizophrenia patients: a case‐based discussion and review. Psychosomatics. 2009;50(6):626–632.
- , , , . Letter: clozapine and agranulocytosis. Lancet. 1975;2(7935):611.
- . Effects of the clozapine national registry system on incidence of deaths related to agranulocytosis. Psychiatr Serv. 1996;47(1):52–56.
- , . White blood cell monitoring during long‐term clozapine treatment. Am J Psychiatry. 2013;170(4):366–369.
- , , . Add‐on filgrastim during clozapine rechallenge in patients with a history of clozapine‐related granulocytopenia/agranulocytosis. Am J Psychiatry. 2009;166(2):236.
- , , . Add‐on filgrastim during clozapine rechallenge unsuccessful in preventing agranulocytosis. Gen Hosp Psychiatry. 2013;35(5):576.e11–12.
- , , , , , . Clozapine‐induced weight gain: prevalence and clinical relevance. Am J Psychiatry. 1992;149(1):68–72.
- , , , et al. Clozapine, diabetes mellitus, hyperlipidemia, and cardiovascular risks and mortality: results of a 10‐year naturalistic study. J Clin Psychiatry. 2005;66(9):1116–1121.
- , , , et al. Effects of adjunctive metformin on metabolic traits in nondiabetic clozapine‐treated patients with schizophrenia and the effect of metformin discontinuation on body weight: a 24‐week, randomized, double‐blind, placebo‐controlled study. J Clin Psychiatry. 2013;74(5):e424–e430.
- , , , . Topiramate for clozapine‐induced seizures. Am J Psychiatry. 2001;158(6):968–969.
- , , , , . Clozapine‐induced acute interstitial nephritis. Lancet. 1999;354(9185):1180–1181.
- , , , , . Update on the clinical efficacy and side effects of clozapine. Schizophr Bull. 1991;17(2):247–261.
- , , . Clozapine‐induced sialorrhea: pathophysiology and management strategies. Psychopharmacology. 2006;185(3):265–273.
- , , . Clozapine drug‐drug interactions: a review of the literature. Hum Psychopharm Clin. 1997;12(1):5–20.
- , , . The effect of smoking and cytochrome P450 CYP1A2 genetic polymorphism on clozapine clearance and dose requirement. Pharmacogenetics. 2003;13(3):169–172.
Topical TXA decreases use of blood transfusions
Photo by Daniel Gay
Using topical tranexamic acid (TXA) in patients undergoing primary total hip and knee arthroplasty can reduce the need for blood transfusions, according to a study published in The Journal of Arthroplasty.
Topical TXA reduced the transfusion rate by 12%, thereby reducing transfusion costs.
Topical TXA also enabled about 9% more patients to be discharged to their homes rather than a skilled nursing facility, and it did not affect the rate of complications.
“Historically, with hip or knee replacement, there was a 25% to 30% chance of a blood transfusion,” said study author John Froehlich, MD, of The Miriam Hospital in Providence, Rhode Island.
“We realized that this high frequency of transfusions was associated with longer hospital stays and a higher risk of infections, which we are always working to avoid. Tranexamic acid has been around for 30 years, but because there was concern about the danger of administering it intravenously, we opted to inject it in the joints. We found it to be effective in reducing ongoing blood loss and the subsequent need for transfusion, and we have now standardized the practice.”
TXA is a synthetic derivative of the amino acid lysine that produces antifibrinolytic activity by competitively inhibiting lysine binding sites on plasminogen molecules. TXA helps the body stabilize blood clot formation, thereby reducing bleeding at surgical sites.
Most protocols of TXA in total joint arthroplasty have involved intravenous delivery. However, studies have indicated that topical injection may provide advantages, such as potentially reduced costs with a single injection, surgeon control, and localization and concentration of the drug more precisely at the surgical site.
“As the evidence for topical TXA grew, our arthroplasty surgeons started adopting topical TXA for total joint arthroplasty,” Dr Froehlich said.
He and his colleagues studied topical TXA in patients undergoing primary hip or knee arthroplasty by 5 surgeons from March 2012 to March 2013. Of the 591 consecutive patients, 311 received topical TXA, and 280 served as controls.
The researchers found that topical TXA reduced the proportion of red blood cell units transfused by 18%, from 28.6% to 10.6% (P<0.001). The drug also reduce the number of patients who required transfusions by 12%, from 17.5% to 5.5% (P<0.001).
On, the other hand, there was no significant difference between the TXA and control groups with regard to tourniquet time, operative time, time in the operating room, or the length of hospital stay.
Still, more patients in the TXA arm than in the control arm were able to go home rather than to a subacute nursing facility—71.4% and 62.1%, respectively (P<0.02).
And TXA conferred a cost benefit based solely on the rate of transfusion reduction. The researchers’ cost analysis revealed a net savings of $8372.66 per 100 patients treated, which amounted to $83.73 per patient.
“[Topical TXA] reduces transfusion rates, increases home disposition, and reduces cost in primary hip and knee arthroplasty,” said study author Lee Rubin, MD, of The Miriam Hospital.
“[W]e have now developed a simple, standardized, and cost-effective protocol for the use of topical TXA during total joint replacement that can be immediately used by any surgeon around the world to improve patient care.”
Photo by Daniel Gay
Using topical tranexamic acid (TXA) in patients undergoing primary total hip and knee arthroplasty can reduce the need for blood transfusions, according to a study published in The Journal of Arthroplasty.
Topical TXA reduced the transfusion rate by 12%, thereby reducing transfusion costs.
Topical TXA also enabled about 9% more patients to be discharged to their homes rather than a skilled nursing facility, and it did not affect the rate of complications.
“Historically, with hip or knee replacement, there was a 25% to 30% chance of a blood transfusion,” said study author John Froehlich, MD, of The Miriam Hospital in Providence, Rhode Island.
“We realized that this high frequency of transfusions was associated with longer hospital stays and a higher risk of infections, which we are always working to avoid. Tranexamic acid has been around for 30 years, but because there was concern about the danger of administering it intravenously, we opted to inject it in the joints. We found it to be effective in reducing ongoing blood loss and the subsequent need for transfusion, and we have now standardized the practice.”
TXA is a synthetic derivative of the amino acid lysine that produces antifibrinolytic activity by competitively inhibiting lysine binding sites on plasminogen molecules. TXA helps the body stabilize blood clot formation, thereby reducing bleeding at surgical sites.
Most protocols of TXA in total joint arthroplasty have involved intravenous delivery. However, studies have indicated that topical injection may provide advantages, such as potentially reduced costs with a single injection, surgeon control, and localization and concentration of the drug more precisely at the surgical site.
“As the evidence for topical TXA grew, our arthroplasty surgeons started adopting topical TXA for total joint arthroplasty,” Dr Froehlich said.
He and his colleagues studied topical TXA in patients undergoing primary hip or knee arthroplasty by 5 surgeons from March 2012 to March 2013. Of the 591 consecutive patients, 311 received topical TXA, and 280 served as controls.
The researchers found that topical TXA reduced the proportion of red blood cell units transfused by 18%, from 28.6% to 10.6% (P<0.001). The drug also reduce the number of patients who required transfusions by 12%, from 17.5% to 5.5% (P<0.001).
On, the other hand, there was no significant difference between the TXA and control groups with regard to tourniquet time, operative time, time in the operating room, or the length of hospital stay.
Still, more patients in the TXA arm than in the control arm were able to go home rather than to a subacute nursing facility—71.4% and 62.1%, respectively (P<0.02).
And TXA conferred a cost benefit based solely on the rate of transfusion reduction. The researchers’ cost analysis revealed a net savings of $8372.66 per 100 patients treated, which amounted to $83.73 per patient.
“[Topical TXA] reduces transfusion rates, increases home disposition, and reduces cost in primary hip and knee arthroplasty,” said study author Lee Rubin, MD, of The Miriam Hospital.
“[W]e have now developed a simple, standardized, and cost-effective protocol for the use of topical TXA during total joint replacement that can be immediately used by any surgeon around the world to improve patient care.”
Photo by Daniel Gay
Using topical tranexamic acid (TXA) in patients undergoing primary total hip and knee arthroplasty can reduce the need for blood transfusions, according to a study published in The Journal of Arthroplasty.
Topical TXA reduced the transfusion rate by 12%, thereby reducing transfusion costs.
Topical TXA also enabled about 9% more patients to be discharged to their homes rather than a skilled nursing facility, and it did not affect the rate of complications.
“Historically, with hip or knee replacement, there was a 25% to 30% chance of a blood transfusion,” said study author John Froehlich, MD, of The Miriam Hospital in Providence, Rhode Island.
“We realized that this high frequency of transfusions was associated with longer hospital stays and a higher risk of infections, which we are always working to avoid. Tranexamic acid has been around for 30 years, but because there was concern about the danger of administering it intravenously, we opted to inject it in the joints. We found it to be effective in reducing ongoing blood loss and the subsequent need for transfusion, and we have now standardized the practice.”
TXA is a synthetic derivative of the amino acid lysine that produces antifibrinolytic activity by competitively inhibiting lysine binding sites on plasminogen molecules. TXA helps the body stabilize blood clot formation, thereby reducing bleeding at surgical sites.
Most protocols of TXA in total joint arthroplasty have involved intravenous delivery. However, studies have indicated that topical injection may provide advantages, such as potentially reduced costs with a single injection, surgeon control, and localization and concentration of the drug more precisely at the surgical site.
“As the evidence for topical TXA grew, our arthroplasty surgeons started adopting topical TXA for total joint arthroplasty,” Dr Froehlich said.
He and his colleagues studied topical TXA in patients undergoing primary hip or knee arthroplasty by 5 surgeons from March 2012 to March 2013. Of the 591 consecutive patients, 311 received topical TXA, and 280 served as controls.
The researchers found that topical TXA reduced the proportion of red blood cell units transfused by 18%, from 28.6% to 10.6% (P<0.001). The drug also reduce the number of patients who required transfusions by 12%, from 17.5% to 5.5% (P<0.001).
On, the other hand, there was no significant difference between the TXA and control groups with regard to tourniquet time, operative time, time in the operating room, or the length of hospital stay.
Still, more patients in the TXA arm than in the control arm were able to go home rather than to a subacute nursing facility—71.4% and 62.1%, respectively (P<0.02).
And TXA conferred a cost benefit based solely on the rate of transfusion reduction. The researchers’ cost analysis revealed a net savings of $8372.66 per 100 patients treated, which amounted to $83.73 per patient.
“[Topical TXA] reduces transfusion rates, increases home disposition, and reduces cost in primary hip and knee arthroplasty,” said study author Lee Rubin, MD, of The Miriam Hospital.
“[W]e have now developed a simple, standardized, and cost-effective protocol for the use of topical TXA during total joint replacement that can be immediately used by any surgeon around the world to improve patient care.”
Team discovers how cerebral malaria kills children
at Queen Elizabeth Hospital
Photo by Jim Peck
After grant money brought magnetic resonance imaging (MRI) to a hospital in Africa, researchers were able to uncover the cause of death in children with cerebral malaria.
MRI scans revealed that, in some children, the brain can become so swollen that it is forced out through the bottom of the skull and compresses the brain stem. This pressure causes the children to stop breathing and die.
The researchers reported these findings in NEJM.
“Because we know now that the brain swelling is what causes death, we can work to find new treatments,” said study author Terrie Taylor, DO, of Michigan State University in East Lansing.
“The next step is to identify what’s causing the swelling and then develop treatments targeting those causes. It’s also possible that using ventilators to keep the children breathing until the swelling subsides might save lives, but ventilators are few and far between in Africa at the moment.”
Scans reveal brain swelling
In 2008, GE Healthcare provided a $1 million MRI to the Queen Elizabeth Hospital in Blantyre, Malawi, where Dr Taylor spends 6 months of every year treating and studying children with malaria.
Dr Taylor and her colleagues used the MRI to view brain images from hundreds of children with cerebral malaria, comparing findings in those who died to those who survived.
The team imaged 168 children with cerebral malaria (as defined by the World Health Organization). Fifteen percent (25/168) of the children died. And 84% of these children (21/25) had evidence of severe brain swelling at admission.
In contrast, the researchers found evidence of severe brain swelling in 27% (39/143) of children who survived. And serial MRI scans revealed decreasing brain volume in the survivors who initially had brain swelling.
“We found that survivors’ brains were either never swollen or decreased in size after 2 to 3 days,” Dr Taylor said. “This was a triumphant moment. I wanted to say to the parasite, ‘Ha! You never thought we’d get an MRI, did you?’”
at Queen Elizabeth Hospital
Photo by Jim Peck
After grant money brought magnetic resonance imaging (MRI) to a hospital in Africa, researchers were able to uncover the cause of death in children with cerebral malaria.
MRI scans revealed that, in some children, the brain can become so swollen that it is forced out through the bottom of the skull and compresses the brain stem. This pressure causes the children to stop breathing and die.
The researchers reported these findings in NEJM.
“Because we know now that the brain swelling is what causes death, we can work to find new treatments,” said study author Terrie Taylor, DO, of Michigan State University in East Lansing.
“The next step is to identify what’s causing the swelling and then develop treatments targeting those causes. It’s also possible that using ventilators to keep the children breathing until the swelling subsides might save lives, but ventilators are few and far between in Africa at the moment.”
Scans reveal brain swelling
In 2008, GE Healthcare provided a $1 million MRI to the Queen Elizabeth Hospital in Blantyre, Malawi, where Dr Taylor spends 6 months of every year treating and studying children with malaria.
Dr Taylor and her colleagues used the MRI to view brain images from hundreds of children with cerebral malaria, comparing findings in those who died to those who survived.
The team imaged 168 children with cerebral malaria (as defined by the World Health Organization). Fifteen percent (25/168) of the children died. And 84% of these children (21/25) had evidence of severe brain swelling at admission.
In contrast, the researchers found evidence of severe brain swelling in 27% (39/143) of children who survived. And serial MRI scans revealed decreasing brain volume in the survivors who initially had brain swelling.
“We found that survivors’ brains were either never swollen or decreased in size after 2 to 3 days,” Dr Taylor said. “This was a triumphant moment. I wanted to say to the parasite, ‘Ha! You never thought we’d get an MRI, did you?’”
at Queen Elizabeth Hospital
Photo by Jim Peck
After grant money brought magnetic resonance imaging (MRI) to a hospital in Africa, researchers were able to uncover the cause of death in children with cerebral malaria.
MRI scans revealed that, in some children, the brain can become so swollen that it is forced out through the bottom of the skull and compresses the brain stem. This pressure causes the children to stop breathing and die.
The researchers reported these findings in NEJM.
“Because we know now that the brain swelling is what causes death, we can work to find new treatments,” said study author Terrie Taylor, DO, of Michigan State University in East Lansing.
“The next step is to identify what’s causing the swelling and then develop treatments targeting those causes. It’s also possible that using ventilators to keep the children breathing until the swelling subsides might save lives, but ventilators are few and far between in Africa at the moment.”
Scans reveal brain swelling
In 2008, GE Healthcare provided a $1 million MRI to the Queen Elizabeth Hospital in Blantyre, Malawi, where Dr Taylor spends 6 months of every year treating and studying children with malaria.
Dr Taylor and her colleagues used the MRI to view brain images from hundreds of children with cerebral malaria, comparing findings in those who died to those who survived.
The team imaged 168 children with cerebral malaria (as defined by the World Health Organization). Fifteen percent (25/168) of the children died. And 84% of these children (21/25) had evidence of severe brain swelling at admission.
In contrast, the researchers found evidence of severe brain swelling in 27% (39/143) of children who survived. And serial MRI scans revealed decreasing brain volume in the survivors who initially had brain swelling.
“We found that survivors’ brains were either never swollen or decreased in size after 2 to 3 days,” Dr Taylor said. “This was a triumphant moment. I wanted to say to the parasite, ‘Ha! You never thought we’d get an MRI, did you?’”
Multifaceted Hospitalist QI Intervention
Waste in US healthcare is a public health threat, with an estimated value of $910 billion per year.[1] It constitutes some of the relatively high per‐discharge healthcare spending seen in the United States when compared to other nations.[2] Waste takes many forms, one of which is excessive use of diagnostic laboratory testing.[1] Many hospital providers obtain common labs, such as complete blood counts (CBCs) and basic metabolic panels (BMPs), in an open‐ended, daily manner for their hospitalized patients, without regard for the patient's clinical condition or despite stability of the previous results. Reasons for ordering these tests in a nonpatient‐centered manner include provider convenience (such as inclusion in an order set), ease of access, habit, or defensive practice.[3, 4, 5] All of these reasons may represent waste.
Although the potential waste of routine daily labs may seem small, the frequency with which they are ordered results in a substantial real and potential cost, both financially and clinically. Multiple studies have shown a link between excessive diagnostic phlebotomy and hospital‐acquired anemia.[6, 7, 8, 9] Hospital‐acquired anemia itself has been associated with increased mortality.[10] In addition to blood loss and financial cost, patient experience and satisfaction are also detrimentally affected by excessive laboratory testing in the form of pain and inconvenience from the act of phlebotomy.[11]
There are many reports of strategies to decrease excessive diagnostic laboratory testing as a means of addressing this waste in the inpatient setting.[12, 13, 14, 15, 16, 17, 18, 19, 20, 21] All of these studies have taken place in a traditional academic setting, and many implemented their intervention through a computer‐based order entry system. Based on the literature search regarding this topic, we found no examples of studies conducted among and within community‐based hospitalist practices. More recently, this issue was highlighted as part of the Choosing Wisely campaign sponsored by the American Board of Internal Medicine Foundation, Consumer Reports, and more than 60 specialty societies. The Society of Hospital Medicine, the professional society for hospitalists, recommended avoidance of repetitive common laboratory testing in the face of clinical stability.[22]
Much has been written about quality improvement (QI) by the Institute for Healthcare Improvement, the Society of Hospitalist Medicine, and others.[23, 24, 25] How best to move from a Choosing Wisely recommendation to highly reliable incorporation in clinical practice in a community setting is not known and likely varies depending upon the care environment. Successful QI interventions are often multifaceted and include academic detailing and provider education, transparent display of data, and regular audit and feedback of performance data.[26, 27, 28, 29] Prior to the publication of the Society of Hospital Medicine's Choosing Wisely recommendations, we chose to implement the recommendation to decrease ordering of daily labs using 3 QI strategies in our community 4‐hospital health system.
METHODS
Study Participants
This activity was undertaken as a QI initiative by Swedish Hospital Medicine (SHM), a 53‐provider employed hospitalist group that staffs a total of 1420 beds across 4 inpatient facilities. SHM has a longstanding record of working together as a team on QI projects.
An informal preliminary audit of our common lab ordering by a member of the study team revealed multiple examples of labs ordered every day without medical‐record evidence of intervention or management decisions being made based on the results. This preliminary activity raised the notion within the hospitalist group that this was a topic ripe for intervention and improvement. Four common labs, CBC, BMP, nutrition panel (called TPN 2 in our system, consisting of a BMP and magnesium and phosphorus) and comprehensive metabolic panel (BMP and liver function tests), formed the bulk of the repetitively ordered labs and were the focus of our activity. We excluded prothrombin time/International Normalized Ratio, as it was less clear that obtaining these daily clearly represented waste. We then reviewed medical literature for successful QI strategies and chose academic detailing, transparent display of data, and audit and feedback as our QI tactics.[29]
Using data from our electronic medical record, we chose a convenience preintervention period of 10 months for our baseline data. We allowed for a 2‐month wash‐in period in August 2013, and a convenience period of 7 months was chosen as the intervention period.
Intervention
An introductory email was sent out in mid‐August 2013 to all hospitalist providers describing the waste and potential harm to patients associated with unnecessary common blood tests, in particular those ordered as daily. The email recommended 2 changes: (1) immediate cessation of the practice of ordering common labs as daily, in an open, unending manner and (2) assessing the need for common labs in the next 24 hours, and ordering based on that need, but no further into the future.
Hospitalist providers were additionally informed that the number of common labs ordered daily would be tracked prospectively, with monthly reporting of individual provider ordering. In addition, the 5 members of the hospitalist team who most frequently ordered common labs as daily during January 2013 to March 2013 were sent individual emails informing them of their top‐5 position.
During the 7‐month intervention period, a monthly email was sent to all members of the hospitalist team with 4 basic components: (1) reiteration of the recommendations and reasoning stated in the original email; (2) a list of all members of the hospitalist team and the corresponding frequency of common labs ordered as daily (open ended) per provider for the month; (3) a recommendation to discontinue any common labs ordered as daily; and (4) at least 1 example of a patient cared for during the month by the hospitalist team, who had at least 1 common lab ordered for at least 5 days in a row, with no mention of the results in the progress notes and no apparent contribution to the management of the medical conditions for which the patient was being treated.
The change in number of tests ordered during the intervention was not shared with the team until early January 2014.
Data Elements and Endpoints
Number of common labs ordered as daily, and the total number of common labs per hospital‐day, ordered by any frequency, on hospitalist patients were abstracted from the electronic medical record. Hospitalist patients were defined as those both admitted and discharged by a hospitalist provider. We chose to compare the 10 months prior to the intervention with the 7 months during the intervention, allowing 1 month as the intervention wash‐in period. No other interventions related to lab ordering occurred during the study period. Additional variables collected included duration of hospitalization, mortality, readmission, and transfusion data. Consistency of providers in the preintervention and intervention period was high. Two providers were included in some of the preintervention data, but were not included in the intervention data, as they both left for other positions. Otherwise, all other providers in the data were consistent between the 2 time periods.
The primary endpoint was chosen a priori as the total number of common labs ordered per hospital‐day. Additionally, we identified a priori potential confounders, including age, sex, and primary discharge diagnosis, as captured by the all‐patient refined diagnosis‐related group (APR‐DRG, hereafter DRG). DRG was chosen as a clinical risk adjustment variable because there does not exist an established method to model the effects of clinical conditions on the propensity to obtain labs, the primary endpoint. Many models used for risk adjustment in patient quality reporting use hospital mortality as the primary endpoint, not the need for laboratory testing.[30, 31] As our primary endpoint was common labs and not mortality, we chose DRG as the best single variable to model changes in the clinical case mix that might affect the number of common labs.
Secondary endpoints were also determined a priori. Out of desire to assess the patient safety implications of an intervention targeting decreased monitoring, we included hospital mortality, duration of hospitalization, and readmission as safety variables. Two secondary endpoints were obtained as possible additional efficacy endpoints to test the hypothesis that the intervention might be associated with a reduction in transfusion burden: red blood cell transfusion and transfusion volume. We also tracked the frequency with which providers ordered common labs as daily in the baseline and intervention periods, as this was the behavior targeted by the interventions.
Costs to the hospital to produce the lab studies were also considered as a secondary endpoint. Median hospital costs were obtained from the first‐quarter, 2013 Premier dataset, a national dataset of hospital costs (basic metabolic panel $14.69, complete blood count $11.68, comprehensive metabolic panel $18.66). Of note, the Premier data did not include cost data on what our institution calls a TPN 2, and BMP cost was used as a substitute, given the overlap of the 2 tests' components and a desire to conservatively estimate the effects on cost to produce. Additionally, we factored in estimate of hospitalist and analyst time at $150/hour and $75/hour, respectively, to conduct that data abstraction and analysis and to manage the program. We did not formally factor in other costs, including electronic medical record acquisition costs.
Statistical Analyses
Descriptive statistics were used to describe the 2 cohorts. To test our primary hypothesis about the association between cohort membership and number of common labs per patient day, a clustered multivariable linear regression model was constructed to adjust for the a priori identified potential confounders, including sex, age, and principle discharge diagnosis. Each DRG was entered as a categorical variable in the model. Clustering was employed to account for correlation of lab ordering behavior by a given hospitalist. Separate clustered multivariable models were constructed to test the association between cohort and secondary outcomes, including duration of hospitalization, readmission, mortality, transfusion frequency, and transfusion volume using the same potential confounders. All P values were 2‐sided, and a P<0.05 was considered statistically significant. All analyses were conducted with Stata 11.2 (StataCorp, College Station, TX). The study was reviewed by the Swedish Health Services Clinical Research Center and determined to be nonhuman subjects research.
RESULTS
Patient Characteristics
Patient characteristics in the before and after cohorts are shown in Table 1. Both proportion of male sex (44.9% vs 44.9%, P=1.0) and the mean age (64.6 vs 64.8 years, P=0.5) did not significantly differ between the 2 cohorts. Interestingly, there was a significant change in the distribution of DRGs between the 2 cohorts, with each of the top 10 DRGs becoming more common in the intervention cohort. For example, the percentage of patients with sepsis or severe sepsis, DRGs 871 and 872, increased by 2.2% (8.2% vs 10.4%, P<0.01).
| Baseline, n=7832 | Intervention, n=5759 | P Valuea | |
|---|---|---|---|
| |||
| Age, y, mean (SD) | 64.6 (19.6) | 64.8 | 0.5 |
| Male, n (%) | 3,514 (44.9) | 2,585 (44.9) | 1.0 |
| Primary discharge diagnosis, DRG no., name, n (%)b | |||
| 871 and 872, severe sepsis | 641 (8.2) | 599 (10.4) | <0.01 |
| 885, psychoses | 72 (0.9) | 141 (2.4) | <0.01 |
| 392, esophagitis, gastroenteritis and miscellaneous intestinal disorders | 171 (2.2) | 225 (3.9) | <0.01 |
| 313, chest pain | 114 (1.5) | 123 (2.1) | <0.01 |
| 378, gastrointestinal bleed | 100 (1.3) | 117 (2.0) | <0.01 |
| 291, congestive heart failure and shock | 83 (1.1) | 101 (1.8) | <0.01 |
| 189, pulmonary edema and respiratory failure | 69 (0.9) | 112 (1.9) | <0.01 |
| 312, syncope and collapse | 82 (1.0) | 119 (2.1) | <0.01 |
| 64, intracranial hemorrhage or cerebral infarction | 49 (0.6) | 54 (0.9) | 0.04 |
| 603, cellulitis | 96 (1.2) | 94 (1.6) | 0.05 |
Primary Endpoint
In the unadjusted comparison, 3 of the 4 common labs showed a similar decrease in the intervention cohort from the baseline (Table 2). For example, the mean number of CBCs ordered per patient‐day decreased by 0.15 labs per patient day (1.06 vs 0.91, P<0.01). The total number of common labs ordered per patient‐day decreased by 0.30 labs per patient‐day (2.06 vs 1.76, P<0.01) in the unadjusted analysis (Figure 1 and Table 2). Part of our hypothesis was that decreasing the number of labs that were ordered as daily, in an open‐ended manner, would likely decrease the number of common labs obtained per day. We found that the number of labs ordered as daily decreased by 0.71 labs per patient‐day (0.872.90 vs 0.161.01, P<0.01), an 81.6% decrease from the preintervention time period.
| Baseline | Intervention | P Valuea | |
|---|---|---|---|
| |||
| Complete blood count, per patient‐day, mean (SD) | 1.06 (0.76) | 0.91 (0.75) | <0.01 |
| Basic metabolic panel, per patient‐day, mean (SD) | 0.68 (0.71) | 0.55 (0.60) | <0.01 |
| Nutrition panel, mean (SD)b | 0.06 (0.24) | 0.07 (0.32) | 0.01 |
| Comprehensive metabolic panel, per patient‐day, mean (SD) | 0.27 (0.49) | 0.23 (0.46) | <0.01 |
| Total no. of basic labs ordered per patient‐day, mean (SD) | 2.06 (1.40) | 1.76 (1.37) | <0.01 |
| Transfused, n (%) | 414 (5.3) | 268 (4.7) | 0.1 |
| Transfused volume, mL, mean (SD) | 847.3 (644.3) | 744.9 (472.0) | 0.02 |
| Length of stay, days, mean (SD) | 3.79 (4.58) | 3.81 (4.50) | 0.7 |
| Readmitted, n (%) | 1049 (13.3) | 733 (12.7) | 0.3 |
| Died, n (%) | 173 (2.2) | 104 (1.8) | 0.1 |
In our multivariable regression model, after adjusting for sex, age, and the primary reason for admission as captured by DRG, the number of common labs ordered per day was reduced by 0.22 (95% CI, 0.34 to 0.11; P<0.01). This represents a 10.7% reduction in common labs ordered per patient day.
Secondary Endpoints
Table 2 shows secondary outcomes of the study. Patient safety endpoints were not changed in unadjusted analyses. For example, the hospital length of stay in number of days was similar in both the baseline and intervention cohorts (3.784.58 vs 3.814.50, P=0.7). There was a nonsignificant reduction in the hospital mortality rate during the intervention period by 0.4% (2.2% vs 1.8%, P=0.1). No significant differences were found when the multivariable model was rerun for each of the 3 secondary endpoints individually, readmissions, mortality, and length of stay.
Two secondary efficacy endpoints were also evaluated. The percentage of patients receiving transfusions did not decrease in either the unadjusted or adjusted analysis. However, the volume of blood transfused per patient who received a transfusion decreased by 91.9 mL in the bivariate analysis (836.8 mL621.4 mL vs 744.9 mL472.0 mL; P=0.03) (Table 2). The decrease, however, was not significant in the multivariable model (127.2 mL; 95% CI, 257.9 to 3.6; P=0.06).
Cost Data
Based on the Premier estimate of the cost to the hospital to perform the common lab tests, the intervention likely decreased direct costs by $16.19 per patient (95% CI, $12.95 to $19.43). The cost saving was decreased by the expense of the intervention, which is estimated to be $8000 and was driven by hospitalist and analyst time. Based on the patient volume in our health system, and factoring in the cost of implementation, we estimate that this intervention resulted in annualized savings of $151,682 (95% CI, $119,746 to $187,618).
DISCUSSION
Ordering common labs daily is a routine practice among providers at many institutions. In fact, at our institution, prior to the intervention, 42% of all common labs were ordered as daily, meaning they were obtained each day without regard to the previous value or the patient's clinical condition. The practice is one of convenience or habit, and many times not clinically indicated.[5, 32]
We observed a significant reduction in the number of common labs ordered as daily, and more importantly, the total number of common labs in the intervention period. The rapid change in provider behavior is notable and likely due to several factors. First, there was a general sentiment among the hospitalists in the merits of the project. Second, there may have been an aversion to the display of lower performance relative to peers in the monthly e‐mails. Third, and perhaps most importantly, our hospitalist team had worked together for many years on projects like this, creating a culture of QI and willingness to change practice patterns in response to data.[33]
Concern about decreasing waste and increasing the value of healthcare abound, particularly in the United States.[1] Decreasing the cost to produce equivalent or improved health outcomes for a given episode of care has been proposed as a way to improve value.[34] This intervention results in modest waste reduction, the benefits of which are readily apparent in a DRG‐based reimbursement model, where the hospital realizes any saving in the cost of producing a hospital stay, as well as in a total cost of care environment, such as could be found in an Accountable Care Organization.
The previous work in the field of lab reduction has all been performed at university‐affiliated academic institutions. We demonstrated that the QI tactics described in the literature can be successfully employed in a community‐based hospitalist practice. This has broad applicability to increasing the value of healthcare and could serve as a model for future community‐based hospitalist QI projects.
The study has several limitations. First, the length of follow‐up is only 7 months, and although there was rapid and effective adoption of the intervention, provider behavior may regress to previous practice patterns over time. Second, the simple before‐after nature of our trial design raises the possibility that environmental influences exist and that changes in ordering behavior may have been the result of something other than the intervention. Most notably, the Choosing Wisely recommendation for hospitalists was published in September of 2013, coinciding with our intervention period.[22] The reduction in number of labs ordered may have been a partial result of these recommendations. Third, the 2 cohorts included different times of the year based on the distribution of DRGs, which likely had a different composition of diagnoses being treated. To address this we adjusted for DRG, but there may have been some residual confounding, as some diagnoses may be managed with more laboratory tests than others in a way that was not fully adjusted for in our model. Fourth, the intervention was made possible because of the substantial and ongoing investments that our health system has made in our electronic medical record and data analytics capability. The variability of these resources across institutions limits generalizability. Fifth, although we used the QI tools that were described, we did not do a formal process map or utilize other Lean or Six Sigma tools. As the healthcare industry continues on its journey to high reliability, these use tools will hopefully become more widespread. We demonstrated that even with these simple tactics, significant progress can be made.
Finally, there exists a concern that decreasing regular laboratory monitoring might be associated with undetected worsening in the patient's clinical status. We did not observe any significant adverse effects on coarse measures of clinical performance, including length of stay, readmission rate, or mortality. However, we did not collect data on all clinical parameters, and it is possible that there could have been an undetected effect on incident renal failure or hemodialysis or intensive care unit transfer. Other studies on this type of intervention have evaluated some of these possible adverse outcomes and have not noted an association.[12, 15, 18, 20, 22] Future studies should evaluate harms associated with implementation of Choosing Wisely and other interventions targeted at waste reduction. Future work is also needed to disseminate more formal and rigorous QI tools and methodologies.
CONCLUSION
We implemented a multifaceted QI intervention including provider education, transparent display of data, and audit and feedback that was associated with a significant reduction in the number of common labs ordered in a large community‐based hospitalist group, without evidence of harm. Further study is needed to understand how hospitalist groups can optimally decrease waste in healthcare.
Disclosures
This work was performed at the Swedish Health System, Seattle, Washington. Dr. Corson served as primary author, designed the study protocol, obtained the data, analyzed all the data and wrote the manuscript and its revisions, and approved the final version of the manuscript. He attests that no undisclosed authors contributed to the manuscript. Dr. Fan designed the study protocol, reviewed the manuscript, and approved the final version of the manuscript. Mr. White reviewed the study protocol, obtained the study data, reviewed the manuscript, and approved the final version of the manuscript. Sean D. Sullivan, PhD, designed the study protocol, obtained study data, reviewed the manuscript, and approved the final version of the manuscript. Dr. Asakura designed the study protocol, reviewed the manuscript, and approved the final version of the manuscript. Dr. Myint reviewed the study protocol and data, reviewed the manuscript, and approved the final version of the manuscript. Dr. Dale designed the study protocol, analyzed the data, reviewed the manuscript, and approved the final version of the manuscript. The authors report no conflicts of interest.
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- . The U.S. health system in perspective: a comparison of twelve industrialized nations. Issue Brief (Commonw Fund). 2011;16:1–14.
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- , . Phlebotomy for diagnostic laboratory tests in adults. Pattern of use and effect on transfusion requirements. N Engl J Med. 1986;314(19):1233–1235.
- , , , et al. Diagnostic blood loss from phlebotomy and hospital‐acquired anemia during acute myocardial infarction. Arch Intern Med. 2011;171(18):1646–1653.
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- , , , et al. A cost‐effective method for reducing the volume of laboratory tests in a university‐associated teaching hospital. Mt Sinai J Med. 2006;73(5):787–794.
- , . Inappropriate use of laboratory services: long term combined approach to modify request patterns. BMJ. 1990;301(6764):1305–1307.
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- , , , , . An administrative intervention to improve the utilization of laboratory tests within a university hospital. Int J Qual Heal Care. 2005;17(3):243–248.
- . Surgical vampires and rising health care expenditure. Arch Surg. 2011;146(5):524–527.
- , , , et al. Trial of strategy for reducing the use of laboratory tests. Br Med J (Clin Res Ed). 1986;292(6524):883–885.
- , , , et al. Improving house staff ordering of three common laboratory tests. Reductions in test ordering need not result in underutilization. Med Care. 1987;25(10):928–935.
- , , , et al. Reducing unnecessary inpatient laboratory testing in a teaching hospital. Am J Clin Pathol. 2006;126(2):200–206.
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- , , , et al. Choosing wisely in adult hospital medicine: five opportunities for improved healthcare value. J Hosp Med. 2013;8(9):486–492.
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Waste in US healthcare is a public health threat, with an estimated value of $910 billion per year.[1] It constitutes some of the relatively high per‐discharge healthcare spending seen in the United States when compared to other nations.[2] Waste takes many forms, one of which is excessive use of diagnostic laboratory testing.[1] Many hospital providers obtain common labs, such as complete blood counts (CBCs) and basic metabolic panels (BMPs), in an open‐ended, daily manner for their hospitalized patients, without regard for the patient's clinical condition or despite stability of the previous results. Reasons for ordering these tests in a nonpatient‐centered manner include provider convenience (such as inclusion in an order set), ease of access, habit, or defensive practice.[3, 4, 5] All of these reasons may represent waste.
Although the potential waste of routine daily labs may seem small, the frequency with which they are ordered results in a substantial real and potential cost, both financially and clinically. Multiple studies have shown a link between excessive diagnostic phlebotomy and hospital‐acquired anemia.[6, 7, 8, 9] Hospital‐acquired anemia itself has been associated with increased mortality.[10] In addition to blood loss and financial cost, patient experience and satisfaction are also detrimentally affected by excessive laboratory testing in the form of pain and inconvenience from the act of phlebotomy.[11]
There are many reports of strategies to decrease excessive diagnostic laboratory testing as a means of addressing this waste in the inpatient setting.[12, 13, 14, 15, 16, 17, 18, 19, 20, 21] All of these studies have taken place in a traditional academic setting, and many implemented their intervention through a computer‐based order entry system. Based on the literature search regarding this topic, we found no examples of studies conducted among and within community‐based hospitalist practices. More recently, this issue was highlighted as part of the Choosing Wisely campaign sponsored by the American Board of Internal Medicine Foundation, Consumer Reports, and more than 60 specialty societies. The Society of Hospital Medicine, the professional society for hospitalists, recommended avoidance of repetitive common laboratory testing in the face of clinical stability.[22]
Much has been written about quality improvement (QI) by the Institute for Healthcare Improvement, the Society of Hospitalist Medicine, and others.[23, 24, 25] How best to move from a Choosing Wisely recommendation to highly reliable incorporation in clinical practice in a community setting is not known and likely varies depending upon the care environment. Successful QI interventions are often multifaceted and include academic detailing and provider education, transparent display of data, and regular audit and feedback of performance data.[26, 27, 28, 29] Prior to the publication of the Society of Hospital Medicine's Choosing Wisely recommendations, we chose to implement the recommendation to decrease ordering of daily labs using 3 QI strategies in our community 4‐hospital health system.
METHODS
Study Participants
This activity was undertaken as a QI initiative by Swedish Hospital Medicine (SHM), a 53‐provider employed hospitalist group that staffs a total of 1420 beds across 4 inpatient facilities. SHM has a longstanding record of working together as a team on QI projects.
An informal preliminary audit of our common lab ordering by a member of the study team revealed multiple examples of labs ordered every day without medical‐record evidence of intervention or management decisions being made based on the results. This preliminary activity raised the notion within the hospitalist group that this was a topic ripe for intervention and improvement. Four common labs, CBC, BMP, nutrition panel (called TPN 2 in our system, consisting of a BMP and magnesium and phosphorus) and comprehensive metabolic panel (BMP and liver function tests), formed the bulk of the repetitively ordered labs and were the focus of our activity. We excluded prothrombin time/International Normalized Ratio, as it was less clear that obtaining these daily clearly represented waste. We then reviewed medical literature for successful QI strategies and chose academic detailing, transparent display of data, and audit and feedback as our QI tactics.[29]
Using data from our electronic medical record, we chose a convenience preintervention period of 10 months for our baseline data. We allowed for a 2‐month wash‐in period in August 2013, and a convenience period of 7 months was chosen as the intervention period.
Intervention
An introductory email was sent out in mid‐August 2013 to all hospitalist providers describing the waste and potential harm to patients associated with unnecessary common blood tests, in particular those ordered as daily. The email recommended 2 changes: (1) immediate cessation of the practice of ordering common labs as daily, in an open, unending manner and (2) assessing the need for common labs in the next 24 hours, and ordering based on that need, but no further into the future.
Hospitalist providers were additionally informed that the number of common labs ordered daily would be tracked prospectively, with monthly reporting of individual provider ordering. In addition, the 5 members of the hospitalist team who most frequently ordered common labs as daily during January 2013 to March 2013 were sent individual emails informing them of their top‐5 position.
During the 7‐month intervention period, a monthly email was sent to all members of the hospitalist team with 4 basic components: (1) reiteration of the recommendations and reasoning stated in the original email; (2) a list of all members of the hospitalist team and the corresponding frequency of common labs ordered as daily (open ended) per provider for the month; (3) a recommendation to discontinue any common labs ordered as daily; and (4) at least 1 example of a patient cared for during the month by the hospitalist team, who had at least 1 common lab ordered for at least 5 days in a row, with no mention of the results in the progress notes and no apparent contribution to the management of the medical conditions for which the patient was being treated.
The change in number of tests ordered during the intervention was not shared with the team until early January 2014.
Data Elements and Endpoints
Number of common labs ordered as daily, and the total number of common labs per hospital‐day, ordered by any frequency, on hospitalist patients were abstracted from the electronic medical record. Hospitalist patients were defined as those both admitted and discharged by a hospitalist provider. We chose to compare the 10 months prior to the intervention with the 7 months during the intervention, allowing 1 month as the intervention wash‐in period. No other interventions related to lab ordering occurred during the study period. Additional variables collected included duration of hospitalization, mortality, readmission, and transfusion data. Consistency of providers in the preintervention and intervention period was high. Two providers were included in some of the preintervention data, but were not included in the intervention data, as they both left for other positions. Otherwise, all other providers in the data were consistent between the 2 time periods.
The primary endpoint was chosen a priori as the total number of common labs ordered per hospital‐day. Additionally, we identified a priori potential confounders, including age, sex, and primary discharge diagnosis, as captured by the all‐patient refined diagnosis‐related group (APR‐DRG, hereafter DRG). DRG was chosen as a clinical risk adjustment variable because there does not exist an established method to model the effects of clinical conditions on the propensity to obtain labs, the primary endpoint. Many models used for risk adjustment in patient quality reporting use hospital mortality as the primary endpoint, not the need for laboratory testing.[30, 31] As our primary endpoint was common labs and not mortality, we chose DRG as the best single variable to model changes in the clinical case mix that might affect the number of common labs.
Secondary endpoints were also determined a priori. Out of desire to assess the patient safety implications of an intervention targeting decreased monitoring, we included hospital mortality, duration of hospitalization, and readmission as safety variables. Two secondary endpoints were obtained as possible additional efficacy endpoints to test the hypothesis that the intervention might be associated with a reduction in transfusion burden: red blood cell transfusion and transfusion volume. We also tracked the frequency with which providers ordered common labs as daily in the baseline and intervention periods, as this was the behavior targeted by the interventions.
Costs to the hospital to produce the lab studies were also considered as a secondary endpoint. Median hospital costs were obtained from the first‐quarter, 2013 Premier dataset, a national dataset of hospital costs (basic metabolic panel $14.69, complete blood count $11.68, comprehensive metabolic panel $18.66). Of note, the Premier data did not include cost data on what our institution calls a TPN 2, and BMP cost was used as a substitute, given the overlap of the 2 tests' components and a desire to conservatively estimate the effects on cost to produce. Additionally, we factored in estimate of hospitalist and analyst time at $150/hour and $75/hour, respectively, to conduct that data abstraction and analysis and to manage the program. We did not formally factor in other costs, including electronic medical record acquisition costs.
Statistical Analyses
Descriptive statistics were used to describe the 2 cohorts. To test our primary hypothesis about the association between cohort membership and number of common labs per patient day, a clustered multivariable linear regression model was constructed to adjust for the a priori identified potential confounders, including sex, age, and principle discharge diagnosis. Each DRG was entered as a categorical variable in the model. Clustering was employed to account for correlation of lab ordering behavior by a given hospitalist. Separate clustered multivariable models were constructed to test the association between cohort and secondary outcomes, including duration of hospitalization, readmission, mortality, transfusion frequency, and transfusion volume using the same potential confounders. All P values were 2‐sided, and a P<0.05 was considered statistically significant. All analyses were conducted with Stata 11.2 (StataCorp, College Station, TX). The study was reviewed by the Swedish Health Services Clinical Research Center and determined to be nonhuman subjects research.
RESULTS
Patient Characteristics
Patient characteristics in the before and after cohorts are shown in Table 1. Both proportion of male sex (44.9% vs 44.9%, P=1.0) and the mean age (64.6 vs 64.8 years, P=0.5) did not significantly differ between the 2 cohorts. Interestingly, there was a significant change in the distribution of DRGs between the 2 cohorts, with each of the top 10 DRGs becoming more common in the intervention cohort. For example, the percentage of patients with sepsis or severe sepsis, DRGs 871 and 872, increased by 2.2% (8.2% vs 10.4%, P<0.01).
| Baseline, n=7832 | Intervention, n=5759 | P Valuea | |
|---|---|---|---|
| |||
| Age, y, mean (SD) | 64.6 (19.6) | 64.8 | 0.5 |
| Male, n (%) | 3,514 (44.9) | 2,585 (44.9) | 1.0 |
| Primary discharge diagnosis, DRG no., name, n (%)b | |||
| 871 and 872, severe sepsis | 641 (8.2) | 599 (10.4) | <0.01 |
| 885, psychoses | 72 (0.9) | 141 (2.4) | <0.01 |
| 392, esophagitis, gastroenteritis and miscellaneous intestinal disorders | 171 (2.2) | 225 (3.9) | <0.01 |
| 313, chest pain | 114 (1.5) | 123 (2.1) | <0.01 |
| 378, gastrointestinal bleed | 100 (1.3) | 117 (2.0) | <0.01 |
| 291, congestive heart failure and shock | 83 (1.1) | 101 (1.8) | <0.01 |
| 189, pulmonary edema and respiratory failure | 69 (0.9) | 112 (1.9) | <0.01 |
| 312, syncope and collapse | 82 (1.0) | 119 (2.1) | <0.01 |
| 64, intracranial hemorrhage or cerebral infarction | 49 (0.6) | 54 (0.9) | 0.04 |
| 603, cellulitis | 96 (1.2) | 94 (1.6) | 0.05 |
Primary Endpoint
In the unadjusted comparison, 3 of the 4 common labs showed a similar decrease in the intervention cohort from the baseline (Table 2). For example, the mean number of CBCs ordered per patient‐day decreased by 0.15 labs per patient day (1.06 vs 0.91, P<0.01). The total number of common labs ordered per patient‐day decreased by 0.30 labs per patient‐day (2.06 vs 1.76, P<0.01) in the unadjusted analysis (Figure 1 and Table 2). Part of our hypothesis was that decreasing the number of labs that were ordered as daily, in an open‐ended manner, would likely decrease the number of common labs obtained per day. We found that the number of labs ordered as daily decreased by 0.71 labs per patient‐day (0.872.90 vs 0.161.01, P<0.01), an 81.6% decrease from the preintervention time period.
| Baseline | Intervention | P Valuea | |
|---|---|---|---|
| |||
| Complete blood count, per patient‐day, mean (SD) | 1.06 (0.76) | 0.91 (0.75) | <0.01 |
| Basic metabolic panel, per patient‐day, mean (SD) | 0.68 (0.71) | 0.55 (0.60) | <0.01 |
| Nutrition panel, mean (SD)b | 0.06 (0.24) | 0.07 (0.32) | 0.01 |
| Comprehensive metabolic panel, per patient‐day, mean (SD) | 0.27 (0.49) | 0.23 (0.46) | <0.01 |
| Total no. of basic labs ordered per patient‐day, mean (SD) | 2.06 (1.40) | 1.76 (1.37) | <0.01 |
| Transfused, n (%) | 414 (5.3) | 268 (4.7) | 0.1 |
| Transfused volume, mL, mean (SD) | 847.3 (644.3) | 744.9 (472.0) | 0.02 |
| Length of stay, days, mean (SD) | 3.79 (4.58) | 3.81 (4.50) | 0.7 |
| Readmitted, n (%) | 1049 (13.3) | 733 (12.7) | 0.3 |
| Died, n (%) | 173 (2.2) | 104 (1.8) | 0.1 |
In our multivariable regression model, after adjusting for sex, age, and the primary reason for admission as captured by DRG, the number of common labs ordered per day was reduced by 0.22 (95% CI, 0.34 to 0.11; P<0.01). This represents a 10.7% reduction in common labs ordered per patient day.
Secondary Endpoints
Table 2 shows secondary outcomes of the study. Patient safety endpoints were not changed in unadjusted analyses. For example, the hospital length of stay in number of days was similar in both the baseline and intervention cohorts (3.784.58 vs 3.814.50, P=0.7). There was a nonsignificant reduction in the hospital mortality rate during the intervention period by 0.4% (2.2% vs 1.8%, P=0.1). No significant differences were found when the multivariable model was rerun for each of the 3 secondary endpoints individually, readmissions, mortality, and length of stay.
Two secondary efficacy endpoints were also evaluated. The percentage of patients receiving transfusions did not decrease in either the unadjusted or adjusted analysis. However, the volume of blood transfused per patient who received a transfusion decreased by 91.9 mL in the bivariate analysis (836.8 mL621.4 mL vs 744.9 mL472.0 mL; P=0.03) (Table 2). The decrease, however, was not significant in the multivariable model (127.2 mL; 95% CI, 257.9 to 3.6; P=0.06).
Cost Data
Based on the Premier estimate of the cost to the hospital to perform the common lab tests, the intervention likely decreased direct costs by $16.19 per patient (95% CI, $12.95 to $19.43). The cost saving was decreased by the expense of the intervention, which is estimated to be $8000 and was driven by hospitalist and analyst time. Based on the patient volume in our health system, and factoring in the cost of implementation, we estimate that this intervention resulted in annualized savings of $151,682 (95% CI, $119,746 to $187,618).
DISCUSSION
Ordering common labs daily is a routine practice among providers at many institutions. In fact, at our institution, prior to the intervention, 42% of all common labs were ordered as daily, meaning they were obtained each day without regard to the previous value or the patient's clinical condition. The practice is one of convenience or habit, and many times not clinically indicated.[5, 32]
We observed a significant reduction in the number of common labs ordered as daily, and more importantly, the total number of common labs in the intervention period. The rapid change in provider behavior is notable and likely due to several factors. First, there was a general sentiment among the hospitalists in the merits of the project. Second, there may have been an aversion to the display of lower performance relative to peers in the monthly e‐mails. Third, and perhaps most importantly, our hospitalist team had worked together for many years on projects like this, creating a culture of QI and willingness to change practice patterns in response to data.[33]
Concern about decreasing waste and increasing the value of healthcare abound, particularly in the United States.[1] Decreasing the cost to produce equivalent or improved health outcomes for a given episode of care has been proposed as a way to improve value.[34] This intervention results in modest waste reduction, the benefits of which are readily apparent in a DRG‐based reimbursement model, where the hospital realizes any saving in the cost of producing a hospital stay, as well as in a total cost of care environment, such as could be found in an Accountable Care Organization.
The previous work in the field of lab reduction has all been performed at university‐affiliated academic institutions. We demonstrated that the QI tactics described in the literature can be successfully employed in a community‐based hospitalist practice. This has broad applicability to increasing the value of healthcare and could serve as a model for future community‐based hospitalist QI projects.
The study has several limitations. First, the length of follow‐up is only 7 months, and although there was rapid and effective adoption of the intervention, provider behavior may regress to previous practice patterns over time. Second, the simple before‐after nature of our trial design raises the possibility that environmental influences exist and that changes in ordering behavior may have been the result of something other than the intervention. Most notably, the Choosing Wisely recommendation for hospitalists was published in September of 2013, coinciding with our intervention period.[22] The reduction in number of labs ordered may have been a partial result of these recommendations. Third, the 2 cohorts included different times of the year based on the distribution of DRGs, which likely had a different composition of diagnoses being treated. To address this we adjusted for DRG, but there may have been some residual confounding, as some diagnoses may be managed with more laboratory tests than others in a way that was not fully adjusted for in our model. Fourth, the intervention was made possible because of the substantial and ongoing investments that our health system has made in our electronic medical record and data analytics capability. The variability of these resources across institutions limits generalizability. Fifth, although we used the QI tools that were described, we did not do a formal process map or utilize other Lean or Six Sigma tools. As the healthcare industry continues on its journey to high reliability, these use tools will hopefully become more widespread. We demonstrated that even with these simple tactics, significant progress can be made.
Finally, there exists a concern that decreasing regular laboratory monitoring might be associated with undetected worsening in the patient's clinical status. We did not observe any significant adverse effects on coarse measures of clinical performance, including length of stay, readmission rate, or mortality. However, we did not collect data on all clinical parameters, and it is possible that there could have been an undetected effect on incident renal failure or hemodialysis or intensive care unit transfer. Other studies on this type of intervention have evaluated some of these possible adverse outcomes and have not noted an association.[12, 15, 18, 20, 22] Future studies should evaluate harms associated with implementation of Choosing Wisely and other interventions targeted at waste reduction. Future work is also needed to disseminate more formal and rigorous QI tools and methodologies.
CONCLUSION
We implemented a multifaceted QI intervention including provider education, transparent display of data, and audit and feedback that was associated with a significant reduction in the number of common labs ordered in a large community‐based hospitalist group, without evidence of harm. Further study is needed to understand how hospitalist groups can optimally decrease waste in healthcare.
Disclosures
This work was performed at the Swedish Health System, Seattle, Washington. Dr. Corson served as primary author, designed the study protocol, obtained the data, analyzed all the data and wrote the manuscript and its revisions, and approved the final version of the manuscript. He attests that no undisclosed authors contributed to the manuscript. Dr. Fan designed the study protocol, reviewed the manuscript, and approved the final version of the manuscript. Mr. White reviewed the study protocol, obtained the study data, reviewed the manuscript, and approved the final version of the manuscript. Sean D. Sullivan, PhD, designed the study protocol, obtained study data, reviewed the manuscript, and approved the final version of the manuscript. Dr. Asakura designed the study protocol, reviewed the manuscript, and approved the final version of the manuscript. Dr. Myint reviewed the study protocol and data, reviewed the manuscript, and approved the final version of the manuscript. Dr. Dale designed the study protocol, analyzed the data, reviewed the manuscript, and approved the final version of the manuscript. The authors report no conflicts of interest.
Waste in US healthcare is a public health threat, with an estimated value of $910 billion per year.[1] It constitutes some of the relatively high per‐discharge healthcare spending seen in the United States when compared to other nations.[2] Waste takes many forms, one of which is excessive use of diagnostic laboratory testing.[1] Many hospital providers obtain common labs, such as complete blood counts (CBCs) and basic metabolic panels (BMPs), in an open‐ended, daily manner for their hospitalized patients, without regard for the patient's clinical condition or despite stability of the previous results. Reasons for ordering these tests in a nonpatient‐centered manner include provider convenience (such as inclusion in an order set), ease of access, habit, or defensive practice.[3, 4, 5] All of these reasons may represent waste.
Although the potential waste of routine daily labs may seem small, the frequency with which they are ordered results in a substantial real and potential cost, both financially and clinically. Multiple studies have shown a link between excessive diagnostic phlebotomy and hospital‐acquired anemia.[6, 7, 8, 9] Hospital‐acquired anemia itself has been associated with increased mortality.[10] In addition to blood loss and financial cost, patient experience and satisfaction are also detrimentally affected by excessive laboratory testing in the form of pain and inconvenience from the act of phlebotomy.[11]
There are many reports of strategies to decrease excessive diagnostic laboratory testing as a means of addressing this waste in the inpatient setting.[12, 13, 14, 15, 16, 17, 18, 19, 20, 21] All of these studies have taken place in a traditional academic setting, and many implemented their intervention through a computer‐based order entry system. Based on the literature search regarding this topic, we found no examples of studies conducted among and within community‐based hospitalist practices. More recently, this issue was highlighted as part of the Choosing Wisely campaign sponsored by the American Board of Internal Medicine Foundation, Consumer Reports, and more than 60 specialty societies. The Society of Hospital Medicine, the professional society for hospitalists, recommended avoidance of repetitive common laboratory testing in the face of clinical stability.[22]
Much has been written about quality improvement (QI) by the Institute for Healthcare Improvement, the Society of Hospitalist Medicine, and others.[23, 24, 25] How best to move from a Choosing Wisely recommendation to highly reliable incorporation in clinical practice in a community setting is not known and likely varies depending upon the care environment. Successful QI interventions are often multifaceted and include academic detailing and provider education, transparent display of data, and regular audit and feedback of performance data.[26, 27, 28, 29] Prior to the publication of the Society of Hospital Medicine's Choosing Wisely recommendations, we chose to implement the recommendation to decrease ordering of daily labs using 3 QI strategies in our community 4‐hospital health system.
METHODS
Study Participants
This activity was undertaken as a QI initiative by Swedish Hospital Medicine (SHM), a 53‐provider employed hospitalist group that staffs a total of 1420 beds across 4 inpatient facilities. SHM has a longstanding record of working together as a team on QI projects.
An informal preliminary audit of our common lab ordering by a member of the study team revealed multiple examples of labs ordered every day without medical‐record evidence of intervention or management decisions being made based on the results. This preliminary activity raised the notion within the hospitalist group that this was a topic ripe for intervention and improvement. Four common labs, CBC, BMP, nutrition panel (called TPN 2 in our system, consisting of a BMP and magnesium and phosphorus) and comprehensive metabolic panel (BMP and liver function tests), formed the bulk of the repetitively ordered labs and were the focus of our activity. We excluded prothrombin time/International Normalized Ratio, as it was less clear that obtaining these daily clearly represented waste. We then reviewed medical literature for successful QI strategies and chose academic detailing, transparent display of data, and audit and feedback as our QI tactics.[29]
Using data from our electronic medical record, we chose a convenience preintervention period of 10 months for our baseline data. We allowed for a 2‐month wash‐in period in August 2013, and a convenience period of 7 months was chosen as the intervention period.
Intervention
An introductory email was sent out in mid‐August 2013 to all hospitalist providers describing the waste and potential harm to patients associated with unnecessary common blood tests, in particular those ordered as daily. The email recommended 2 changes: (1) immediate cessation of the practice of ordering common labs as daily, in an open, unending manner and (2) assessing the need for common labs in the next 24 hours, and ordering based on that need, but no further into the future.
Hospitalist providers were additionally informed that the number of common labs ordered daily would be tracked prospectively, with monthly reporting of individual provider ordering. In addition, the 5 members of the hospitalist team who most frequently ordered common labs as daily during January 2013 to March 2013 were sent individual emails informing them of their top‐5 position.
During the 7‐month intervention period, a monthly email was sent to all members of the hospitalist team with 4 basic components: (1) reiteration of the recommendations and reasoning stated in the original email; (2) a list of all members of the hospitalist team and the corresponding frequency of common labs ordered as daily (open ended) per provider for the month; (3) a recommendation to discontinue any common labs ordered as daily; and (4) at least 1 example of a patient cared for during the month by the hospitalist team, who had at least 1 common lab ordered for at least 5 days in a row, with no mention of the results in the progress notes and no apparent contribution to the management of the medical conditions for which the patient was being treated.
The change in number of tests ordered during the intervention was not shared with the team until early January 2014.
Data Elements and Endpoints
Number of common labs ordered as daily, and the total number of common labs per hospital‐day, ordered by any frequency, on hospitalist patients were abstracted from the electronic medical record. Hospitalist patients were defined as those both admitted and discharged by a hospitalist provider. We chose to compare the 10 months prior to the intervention with the 7 months during the intervention, allowing 1 month as the intervention wash‐in period. No other interventions related to lab ordering occurred during the study period. Additional variables collected included duration of hospitalization, mortality, readmission, and transfusion data. Consistency of providers in the preintervention and intervention period was high. Two providers were included in some of the preintervention data, but were not included in the intervention data, as they both left for other positions. Otherwise, all other providers in the data were consistent between the 2 time periods.
The primary endpoint was chosen a priori as the total number of common labs ordered per hospital‐day. Additionally, we identified a priori potential confounders, including age, sex, and primary discharge diagnosis, as captured by the all‐patient refined diagnosis‐related group (APR‐DRG, hereafter DRG). DRG was chosen as a clinical risk adjustment variable because there does not exist an established method to model the effects of clinical conditions on the propensity to obtain labs, the primary endpoint. Many models used for risk adjustment in patient quality reporting use hospital mortality as the primary endpoint, not the need for laboratory testing.[30, 31] As our primary endpoint was common labs and not mortality, we chose DRG as the best single variable to model changes in the clinical case mix that might affect the number of common labs.
Secondary endpoints were also determined a priori. Out of desire to assess the patient safety implications of an intervention targeting decreased monitoring, we included hospital mortality, duration of hospitalization, and readmission as safety variables. Two secondary endpoints were obtained as possible additional efficacy endpoints to test the hypothesis that the intervention might be associated with a reduction in transfusion burden: red blood cell transfusion and transfusion volume. We also tracked the frequency with which providers ordered common labs as daily in the baseline and intervention periods, as this was the behavior targeted by the interventions.
Costs to the hospital to produce the lab studies were also considered as a secondary endpoint. Median hospital costs were obtained from the first‐quarter, 2013 Premier dataset, a national dataset of hospital costs (basic metabolic panel $14.69, complete blood count $11.68, comprehensive metabolic panel $18.66). Of note, the Premier data did not include cost data on what our institution calls a TPN 2, and BMP cost was used as a substitute, given the overlap of the 2 tests' components and a desire to conservatively estimate the effects on cost to produce. Additionally, we factored in estimate of hospitalist and analyst time at $150/hour and $75/hour, respectively, to conduct that data abstraction and analysis and to manage the program. We did not formally factor in other costs, including electronic medical record acquisition costs.
Statistical Analyses
Descriptive statistics were used to describe the 2 cohorts. To test our primary hypothesis about the association between cohort membership and number of common labs per patient day, a clustered multivariable linear regression model was constructed to adjust for the a priori identified potential confounders, including sex, age, and principle discharge diagnosis. Each DRG was entered as a categorical variable in the model. Clustering was employed to account for correlation of lab ordering behavior by a given hospitalist. Separate clustered multivariable models were constructed to test the association between cohort and secondary outcomes, including duration of hospitalization, readmission, mortality, transfusion frequency, and transfusion volume using the same potential confounders. All P values were 2‐sided, and a P<0.05 was considered statistically significant. All analyses were conducted with Stata 11.2 (StataCorp, College Station, TX). The study was reviewed by the Swedish Health Services Clinical Research Center and determined to be nonhuman subjects research.
RESULTS
Patient Characteristics
Patient characteristics in the before and after cohorts are shown in Table 1. Both proportion of male sex (44.9% vs 44.9%, P=1.0) and the mean age (64.6 vs 64.8 years, P=0.5) did not significantly differ between the 2 cohorts. Interestingly, there was a significant change in the distribution of DRGs between the 2 cohorts, with each of the top 10 DRGs becoming more common in the intervention cohort. For example, the percentage of patients with sepsis or severe sepsis, DRGs 871 and 872, increased by 2.2% (8.2% vs 10.4%, P<0.01).
| Baseline, n=7832 | Intervention, n=5759 | P Valuea | |
|---|---|---|---|
| |||
| Age, y, mean (SD) | 64.6 (19.6) | 64.8 | 0.5 |
| Male, n (%) | 3,514 (44.9) | 2,585 (44.9) | 1.0 |
| Primary discharge diagnosis, DRG no., name, n (%)b | |||
| 871 and 872, severe sepsis | 641 (8.2) | 599 (10.4) | <0.01 |
| 885, psychoses | 72 (0.9) | 141 (2.4) | <0.01 |
| 392, esophagitis, gastroenteritis and miscellaneous intestinal disorders | 171 (2.2) | 225 (3.9) | <0.01 |
| 313, chest pain | 114 (1.5) | 123 (2.1) | <0.01 |
| 378, gastrointestinal bleed | 100 (1.3) | 117 (2.0) | <0.01 |
| 291, congestive heart failure and shock | 83 (1.1) | 101 (1.8) | <0.01 |
| 189, pulmonary edema and respiratory failure | 69 (0.9) | 112 (1.9) | <0.01 |
| 312, syncope and collapse | 82 (1.0) | 119 (2.1) | <0.01 |
| 64, intracranial hemorrhage or cerebral infarction | 49 (0.6) | 54 (0.9) | 0.04 |
| 603, cellulitis | 96 (1.2) | 94 (1.6) | 0.05 |
Primary Endpoint
In the unadjusted comparison, 3 of the 4 common labs showed a similar decrease in the intervention cohort from the baseline (Table 2). For example, the mean number of CBCs ordered per patient‐day decreased by 0.15 labs per patient day (1.06 vs 0.91, P<0.01). The total number of common labs ordered per patient‐day decreased by 0.30 labs per patient‐day (2.06 vs 1.76, P<0.01) in the unadjusted analysis (Figure 1 and Table 2). Part of our hypothesis was that decreasing the number of labs that were ordered as daily, in an open‐ended manner, would likely decrease the number of common labs obtained per day. We found that the number of labs ordered as daily decreased by 0.71 labs per patient‐day (0.872.90 vs 0.161.01, P<0.01), an 81.6% decrease from the preintervention time period.
| Baseline | Intervention | P Valuea | |
|---|---|---|---|
| |||
| Complete blood count, per patient‐day, mean (SD) | 1.06 (0.76) | 0.91 (0.75) | <0.01 |
| Basic metabolic panel, per patient‐day, mean (SD) | 0.68 (0.71) | 0.55 (0.60) | <0.01 |
| Nutrition panel, mean (SD)b | 0.06 (0.24) | 0.07 (0.32) | 0.01 |
| Comprehensive metabolic panel, per patient‐day, mean (SD) | 0.27 (0.49) | 0.23 (0.46) | <0.01 |
| Total no. of basic labs ordered per patient‐day, mean (SD) | 2.06 (1.40) | 1.76 (1.37) | <0.01 |
| Transfused, n (%) | 414 (5.3) | 268 (4.7) | 0.1 |
| Transfused volume, mL, mean (SD) | 847.3 (644.3) | 744.9 (472.0) | 0.02 |
| Length of stay, days, mean (SD) | 3.79 (4.58) | 3.81 (4.50) | 0.7 |
| Readmitted, n (%) | 1049 (13.3) | 733 (12.7) | 0.3 |
| Died, n (%) | 173 (2.2) | 104 (1.8) | 0.1 |
In our multivariable regression model, after adjusting for sex, age, and the primary reason for admission as captured by DRG, the number of common labs ordered per day was reduced by 0.22 (95% CI, 0.34 to 0.11; P<0.01). This represents a 10.7% reduction in common labs ordered per patient day.
Secondary Endpoints
Table 2 shows secondary outcomes of the study. Patient safety endpoints were not changed in unadjusted analyses. For example, the hospital length of stay in number of days was similar in both the baseline and intervention cohorts (3.784.58 vs 3.814.50, P=0.7). There was a nonsignificant reduction in the hospital mortality rate during the intervention period by 0.4% (2.2% vs 1.8%, P=0.1). No significant differences were found when the multivariable model was rerun for each of the 3 secondary endpoints individually, readmissions, mortality, and length of stay.
Two secondary efficacy endpoints were also evaluated. The percentage of patients receiving transfusions did not decrease in either the unadjusted or adjusted analysis. However, the volume of blood transfused per patient who received a transfusion decreased by 91.9 mL in the bivariate analysis (836.8 mL621.4 mL vs 744.9 mL472.0 mL; P=0.03) (Table 2). The decrease, however, was not significant in the multivariable model (127.2 mL; 95% CI, 257.9 to 3.6; P=0.06).
Cost Data
Based on the Premier estimate of the cost to the hospital to perform the common lab tests, the intervention likely decreased direct costs by $16.19 per patient (95% CI, $12.95 to $19.43). The cost saving was decreased by the expense of the intervention, which is estimated to be $8000 and was driven by hospitalist and analyst time. Based on the patient volume in our health system, and factoring in the cost of implementation, we estimate that this intervention resulted in annualized savings of $151,682 (95% CI, $119,746 to $187,618).
DISCUSSION
Ordering common labs daily is a routine practice among providers at many institutions. In fact, at our institution, prior to the intervention, 42% of all common labs were ordered as daily, meaning they were obtained each day without regard to the previous value or the patient's clinical condition. The practice is one of convenience or habit, and many times not clinically indicated.[5, 32]
We observed a significant reduction in the number of common labs ordered as daily, and more importantly, the total number of common labs in the intervention period. The rapid change in provider behavior is notable and likely due to several factors. First, there was a general sentiment among the hospitalists in the merits of the project. Second, there may have been an aversion to the display of lower performance relative to peers in the monthly e‐mails. Third, and perhaps most importantly, our hospitalist team had worked together for many years on projects like this, creating a culture of QI and willingness to change practice patterns in response to data.[33]
Concern about decreasing waste and increasing the value of healthcare abound, particularly in the United States.[1] Decreasing the cost to produce equivalent or improved health outcomes for a given episode of care has been proposed as a way to improve value.[34] This intervention results in modest waste reduction, the benefits of which are readily apparent in a DRG‐based reimbursement model, where the hospital realizes any saving in the cost of producing a hospital stay, as well as in a total cost of care environment, such as could be found in an Accountable Care Organization.
The previous work in the field of lab reduction has all been performed at university‐affiliated academic institutions. We demonstrated that the QI tactics described in the literature can be successfully employed in a community‐based hospitalist practice. This has broad applicability to increasing the value of healthcare and could serve as a model for future community‐based hospitalist QI projects.
The study has several limitations. First, the length of follow‐up is only 7 months, and although there was rapid and effective adoption of the intervention, provider behavior may regress to previous practice patterns over time. Second, the simple before‐after nature of our trial design raises the possibility that environmental influences exist and that changes in ordering behavior may have been the result of something other than the intervention. Most notably, the Choosing Wisely recommendation for hospitalists was published in September of 2013, coinciding with our intervention period.[22] The reduction in number of labs ordered may have been a partial result of these recommendations. Third, the 2 cohorts included different times of the year based on the distribution of DRGs, which likely had a different composition of diagnoses being treated. To address this we adjusted for DRG, but there may have been some residual confounding, as some diagnoses may be managed with more laboratory tests than others in a way that was not fully adjusted for in our model. Fourth, the intervention was made possible because of the substantial and ongoing investments that our health system has made in our electronic medical record and data analytics capability. The variability of these resources across institutions limits generalizability. Fifth, although we used the QI tools that were described, we did not do a formal process map or utilize other Lean or Six Sigma tools. As the healthcare industry continues on its journey to high reliability, these use tools will hopefully become more widespread. We demonstrated that even with these simple tactics, significant progress can be made.
Finally, there exists a concern that decreasing regular laboratory monitoring might be associated with undetected worsening in the patient's clinical status. We did not observe any significant adverse effects on coarse measures of clinical performance, including length of stay, readmission rate, or mortality. However, we did not collect data on all clinical parameters, and it is possible that there could have been an undetected effect on incident renal failure or hemodialysis or intensive care unit transfer. Other studies on this type of intervention have evaluated some of these possible adverse outcomes and have not noted an association.[12, 15, 18, 20, 22] Future studies should evaluate harms associated with implementation of Choosing Wisely and other interventions targeted at waste reduction. Future work is also needed to disseminate more formal and rigorous QI tools and methodologies.
CONCLUSION
We implemented a multifaceted QI intervention including provider education, transparent display of data, and audit and feedback that was associated with a significant reduction in the number of common labs ordered in a large community‐based hospitalist group, without evidence of harm. Further study is needed to understand how hospitalist groups can optimally decrease waste in healthcare.
Disclosures
This work was performed at the Swedish Health System, Seattle, Washington. Dr. Corson served as primary author, designed the study protocol, obtained the data, analyzed all the data and wrote the manuscript and its revisions, and approved the final version of the manuscript. He attests that no undisclosed authors contributed to the manuscript. Dr. Fan designed the study protocol, reviewed the manuscript, and approved the final version of the manuscript. Mr. White reviewed the study protocol, obtained the study data, reviewed the manuscript, and approved the final version of the manuscript. Sean D. Sullivan, PhD, designed the study protocol, obtained study data, reviewed the manuscript, and approved the final version of the manuscript. Dr. Asakura designed the study protocol, reviewed the manuscript, and approved the final version of the manuscript. Dr. Myint reviewed the study protocol and data, reviewed the manuscript, and approved the final version of the manuscript. Dr. Dale designed the study protocol, analyzed the data, reviewed the manuscript, and approved the final version of the manuscript. The authors report no conflicts of interest.
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- . Quality Improvement in the intensive care unit. In: Scales DC, Rubenfeld GD, eds. The Organization of Critical Care. New York, NY: Humana Press; 2014:279.
- , , , et al. Intensive care unit quality improvement: a “how‐to” guide for the interdisciplinary team. Crit Care Med. 2006;34:211–218.
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- , , , et al. A multifaceted intervention for quality improvement in a network of intensive care units: a cluster randomized trial. JAMA. 2011;305:363–372.
- O'Neill SM. How do quality improvement interventions succeed? Archetypes of success and failure. Available at: http://www.rand.org/pubs/rgs_dissertations/RGSD282.html. Published 2011.
- , , , et al. Effect of a multifaceted intervention on use of evidence‐based therapies in patients with acute coronary syndromes in Brazil: the BRIDGE‐ACS randomized trial. JAMA. 2012;307:2041–2049.
- , , , et al. Audit and feedback: effects on professional practice and healthcare outcomes. Cochrane Database Syst Rev. 2012;6:CD000259.
- , , , . Impact of the present‐on‐admission indicator on hospital quality measurement: experience with the Agency for Healthcare Research and Quality (AHRQ) Inpatient Quality Indicators. Med Care. 2008;46:112–119.
- , , , et al. Enhancement of claims data to improve risk adjustment of hospital mortality. JAMA. 2007;297:71–76.
- , , , . Primary care use of laboratory tests in Spain: measurement through appropriateness indicators. Clin Lab. 2014;60(3):483–490.
- , , , et al. What distinguishes top‐performing hospitals in acute myocardial infarction mortality rates? a qualitative study. Ann Intern Med. 2011;154(6):384–390.
- . What is value in health care? N Engl J Med. 2010;363(26):2477–2481.
- . Eliminating “waste” in health care. JAMA. 2012;307(14):1513–1516.
- . The U.S. health system in perspective: a comparison of twelve industrialized nations. Issue Brief (Commonw Fund). 2011;16:1–14.
- , . Is the defensive use of diagnostic tests good for patients, or bad? Med Decis Mak. 1998;18(1):19–28.
- , . Physician characteristics and organizational factors influencing use of ambulatory tests. Med Decis Making. 1985;5:401–415.
- , , ; Pilot Group of the Appropriate Utilization of Laboratory Tests (REDCONLAB) Working Group. Differences in laboratory requesting patterns in emergency department in Spain. Ann Clin Biochem. 2013;50:353–359.
- , . Hospital‐acquired anemia. J Med Assoc Thail. 2006;89(1):63–67.
- , , , , . Do blood tests cause anemia in hospitalized patients? The effect of diagnostic phlebotomy on hemoglobin and hematocrit levels. J Gen Intern Med. 2005;20(6):520–524.
- , . Phlebotomy for diagnostic laboratory tests in adults. Pattern of use and effect on transfusion requirements. N Engl J Med. 1986;314(19):1233–1235.
- , , , et al. Diagnostic blood loss from phlebotomy and hospital‐acquired anemia during acute myocardial infarction. Arch Intern Med. 2011;171(18):1646–1653.
- , , , et al. Hospital‐acquired anemia: prevalence, outcomes, and healthcare implications. J Hosp Med. 2013;8(9):506–512.
- , , . Laboratory phlebotomy. College of American Pathologists Q‐Probe study of patient satisfaction and complications in 23,783 patients. Arch Pathol Lab Med. 1991;115:867–872.
- , , , et al. A cost‐effective method for reducing the volume of laboratory tests in a university‐associated teaching hospital. Mt Sinai J Med. 2006;73(5):787–794.
- , . Inappropriate use of laboratory services: long term combined approach to modify request patterns. BMJ. 1990;301(6764):1305–1307.
- , . Effect of a controlled feedback intervention on laboratory test ordering by community physicians. Clin Chem. 2004;50(2):321–326.
- , , , , . An administrative intervention to improve the utilization of laboratory tests within a university hospital. Int J Qual Heal Care. 2005;17(3):243–248.
- . Surgical vampires and rising health care expenditure. Arch Surg. 2011;146(5):524–527.
- , , , et al. Trial of strategy for reducing the use of laboratory tests. Br Med J (Clin Res Ed). 1986;292(6524):883–885.
- , , , et al. Improving house staff ordering of three common laboratory tests. Reductions in test ordering need not result in underutilization. Med Care. 1987;25(10):928–935.
- , , , et al. Reducing unnecessary inpatient laboratory testing in a teaching hospital. Am J Clin Pathol. 2006;126(2):200–206.
- , , , et al. Improving patient care the impact of peer management on test‐ordering behavior. Ann Intern Med. 2004;141(3):196–204.
- , , . The laboratory test justified. An effective means to reduce routine laboratory testing. Am J Clin Pathol. 1985;86(6):756–759.
- , , , et al. Choosing wisely in adult hospital medicine: five opportunities for improved healthcare value. J Hosp Med. 2013;8(9):486–492.
- . Quality Improvement in the intensive care unit. In: Scales DC, Rubenfeld GD, eds. The Organization of Critical Care. New York, NY: Humana Press; 2014:279.
- , , , et al. Intensive care unit quality improvement: a “how‐to” guide for the interdisciplinary team. Crit Care Med. 2006;34:211–218.
- . Navigating adaptive challenges in quality improvement. BMJ Qual Safety. 2011;20(7):560–563.
- , , , et al. A multifaceted intervention for quality improvement in a network of intensive care units: a cluster randomized trial. JAMA. 2011;305:363–372.
- O'Neill SM. How do quality improvement interventions succeed? Archetypes of success and failure. Available at: http://www.rand.org/pubs/rgs_dissertations/RGSD282.html. Published 2011.
- , , , et al. Effect of a multifaceted intervention on use of evidence‐based therapies in patients with acute coronary syndromes in Brazil: the BRIDGE‐ACS randomized trial. JAMA. 2012;307:2041–2049.
- , , , et al. Audit and feedback: effects on professional practice and healthcare outcomes. Cochrane Database Syst Rev. 2012;6:CD000259.
- , , , . Impact of the present‐on‐admission indicator on hospital quality measurement: experience with the Agency for Healthcare Research and Quality (AHRQ) Inpatient Quality Indicators. Med Care. 2008;46:112–119.
- , , , et al. Enhancement of claims data to improve risk adjustment of hospital mortality. JAMA. 2007;297:71–76.
- , , , . Primary care use of laboratory tests in Spain: measurement through appropriateness indicators. Clin Lab. 2014;60(3):483–490.
- , , , et al. What distinguishes top‐performing hospitals in acute myocardial infarction mortality rates? a qualitative study. Ann Intern Med. 2011;154(6):384–390.
- . What is value in health care? N Engl J Med. 2010;363(26):2477–2481.
Group traces clonal evolution of B-ALL
In tracing the clonal evolution of B-cell acute lymphoblastic leukemia (B-ALL) from diagnosis to relapse, researchers discovered that clonal diversity is comparable in both states.
They also identified mutations associated with B-ALL relapse and found that clonal survival is not dependent upon mutation burden.
In most of the cases the researchers analyzed, a single, minor clone survived therapy, acquired additional mutations, and drove disease relapse.
Jinghui Zhang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues recounted these findings in Nature Communications.
The researchers performed deep, whole-exome sequencing on cell samples from 20 young patients (ages 2 to 19) with relapsed B-ALL. The samples were collected at diagnosis, remission, and relapse.
“[W]e wanted to find out the underlying mechanism leading to cancer relapse,” Dr Zhang said. “When the cancer recurs, is it a completely different cancer, or is it an extension, or change, arising from pre-existing cancer?”
The researchers were able to detect the mutations in both the “rising” and “falling” clones—those that survive therapy and those that don’t—at the different disease stages and pinpoint the mutations that drove the leukemia.
Seven genes were highly likely to be mutated in relapsed disease—NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS, and IKZF1.
The researchers also characterized how diverse those mutations were at diagnosis and relapse. They found that B-ALL cells were mutating just as wildly and diversely in one phase of disease as in the other.
“This finding was interesting, because most people think that the clone that has the most mutations is more likely to survive therapy and evolve, but that doesn’t seem to be the case,” Dr Zhang said.
In most cases, relapse was driven by a minor subclone that had survived therapy and was present at an extremely low level. The researchers said this finding suggests a need to change the way we assess patients after treatment to determine the likelihood of relapse.
“When we are analyzing for the level of minimum residual disease in monitoring remission in patients, we should not only pay attention to the mutations in the predominant clone,” Dr Zhang said. “We should also be tracking what kinds of mutations exist in the minor subclones.”
In tracing the clonal evolution of B-cell acute lymphoblastic leukemia (B-ALL) from diagnosis to relapse, researchers discovered that clonal diversity is comparable in both states.
They also identified mutations associated with B-ALL relapse and found that clonal survival is not dependent upon mutation burden.
In most of the cases the researchers analyzed, a single, minor clone survived therapy, acquired additional mutations, and drove disease relapse.
Jinghui Zhang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues recounted these findings in Nature Communications.
The researchers performed deep, whole-exome sequencing on cell samples from 20 young patients (ages 2 to 19) with relapsed B-ALL. The samples were collected at diagnosis, remission, and relapse.
“[W]e wanted to find out the underlying mechanism leading to cancer relapse,” Dr Zhang said. “When the cancer recurs, is it a completely different cancer, or is it an extension, or change, arising from pre-existing cancer?”
The researchers were able to detect the mutations in both the “rising” and “falling” clones—those that survive therapy and those that don’t—at the different disease stages and pinpoint the mutations that drove the leukemia.
Seven genes were highly likely to be mutated in relapsed disease—NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS, and IKZF1.
The researchers also characterized how diverse those mutations were at diagnosis and relapse. They found that B-ALL cells were mutating just as wildly and diversely in one phase of disease as in the other.
“This finding was interesting, because most people think that the clone that has the most mutations is more likely to survive therapy and evolve, but that doesn’t seem to be the case,” Dr Zhang said.
In most cases, relapse was driven by a minor subclone that had survived therapy and was present at an extremely low level. The researchers said this finding suggests a need to change the way we assess patients after treatment to determine the likelihood of relapse.
“When we are analyzing for the level of minimum residual disease in monitoring remission in patients, we should not only pay attention to the mutations in the predominant clone,” Dr Zhang said. “We should also be tracking what kinds of mutations exist in the minor subclones.”
In tracing the clonal evolution of B-cell acute lymphoblastic leukemia (B-ALL) from diagnosis to relapse, researchers discovered that clonal diversity is comparable in both states.
They also identified mutations associated with B-ALL relapse and found that clonal survival is not dependent upon mutation burden.
In most of the cases the researchers analyzed, a single, minor clone survived therapy, acquired additional mutations, and drove disease relapse.
Jinghui Zhang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues recounted these findings in Nature Communications.
The researchers performed deep, whole-exome sequencing on cell samples from 20 young patients (ages 2 to 19) with relapsed B-ALL. The samples were collected at diagnosis, remission, and relapse.
“[W]e wanted to find out the underlying mechanism leading to cancer relapse,” Dr Zhang said. “When the cancer recurs, is it a completely different cancer, or is it an extension, or change, arising from pre-existing cancer?”
The researchers were able to detect the mutations in both the “rising” and “falling” clones—those that survive therapy and those that don’t—at the different disease stages and pinpoint the mutations that drove the leukemia.
Seven genes were highly likely to be mutated in relapsed disease—NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS, and IKZF1.
The researchers also characterized how diverse those mutations were at diagnosis and relapse. They found that B-ALL cells were mutating just as wildly and diversely in one phase of disease as in the other.
“This finding was interesting, because most people think that the clone that has the most mutations is more likely to survive therapy and evolve, but that doesn’t seem to be the case,” Dr Zhang said.
In most cases, relapse was driven by a minor subclone that had survived therapy and was present at an extremely low level. The researchers said this finding suggests a need to change the way we assess patients after treatment to determine the likelihood of relapse.
“When we are analyzing for the level of minimum residual disease in monitoring remission in patients, we should not only pay attention to the mutations in the predominant clone,” Dr Zhang said. “We should also be tracking what kinds of mutations exist in the minor subclones.”
Malaria interventions prove insufficient
Photo by James Gathany
Current malaria interventions are failing to control the disease in high-transmission areas of sub-Saharan Africa, according to research published in The American Journal of Tropical Medicine & Hygiene.
A 2-year surveillance study revealed that the incidence of malaria in rural Uganda is high and continues to rise.
Researchers said this study offers the most accurate, comprehensive, and up-to-date measurement of the malaria disease burden in Uganda.
“Our findings suggest that current efforts at controlling malaria may not be as effective as previously believed in high-transmission areas, where the disease is the biggest threat,” said Grant Dorsey, MD, PhD, of the University of California, San Francisco.
“It’s important to tell the less happy story that we have not yet seen advances in more rural areas, including at least 2 sites in Uganda, where transmission has been historically high.”
To reach an accurate assessment of the malaria incidence in Uganda, Dr Dorsey and his colleagues gathered comprehensive surveillance data over 24 months, from August 2011 to September 2013.
Ultimately, the team evaluated 703 children between the ages of 6 months and 10 years. The children were randomly selected from 3 areas of Uganda with differing malaria characteristics.
The researchers found the incidence of malaria infection decreased in the relatively low-transmission, peri-urban Walukuba area during the study period—from an average of 0.51 to 0.31 episodes of malaria per person per year (P=0.001).
However, the incidence increased in the 2 rural areas. Episodes of malaria per person per year rose from an average of 0.97 to 1.93 (P<0.001) in the moderate-transmission area of Kihihi and rose from an average of 2.33 to 3.30 (P<0.001) in Nagongera, a high-transmission rural area near the southeastern border with Kenya.
Throughout the study period, families were provided with bednets and had access to 24-hour medical care free of charge at a designated study clinic for episodes of fever. The children were also routinely tested for malaria every 3 months, whether they had symptoms or not.
In addition, the researchers collected mosquito specimens monthly from light traps that were strategically placed in each house to estimate the percentages of malaria-carrying mosquitoes in the study areas.
Healthcare workers provided over 2500 treatments for malaria over the course of the study.
“Children in our study experienced a significantly high rate of infection, and that rate increased in the 2 rural areas,” Dr Dorsey said. “Based on prior data, our higher transmission sites are very likely to be representative of most of Uganda and perhaps of most other rural areas in sub-Saharan Africa as well.”
The researchers said these results suggest a need to further scale up campaigns to distribute insecticide-treated bednets and spray homes with insecticides. And high-transmission countries like Uganda may also require new interventions, such as using malaria drugs for prevention and controlling mosquito larvae, in order to match the malaria reduction successes seen elsewhere in the world.
In a related editorial, Steven Meshnick, MD, PhD, of the University of North Carolina, Chapel Hill, wrote, “The real take-home message of this study may be that malaria control in Africa requires sustained and consistent efforts over much more than 2 years.”
Photo by James Gathany
Current malaria interventions are failing to control the disease in high-transmission areas of sub-Saharan Africa, according to research published in The American Journal of Tropical Medicine & Hygiene.
A 2-year surveillance study revealed that the incidence of malaria in rural Uganda is high and continues to rise.
Researchers said this study offers the most accurate, comprehensive, and up-to-date measurement of the malaria disease burden in Uganda.
“Our findings suggest that current efforts at controlling malaria may not be as effective as previously believed in high-transmission areas, where the disease is the biggest threat,” said Grant Dorsey, MD, PhD, of the University of California, San Francisco.
“It’s important to tell the less happy story that we have not yet seen advances in more rural areas, including at least 2 sites in Uganda, where transmission has been historically high.”
To reach an accurate assessment of the malaria incidence in Uganda, Dr Dorsey and his colleagues gathered comprehensive surveillance data over 24 months, from August 2011 to September 2013.
Ultimately, the team evaluated 703 children between the ages of 6 months and 10 years. The children were randomly selected from 3 areas of Uganda with differing malaria characteristics.
The researchers found the incidence of malaria infection decreased in the relatively low-transmission, peri-urban Walukuba area during the study period—from an average of 0.51 to 0.31 episodes of malaria per person per year (P=0.001).
However, the incidence increased in the 2 rural areas. Episodes of malaria per person per year rose from an average of 0.97 to 1.93 (P<0.001) in the moderate-transmission area of Kihihi and rose from an average of 2.33 to 3.30 (P<0.001) in Nagongera, a high-transmission rural area near the southeastern border with Kenya.
Throughout the study period, families were provided with bednets and had access to 24-hour medical care free of charge at a designated study clinic for episodes of fever. The children were also routinely tested for malaria every 3 months, whether they had symptoms or not.
In addition, the researchers collected mosquito specimens monthly from light traps that were strategically placed in each house to estimate the percentages of malaria-carrying mosquitoes in the study areas.
Healthcare workers provided over 2500 treatments for malaria over the course of the study.
“Children in our study experienced a significantly high rate of infection, and that rate increased in the 2 rural areas,” Dr Dorsey said. “Based on prior data, our higher transmission sites are very likely to be representative of most of Uganda and perhaps of most other rural areas in sub-Saharan Africa as well.”
The researchers said these results suggest a need to further scale up campaigns to distribute insecticide-treated bednets and spray homes with insecticides. And high-transmission countries like Uganda may also require new interventions, such as using malaria drugs for prevention and controlling mosquito larvae, in order to match the malaria reduction successes seen elsewhere in the world.
In a related editorial, Steven Meshnick, MD, PhD, of the University of North Carolina, Chapel Hill, wrote, “The real take-home message of this study may be that malaria control in Africa requires sustained and consistent efforts over much more than 2 years.”
Photo by James Gathany
Current malaria interventions are failing to control the disease in high-transmission areas of sub-Saharan Africa, according to research published in The American Journal of Tropical Medicine & Hygiene.
A 2-year surveillance study revealed that the incidence of malaria in rural Uganda is high and continues to rise.
Researchers said this study offers the most accurate, comprehensive, and up-to-date measurement of the malaria disease burden in Uganda.
“Our findings suggest that current efforts at controlling malaria may not be as effective as previously believed in high-transmission areas, where the disease is the biggest threat,” said Grant Dorsey, MD, PhD, of the University of California, San Francisco.
“It’s important to tell the less happy story that we have not yet seen advances in more rural areas, including at least 2 sites in Uganda, where transmission has been historically high.”
To reach an accurate assessment of the malaria incidence in Uganda, Dr Dorsey and his colleagues gathered comprehensive surveillance data over 24 months, from August 2011 to September 2013.
Ultimately, the team evaluated 703 children between the ages of 6 months and 10 years. The children were randomly selected from 3 areas of Uganda with differing malaria characteristics.
The researchers found the incidence of malaria infection decreased in the relatively low-transmission, peri-urban Walukuba area during the study period—from an average of 0.51 to 0.31 episodes of malaria per person per year (P=0.001).
However, the incidence increased in the 2 rural areas. Episodes of malaria per person per year rose from an average of 0.97 to 1.93 (P<0.001) in the moderate-transmission area of Kihihi and rose from an average of 2.33 to 3.30 (P<0.001) in Nagongera, a high-transmission rural area near the southeastern border with Kenya.
Throughout the study period, families were provided with bednets and had access to 24-hour medical care free of charge at a designated study clinic for episodes of fever. The children were also routinely tested for malaria every 3 months, whether they had symptoms or not.
In addition, the researchers collected mosquito specimens monthly from light traps that were strategically placed in each house to estimate the percentages of malaria-carrying mosquitoes in the study areas.
Healthcare workers provided over 2500 treatments for malaria over the course of the study.
“Children in our study experienced a significantly high rate of infection, and that rate increased in the 2 rural areas,” Dr Dorsey said. “Based on prior data, our higher transmission sites are very likely to be representative of most of Uganda and perhaps of most other rural areas in sub-Saharan Africa as well.”
The researchers said these results suggest a need to further scale up campaigns to distribute insecticide-treated bednets and spray homes with insecticides. And high-transmission countries like Uganda may also require new interventions, such as using malaria drugs for prevention and controlling mosquito larvae, in order to match the malaria reduction successes seen elsewhere in the world.
In a related editorial, Steven Meshnick, MD, PhD, of the University of North Carolina, Chapel Hill, wrote, “The real take-home message of this study may be that malaria control in Africa requires sustained and consistent efforts over much more than 2 years.”
Drug appears feasible for hard-to-treat myelofibrosis
myelofibrosis
Results of a phase 2 study suggest the JAK2/FLT3 inhibitor pacritinib is a feasible treatment option for patients with myelofibrosis who cannot receive or do not respond well to standard therapies.
The drug reduced patients’ spleen volume and improved disease-related symptoms without causing clinically significant myelosuppression.
And pacritinib was considered well-tolerated, even in patients with disease-related anemia and thrombocytopenia.
“Currently, myelofibrosis patients with anemia and thrombocytopenia have limited treatment options for splenomegaly and constitutional symptoms, and
these data show that pacritinib has potential to help patients that are sub-optimally managed on currently available treatments,” said study author Rami S. Komrokji, MD, of the Moffitt Cancer Center in Tampa, Florida.
Dr Komrokji and his colleagues reported these results in Blood. The study was sponsored by CTI Biopharma, the company developing pacritinib.
The researchers evaluated the safety and efficacy of pacritinib in myelofibrosis patients who had clinical splenomegaly that was poorly controlled with standard therapies or who were newly diagnosed with intermediate- or high-risk disease and not considered candidates for standard therapy.
Patients were allowed to enroll irrespective of their degree of thrombocytopenia or anemia. At study entry, 40% of patients had hemoglobin levels below 10 g/dL, and 43% had platelet counts less than 100,000/µL.
A total of 35 patients were enrolled and treated with pacritinib administered at 400 mg once daily in 28-day cycles. The patients’ median age was 69 years.
The primary endpoint was assessment of the spleen response rate, defined as the proportion of subjects achieving 35% or greater reduction in spleen volume from baseline up to week 24, measured by MRI or CT.
A secondary endpoint was the proportion of patients with a 50% or greater reduction in spleen size as determined by physical exam.
The researchers also assessed the proportion of patients with a 50% or greater reduction in total symptom score, which included symptoms of abdominal pain,
bone pain, early satiety, fatigue, inactivity, night sweats, and pruritus, from baseline up to week 24.
Results showed that 30.8% of the evaluable patients (8/26) had a 35% or greater reduction in spleen volume by CT or MRI scan, with 42% of patients reaching a
35% or greater reduction by the end of treatment.
In addition, 42.4% of evaluable patients (14/33) achieved a 50% or greater reduction in spleen size by physical exam. And 48.4% of evaluable patients (15/31) achieved a 50% or greater reduction in total symptom score.
The most common treatment-emergent adverse events were grade 1-2 diarrhea (69%) and nausea (49%). Anemia and thrombocytopenia adverse events were reported in 12 (34.3%) and 8 (22.9%) patients, respectively.
Nine patients (26%) stopped taking pacritinib due to adverse events, but 3 of the events were deemed unrelated to the drug.
There were 5 deaths, 3 of which were due to serious adverse events. Of those, 1 (subdural hematoma) was considered possibly related to pacritinib treatment.
myelofibrosis
Results of a phase 2 study suggest the JAK2/FLT3 inhibitor pacritinib is a feasible treatment option for patients with myelofibrosis who cannot receive or do not respond well to standard therapies.
The drug reduced patients’ spleen volume and improved disease-related symptoms without causing clinically significant myelosuppression.
And pacritinib was considered well-tolerated, even in patients with disease-related anemia and thrombocytopenia.
“Currently, myelofibrosis patients with anemia and thrombocytopenia have limited treatment options for splenomegaly and constitutional symptoms, and
these data show that pacritinib has potential to help patients that are sub-optimally managed on currently available treatments,” said study author Rami S. Komrokji, MD, of the Moffitt Cancer Center in Tampa, Florida.
Dr Komrokji and his colleagues reported these results in Blood. The study was sponsored by CTI Biopharma, the company developing pacritinib.
The researchers evaluated the safety and efficacy of pacritinib in myelofibrosis patients who had clinical splenomegaly that was poorly controlled with standard therapies or who were newly diagnosed with intermediate- or high-risk disease and not considered candidates for standard therapy.
Patients were allowed to enroll irrespective of their degree of thrombocytopenia or anemia. At study entry, 40% of patients had hemoglobin levels below 10 g/dL, and 43% had platelet counts less than 100,000/µL.
A total of 35 patients were enrolled and treated with pacritinib administered at 400 mg once daily in 28-day cycles. The patients’ median age was 69 years.
The primary endpoint was assessment of the spleen response rate, defined as the proportion of subjects achieving 35% or greater reduction in spleen volume from baseline up to week 24, measured by MRI or CT.
A secondary endpoint was the proportion of patients with a 50% or greater reduction in spleen size as determined by physical exam.
The researchers also assessed the proportion of patients with a 50% or greater reduction in total symptom score, which included symptoms of abdominal pain,
bone pain, early satiety, fatigue, inactivity, night sweats, and pruritus, from baseline up to week 24.
Results showed that 30.8% of the evaluable patients (8/26) had a 35% or greater reduction in spleen volume by CT or MRI scan, with 42% of patients reaching a
35% or greater reduction by the end of treatment.
In addition, 42.4% of evaluable patients (14/33) achieved a 50% or greater reduction in spleen size by physical exam. And 48.4% of evaluable patients (15/31) achieved a 50% or greater reduction in total symptom score.
The most common treatment-emergent adverse events were grade 1-2 diarrhea (69%) and nausea (49%). Anemia and thrombocytopenia adverse events were reported in 12 (34.3%) and 8 (22.9%) patients, respectively.
Nine patients (26%) stopped taking pacritinib due to adverse events, but 3 of the events were deemed unrelated to the drug.
There were 5 deaths, 3 of which were due to serious adverse events. Of those, 1 (subdural hematoma) was considered possibly related to pacritinib treatment.
myelofibrosis
Results of a phase 2 study suggest the JAK2/FLT3 inhibitor pacritinib is a feasible treatment option for patients with myelofibrosis who cannot receive or do not respond well to standard therapies.
The drug reduced patients’ spleen volume and improved disease-related symptoms without causing clinically significant myelosuppression.
And pacritinib was considered well-tolerated, even in patients with disease-related anemia and thrombocytopenia.
“Currently, myelofibrosis patients with anemia and thrombocytopenia have limited treatment options for splenomegaly and constitutional symptoms, and
these data show that pacritinib has potential to help patients that are sub-optimally managed on currently available treatments,” said study author Rami S. Komrokji, MD, of the Moffitt Cancer Center in Tampa, Florida.
Dr Komrokji and his colleagues reported these results in Blood. The study was sponsored by CTI Biopharma, the company developing pacritinib.
The researchers evaluated the safety and efficacy of pacritinib in myelofibrosis patients who had clinical splenomegaly that was poorly controlled with standard therapies or who were newly diagnosed with intermediate- or high-risk disease and not considered candidates for standard therapy.
Patients were allowed to enroll irrespective of their degree of thrombocytopenia or anemia. At study entry, 40% of patients had hemoglobin levels below 10 g/dL, and 43% had platelet counts less than 100,000/µL.
A total of 35 patients were enrolled and treated with pacritinib administered at 400 mg once daily in 28-day cycles. The patients’ median age was 69 years.
The primary endpoint was assessment of the spleen response rate, defined as the proportion of subjects achieving 35% or greater reduction in spleen volume from baseline up to week 24, measured by MRI or CT.
A secondary endpoint was the proportion of patients with a 50% or greater reduction in spleen size as determined by physical exam.
The researchers also assessed the proportion of patients with a 50% or greater reduction in total symptom score, which included symptoms of abdominal pain,
bone pain, early satiety, fatigue, inactivity, night sweats, and pruritus, from baseline up to week 24.
Results showed that 30.8% of the evaluable patients (8/26) had a 35% or greater reduction in spleen volume by CT or MRI scan, with 42% of patients reaching a
35% or greater reduction by the end of treatment.
In addition, 42.4% of evaluable patients (14/33) achieved a 50% or greater reduction in spleen size by physical exam. And 48.4% of evaluable patients (15/31) achieved a 50% or greater reduction in total symptom score.
The most common treatment-emergent adverse events were grade 1-2 diarrhea (69%) and nausea (49%). Anemia and thrombocytopenia adverse events were reported in 12 (34.3%) and 8 (22.9%) patients, respectively.
Nine patients (26%) stopped taking pacritinib due to adverse events, but 3 of the events were deemed unrelated to the drug.
There were 5 deaths, 3 of which were due to serious adverse events. Of those, 1 (subdural hematoma) was considered possibly related to pacritinib treatment.
Experts urge review of global sepsis guidelines
Investigators are calling for a global review of guidelines used to diagnose sepsis, after a study showed that 1 in 8 patients with infections severe enough to necessitate admission to an intensive care unit did not meet current diagnostic criteria.
The researchers identified 109,663 patients with possible sepsis who had infection and organ failure. However, more than 13,000 patients from this group did not meet the classic criteria used to diagnose sepsis.
“To be diagnosed with sepsis, a patient must be thought to have an infection and exhibit at least 2 of the following criteria: abnormal body temperature or white blood cell count, high heart rate, high respiratory rate, or low carbon dioxide level in the blood,” said Maija Kaukonen, MD, PhD, of Monash University in Melbourne, Victoria, Australia.
“But our study found that many patients—for example, the elderly or those on medications that affect heart rate or the immune system—may not meet the classic criteria to diagnose sepsis, despite having severe infections and organ failure. If we continue to use these criteria, we may miss the opportunity to identify many critically ill patients with sepsis.”
The study was published in NEJM.
The investigators studied 1,171,797 patients from 172 intensive care units in New Zealand and Australia.
The team identified patients with infection and organ failure and categorized them according to whether they had signs meeting 2 or more systemic inflammatory response syndrome (SIRS) criteria (SIRS-positive severe sepsis) or less than 2 SIRS criteria (SIRS-negative severe sepsis).
Of the 109,663 patients who had infection and organ failure, 96,385 (87.9%) had SIRS-positive severe sepsis and 13,278 (12.1%) had SIRS-negative severe sepsis.
Over 14 years, the 2 patient groups had similar characteristics and changes in mortality. Mortality decreased from 36.1% (829/2296) to 18.3% (2037/11,119) in the SIRS-positive group (P<0.001) and from 27.7% (100/361) to 9.3% (122/1315) in the SIRS-negative group (P<0.001).
This similarity between the groups remained after the researchers adjusted their analysis for baseline characteristics. In both groups, the odds ratio was 0.96 (P=0.12).
The investigators also noted that, in the adjusted analysis, mortality increased linearly with each additional SIRS criterion (P<0.001), without any transitional increase in risk at a threshold of 2 SIRS criteria.
Rinaldo Bellomo, MD, PhD, also of Monash University, conceived this study. He said that although the classic definition of sepsis has been widely used throughout the world, he believed that, after 20 years, it was time for it to be reviewed.
“There are clear signs from this study that if we continue to use these criteria, we may fail to identify septic patients and, therefore, potentially delay their treatment,” he said.
Investigators are calling for a global review of guidelines used to diagnose sepsis, after a study showed that 1 in 8 patients with infections severe enough to necessitate admission to an intensive care unit did not meet current diagnostic criteria.
The researchers identified 109,663 patients with possible sepsis who had infection and organ failure. However, more than 13,000 patients from this group did not meet the classic criteria used to diagnose sepsis.
“To be diagnosed with sepsis, a patient must be thought to have an infection and exhibit at least 2 of the following criteria: abnormal body temperature or white blood cell count, high heart rate, high respiratory rate, or low carbon dioxide level in the blood,” said Maija Kaukonen, MD, PhD, of Monash University in Melbourne, Victoria, Australia.
“But our study found that many patients—for example, the elderly or those on medications that affect heart rate or the immune system—may not meet the classic criteria to diagnose sepsis, despite having severe infections and organ failure. If we continue to use these criteria, we may miss the opportunity to identify many critically ill patients with sepsis.”
The study was published in NEJM.
The investigators studied 1,171,797 patients from 172 intensive care units in New Zealand and Australia.
The team identified patients with infection and organ failure and categorized them according to whether they had signs meeting 2 or more systemic inflammatory response syndrome (SIRS) criteria (SIRS-positive severe sepsis) or less than 2 SIRS criteria (SIRS-negative severe sepsis).
Of the 109,663 patients who had infection and organ failure, 96,385 (87.9%) had SIRS-positive severe sepsis and 13,278 (12.1%) had SIRS-negative severe sepsis.
Over 14 years, the 2 patient groups had similar characteristics and changes in mortality. Mortality decreased from 36.1% (829/2296) to 18.3% (2037/11,119) in the SIRS-positive group (P<0.001) and from 27.7% (100/361) to 9.3% (122/1315) in the SIRS-negative group (P<0.001).
This similarity between the groups remained after the researchers adjusted their analysis for baseline characteristics. In both groups, the odds ratio was 0.96 (P=0.12).
The investigators also noted that, in the adjusted analysis, mortality increased linearly with each additional SIRS criterion (P<0.001), without any transitional increase in risk at a threshold of 2 SIRS criteria.
Rinaldo Bellomo, MD, PhD, also of Monash University, conceived this study. He said that although the classic definition of sepsis has been widely used throughout the world, he believed that, after 20 years, it was time for it to be reviewed.
“There are clear signs from this study that if we continue to use these criteria, we may fail to identify septic patients and, therefore, potentially delay their treatment,” he said.
Investigators are calling for a global review of guidelines used to diagnose sepsis, after a study showed that 1 in 8 patients with infections severe enough to necessitate admission to an intensive care unit did not meet current diagnostic criteria.
The researchers identified 109,663 patients with possible sepsis who had infection and organ failure. However, more than 13,000 patients from this group did not meet the classic criteria used to diagnose sepsis.
“To be diagnosed with sepsis, a patient must be thought to have an infection and exhibit at least 2 of the following criteria: abnormal body temperature or white blood cell count, high heart rate, high respiratory rate, or low carbon dioxide level in the blood,” said Maija Kaukonen, MD, PhD, of Monash University in Melbourne, Victoria, Australia.
“But our study found that many patients—for example, the elderly or those on medications that affect heart rate or the immune system—may not meet the classic criteria to diagnose sepsis, despite having severe infections and organ failure. If we continue to use these criteria, we may miss the opportunity to identify many critically ill patients with sepsis.”
The study was published in NEJM.
The investigators studied 1,171,797 patients from 172 intensive care units in New Zealand and Australia.
The team identified patients with infection and organ failure and categorized them according to whether they had signs meeting 2 or more systemic inflammatory response syndrome (SIRS) criteria (SIRS-positive severe sepsis) or less than 2 SIRS criteria (SIRS-negative severe sepsis).
Of the 109,663 patients who had infection and organ failure, 96,385 (87.9%) had SIRS-positive severe sepsis and 13,278 (12.1%) had SIRS-negative severe sepsis.
Over 14 years, the 2 patient groups had similar characteristics and changes in mortality. Mortality decreased from 36.1% (829/2296) to 18.3% (2037/11,119) in the SIRS-positive group (P<0.001) and from 27.7% (100/361) to 9.3% (122/1315) in the SIRS-negative group (P<0.001).
This similarity between the groups remained after the researchers adjusted their analysis for baseline characteristics. In both groups, the odds ratio was 0.96 (P=0.12).
The investigators also noted that, in the adjusted analysis, mortality increased linearly with each additional SIRS criterion (P<0.001), without any transitional increase in risk at a threshold of 2 SIRS criteria.
Rinaldo Bellomo, MD, PhD, also of Monash University, conceived this study. He said that although the classic definition of sepsis has been widely used throughout the world, he believed that, after 20 years, it was time for it to be reviewed.
“There are clear signs from this study that if we continue to use these criteria, we may fail to identify septic patients and, therefore, potentially delay their treatment,” he said.