Noll L. Campbell, PharmD, BCPP, CGP, FASCP

Delirium is a syndrome of disturbance of consciousness, with reduced ability to focus, sustain, or shift attention, that occurs over a short period of time and fluctuates over the course of the day.1 It encompasses a variety of cognitive, behavioral, and psychological symptoms including inattention, short‐term memory loss, sleep disturbances, agitated behaviors, delusions, and visual hallucinations.2 Delirium complicates the care of 70% to 80% of mechanically ventilated patients in intensive care units (ICUs).3 Of 13 million patients aged 65 and older hospitalized in 2002, 10% to 52% had delirium at some point during their admission.4, 5

Patients experiencing delirium have a higher probability of death during their hospital stay, adjusted for age, gender, race, and comorbidities.3, 6, 7 They are more vulnerable to hospital‐acquired complications leading to prolonged ICU and hospital stay, new institutionalization, and higher healthcare costs.3, 6, 7 Even with such a range of poor outcomes, the rates of delirium recognition are low,8 resulting in inadequate management.9 There has been considerable growth in the number of articles published on delirium in recent years. Therefore, it is of value to provide a state‐of‐the‐art summary of robust evidence in the field to healthcare personnel and delirium investigators.

We systematically reviewed the literature to identify published systematic evidence reviews (SERs), which evaluated the evidence on delirium risk factors, diagnosis, pathogenesis, prevention, treatment, and outcomes. We then summarized the data from the methodologically sound SERs to provide the reader with a clinically oriented summary of delirium literature for patient care. We also identify current gaps in delirium literature, and present future directions for delirium investigators to design studies that will enhance delirium care.

DATA SOURCES AND REVIEW METHODS

The domains of risk factors, diagnosis, pathophysiology, prevention, treatment, and outcomes were selected a priori to capture all relevant SERs regarding delirium based on the framework suggested by the American Delirium Society task force.10 To maximize article retrieval, a 3‐step search strategy was applied. First, we searched the electronic database utilizing OVID Medline, PubMed, the Cochrane Library, and Cumulative Index of Nursing and Allied Health Literature (CINAHL) using the following delirium‐specific search terms: delirium, confusion, agitation, mental status change, inattention, encephalopathy, organic mental disorders, and disorientation. We combined the above terms with the following study design terms: technical report, systematic evidence review, systematic review, meta‐analysis, editorial, and clinical reviews. We limited our search to human subjects. We excluded studies that: a) enrolled patients aged <18; b) enrolled patients with current or past Diagnostic and Statistical Manual of Mental Disorders (DSM) Axis I psychotic disorders; c) did not have standardized delirium evaluation; d) evaluated alcohol or substance abuse‐related delirium; e) did not use a systematic search method for identifying delirium‐related articles; and f) evaluated delirium sub‐types. We searched articles published from January 1966 through April 2011. Second, a manual search of references of the retrieved papers plus an Internet search using Google Scholar was conducted to find additional SERs. Titles and abstracts were screened by 2 reviewers (B.A.K., M.Z.). Authors of the included studies were contacted as necessary. Third, a library professional at the Indiana University School of Medicine independently performed a literature search, and those results were compared with our search to retrieve any missing SERs.

The methodological quality of each SER was independently assessed by 2 reviewers (B.A.K., M.Z.) using the United States Preventive Services Task Force (USPSTF) Critical Appraisal for SER.11 This scale assesses parameters that are critical to the scientific credibility of an SER and categorizes the SER as poor, fair, or good (Table 1). The 2 reviewers (B.A.K., M.Z.) used a data extraction form to record the following information from each SER: primary author, publication year, number and type of studies, number of participants and their mean age, study population, method for delirium diagnosis, risk factors, preventive and therapeutic interventions, and outcomes. Any disagreement between reviewers in SER selection, data extraction, or SER appraisal was resolved through discussion with a third reviewer (M.A.B.). The conflicting findings among SERs were resolved by consensus and by including the findings from a good SER over a fair SER.

RESULTS

Our search yielded 76,060 potential citations, out of which we identified 38 SERs meeting our inclusion criteria (Table 2). Figure 1 outlines our search strategy. Based on the USPSTF criteria, 22 SERs graded as good or fair provided the data to establish our review.

Figure 1

DISCUSSION AND CLINICAL IMPLICATIONS

Our study identified age, cognitive impairment, depression, and mepiridine use for analgesia as risk factors for delirium in surgical patients. Drugs with anticholinergic properties were implicated in delirium development in both medical and surgical patients. The CAM has the best available data to be used as a diagnostic tool for delirium. Multicomponent interventions to prevent delirium occurrence are effective in a non‐cognitively impaired population, and low‐dose haloperidol prophylaxis decreases delirium duration and severity without affecting delirium incidence in hip surgery patients. There is no advantage of using atypical antipsychotics over haloperidol in treating delirium, and low‐dose haloperidol is as effective as a higher dose without unwarranted extrapyramidal side effects. Delirium carries a poor prognosis with an increased risk of death, institutionalization, and dementia.

Hospitals may benefit from implementing multicomponent strategies, focusing on at‐risk elderly medical and surgical patients, administered by a multidisciplinary team to reduce delirium incidence. For ICU physicians and administrators, development of sedation guidelines minimizing the use of benzodiazepines will decrease the risk of delirium development.

A structured approach in diagnosing delirium is required to maximize identification. Use of the CAM, based on best available data is recommended. However, the length of time in doing the CAM (more than 10 minutes with the requisite mental status examination) and insensitivity in nonexpert hands suggest a need for alternative screening tools. Haloperidol should be the preferred first‐line pharmacological therapy for delirium, with atypical antipsychotics reserved for patients with contraindications to haloperidol or those who are refractory to therapy with haloperidol. Figure 2 delineates a clinical model for delirium management derived from the findings in the Results section.

Figure 2

FUTURE RESEARCH DIRECTIONS

We identified multiple areas without clear guidelines that could provide opportunities for future research. A role for routine delirium screening can be clarified through a well‐designed delirium screening trial investigating the benefits of delirium screening, coupled with a multicomponent intervention versus usual care. Use of pharmacotherapy in delirium prevention needs to be explored further in a large randomized trial, with 3 arms to compare typical antipsychotics, atypical antipsychotics, and placebo in patients at risk for delirium with a primary outcome of delirium incidence. In regard to delirium treatment, a large randomized trial to compare haloperidol with atypical antipsychotics, with a placebo arm focusing not only on delirium duration and severity, but also on long‐term outcomes such as rehospitalizations, institutionalization, cognitive impairment, and mortality, is warranted. Figure 3 points out potential areas for researchers to investigate hypotheses generated by our review and thereby improve delirium care.

Figure 3

To our knowledge, our SER presents the first summary of SERs in delirium. Prior to this review, Michaud et al9 and National Institute for Health and Clinical Excellence48 published delirium guidelines, but in both of these guidelines, evidence was collected from a multitude of studies ranging in methodology from scientific review and meta‐analysis to observational studies, and the majority of recommendations were based on expert opinion. On the contrary, our review was limited to rigorously conducted SERs; hence, we utilized the highest level, critically appraised evidence to provide guidance to clinicians and researchers.

Limitations include a diverse group of studies with a heterogeneous population of patients, preventing pooling of results. We did not review each individual study included in the 38 SERs. We excluded non‐English language SERs, studies evaluating delirium subtypes, alcohol or substance abuse‐related delirium, or delirium associated with psychiatric disorders. As we only reviewed SERs, some notable studies not included in the SERs may have been missed.

CONCLUSION

Delirium among hospitalized patients is a common syndrome with a significant burden to the healthcare system and society. The field of delirium has seen considerable advances in diagnosis, prevention, and treatment over the last decade. Even with this advancement, there are still areas of uncertainty, such as: the benefits and costs of delirium screening; the benefits and harms of single or combined pharmacological agents for delirium prevention and treatment; the development of a set of reliable biomarkers for delirium diagnosis, prognosis, and response to therapy; the long‐term effect of delirium‐specific therapeutics on patients' cognitive, physical, and psychological functions; and the relationship between delirium and the development of Alzheimer's disease. As our understanding of delirium's impact on patients and healthcare improves, delirium should be identified as an indicator of poor long‐term prognosis, and should prompt immediate and effective evidence‐based management strategies, like any other critical illness.

Delirium is a syndrome of disturbance of consciousness, with reduced ability to focus, sustain, or shift attention, that occurs over a short period of time and fluctuates over the course of the day.1 It encompasses a variety of cognitive, behavioral, and psychological symptoms including inattention, short‐term memory loss, sleep disturbances, agitated behaviors, delusions, and visual hallucinations.2 Delirium complicates the care of 70% to 80% of mechanically ventilated patients in intensive care units (ICUs).3 Of 13 million patients aged 65 and older hospitalized in 2002, 10% to 52% had delirium at some point during their admission.4, 5

Patients experiencing delirium have a higher probability of death during their hospital stay, adjusted for age, gender, race, and comorbidities.3, 6, 7 They are more vulnerable to hospital‐acquired complications leading to prolonged ICU and hospital stay, new institutionalization, and higher healthcare costs.3, 6, 7 Even with such a range of poor outcomes, the rates of delirium recognition are low,8 resulting in inadequate management.9 There has been considerable growth in the number of articles published on delirium in recent years. Therefore, it is of value to provide a state‐of‐the‐art summary of robust evidence in the field to healthcare personnel and delirium investigators.

We systematically reviewed the literature to identify published systematic evidence reviews (SERs), which evaluated the evidence on delirium risk factors, diagnosis, pathogenesis, prevention, treatment, and outcomes. We then summarized the data from the methodologically sound SERs to provide the reader with a clinically oriented summary of delirium literature for patient care. We also identify current gaps in delirium literature, and present future directions for delirium investigators to design studies that will enhance delirium care.

DATA SOURCES AND REVIEW METHODS

The domains of risk factors, diagnosis, pathophysiology, prevention, treatment, and outcomes were selected a priori to capture all relevant SERs regarding delirium based on the framework suggested by the American Delirium Society task force.10 To maximize article retrieval, a 3‐step search strategy was applied. First, we searched the electronic database utilizing OVID Medline, PubMed, the Cochrane Library, and Cumulative Index of Nursing and Allied Health Literature (CINAHL) using the following delirium‐specific search terms: delirium, confusion, agitation, mental status change, inattention, encephalopathy, organic mental disorders, and disorientation. We combined the above terms with the following study design terms: technical report, systematic evidence review, systematic review, meta‐analysis, editorial, and clinical reviews. We limited our search to human subjects. We excluded studies that: a) enrolled patients aged <18; b) enrolled patients with current or past Diagnostic and Statistical Manual of Mental Disorders (DSM) Axis I psychotic disorders; c) did not have standardized delirium evaluation; d) evaluated alcohol or substance abuse‐related delirium; e) did not use a systematic search method for identifying delirium‐related articles; and f) evaluated delirium sub‐types. We searched articles published from January 1966 through April 2011. Second, a manual search of references of the retrieved papers plus an Internet search using Google Scholar was conducted to find additional SERs. Titles and abstracts were screened by 2 reviewers (B.A.K., M.Z.). Authors of the included studies were contacted as necessary. Third, a library professional at the Indiana University School of Medicine independently performed a literature search, and those results were compared with our search to retrieve any missing SERs.

The methodological quality of each SER was independently assessed by 2 reviewers (B.A.K., M.Z.) using the United States Preventive Services Task Force (USPSTF) Critical Appraisal for SER.11 This scale assesses parameters that are critical to the scientific credibility of an SER and categorizes the SER as poor, fair, or good (Table 1). The 2 reviewers (B.A.K., M.Z.) used a data extraction form to record the following information from each SER: primary author, publication year, number and type of studies, number of participants and their mean age, study population, method for delirium diagnosis, risk factors, preventive and therapeutic interventions, and outcomes. Any disagreement between reviewers in SER selection, data extraction, or SER appraisal was resolved through discussion with a third reviewer (M.A.B.). The conflicting findings among SERs were resolved by consensus and by including the findings from a good SER over a fair SER.

RESULTS

Our search yielded 76,060 potential citations, out of which we identified 38 SERs meeting our inclusion criteria (Table 2). Figure 1 outlines our search strategy. Based on the USPSTF criteria, 22 SERs graded as good or fair provided the data to establish our review.

Figure 1

DISCUSSION AND CLINICAL IMPLICATIONS

Our study identified age, cognitive impairment, depression, and mepiridine use for analgesia as risk factors for delirium in surgical patients. Drugs with anticholinergic properties were implicated in delirium development in both medical and surgical patients. The CAM has the best available data to be used as a diagnostic tool for delirium. Multicomponent interventions to prevent delirium occurrence are effective in a non‐cognitively impaired population, and low‐dose haloperidol prophylaxis decreases delirium duration and severity without affecting delirium incidence in hip surgery patients. There is no advantage of using atypical antipsychotics over haloperidol in treating delirium, and low‐dose haloperidol is as effective as a higher dose without unwarranted extrapyramidal side effects. Delirium carries a poor prognosis with an increased risk of death, institutionalization, and dementia.

Hospitals may benefit from implementing multicomponent strategies, focusing on at‐risk elderly medical and surgical patients, administered by a multidisciplinary team to reduce delirium incidence. For ICU physicians and administrators, development of sedation guidelines minimizing the use of benzodiazepines will decrease the risk of delirium development.

A structured approach in diagnosing delirium is required to maximize identification. Use of the CAM, based on best available data is recommended. However, the length of time in doing the CAM (more than 10 minutes with the requisite mental status examination) and insensitivity in nonexpert hands suggest a need for alternative screening tools. Haloperidol should be the preferred first‐line pharmacological therapy for delirium, with atypical antipsychotics reserved for patients with contraindications to haloperidol or those who are refractory to therapy with haloperidol. Figure 2 delineates a clinical model for delirium management derived from the findings in the Results section.

Figure 2

FUTURE RESEARCH DIRECTIONS

We identified multiple areas without clear guidelines that could provide opportunities for future research. A role for routine delirium screening can be clarified through a well‐designed delirium screening trial investigating the benefits of delirium screening, coupled with a multicomponent intervention versus usual care. Use of pharmacotherapy in delirium prevention needs to be explored further in a large randomized trial, with 3 arms to compare typical antipsychotics, atypical antipsychotics, and placebo in patients at risk for delirium with a primary outcome of delirium incidence. In regard to delirium treatment, a large randomized trial to compare haloperidol with atypical antipsychotics, with a placebo arm focusing not only on delirium duration and severity, but also on long‐term outcomes such as rehospitalizations, institutionalization, cognitive impairment, and mortality, is warranted. Figure 3 points out potential areas for researchers to investigate hypotheses generated by our review and thereby improve delirium care.

Figure 3

To our knowledge, our SER presents the first summary of SERs in delirium. Prior to this review, Michaud et al9 and National Institute for Health and Clinical Excellence48 published delirium guidelines, but in both of these guidelines, evidence was collected from a multitude of studies ranging in methodology from scientific review and meta‐analysis to observational studies, and the majority of recommendations were based on expert opinion. On the contrary, our review was limited to rigorously conducted SERs; hence, we utilized the highest level, critically appraised evidence to provide guidance to clinicians and researchers.

Limitations include a diverse group of studies with a heterogeneous population of patients, preventing pooling of results. We did not review each individual study included in the 38 SERs. We excluded non‐English language SERs, studies evaluating delirium subtypes, alcohol or substance abuse‐related delirium, or delirium associated with psychiatric disorders. As we only reviewed SERs, some notable studies not included in the SERs may have been missed.

CONCLUSION

Delirium among hospitalized patients is a common syndrome with a significant burden to the healthcare system and society. The field of delirium has seen considerable advances in diagnosis, prevention, and treatment over the last decade. Even with this advancement, there are still areas of uncertainty, such as: the benefits and costs of delirium screening; the benefits and harms of single or combined pharmacological agents for delirium prevention and treatment; the development of a set of reliable biomarkers for delirium diagnosis, prognosis, and response to therapy; the long‐term effect of delirium‐specific therapeutics on patients' cognitive, physical, and psychological functions; and the relationship between delirium and the development of Alzheimer's disease. As our understanding of delirium's impact on patients and healthcare improves, delirium should be identified as an indicator of poor long‐term prognosis, and should prompt immediate and effective evidence‐based management strategies, like any other critical illness.

Delirium is a syndrome of disturbance of consciousness, with reduced ability to focus, sustain, or shift attention, that occurs over a short period of time and fluctuates over the course of the day.1 It encompasses a variety of cognitive, behavioral, and psychological symptoms including inattention, short‐term memory loss, sleep disturbances, agitated behaviors, delusions, and visual hallucinations.2 Delirium complicates the care of 70% to 80% of mechanically ventilated patients in intensive care units (ICUs).3 Of 13 million patients aged 65 and older hospitalized in 2002, 10% to 52% had delirium at some point during their admission.4, 5

Patients experiencing delirium have a higher probability of death during their hospital stay, adjusted for age, gender, race, and comorbidities.3, 6, 7 They are more vulnerable to hospital‐acquired complications leading to prolonged ICU and hospital stay, new institutionalization, and higher healthcare costs.3, 6, 7 Even with such a range of poor outcomes, the rates of delirium recognition are low,8 resulting in inadequate management.9 There has been considerable growth in the number of articles published on delirium in recent years. Therefore, it is of value to provide a state‐of‐the‐art summary of robust evidence in the field to healthcare personnel and delirium investigators.

We systematically reviewed the literature to identify published systematic evidence reviews (SERs), which evaluated the evidence on delirium risk factors, diagnosis, pathogenesis, prevention, treatment, and outcomes. We then summarized the data from the methodologically sound SERs to provide the reader with a clinically oriented summary of delirium literature for patient care. We also identify current gaps in delirium literature, and present future directions for delirium investigators to design studies that will enhance delirium care.

DATA SOURCES AND REVIEW METHODS

The domains of risk factors, diagnosis, pathophysiology, prevention, treatment, and outcomes were selected a priori to capture all relevant SERs regarding delirium based on the framework suggested by the American Delirium Society task force.10 To maximize article retrieval, a 3‐step search strategy was applied. First, we searched the electronic database utilizing OVID Medline, PubMed, the Cochrane Library, and Cumulative Index of Nursing and Allied Health Literature (CINAHL) using the following delirium‐specific search terms: delirium, confusion, agitation, mental status change, inattention, encephalopathy, organic mental disorders, and disorientation. We combined the above terms with the following study design terms: technical report, systematic evidence review, systematic review, meta‐analysis, editorial, and clinical reviews. We limited our search to human subjects. We excluded studies that: a) enrolled patients aged <18; b) enrolled patients with current or past Diagnostic and Statistical Manual of Mental Disorders (DSM) Axis I psychotic disorders; c) did not have standardized delirium evaluation; d) evaluated alcohol or substance abuse‐related delirium; e) did not use a systematic search method for identifying delirium‐related articles; and f) evaluated delirium sub‐types. We searched articles published from January 1966 through April 2011. Second, a manual search of references of the retrieved papers plus an Internet search using Google Scholar was conducted to find additional SERs. Titles and abstracts were screened by 2 reviewers (B.A.K., M.Z.). Authors of the included studies were contacted as necessary. Third, a library professional at the Indiana University School of Medicine independently performed a literature search, and those results were compared with our search to retrieve any missing SERs.

The methodological quality of each SER was independently assessed by 2 reviewers (B.A.K., M.Z.) using the United States Preventive Services Task Force (USPSTF) Critical Appraisal for SER.11 This scale assesses parameters that are critical to the scientific credibility of an SER and categorizes the SER as poor, fair, or good (Table 1). The 2 reviewers (B.A.K., M.Z.) used a data extraction form to record the following information from each SER: primary author, publication year, number and type of studies, number of participants and their mean age, study population, method for delirium diagnosis, risk factors, preventive and therapeutic interventions, and outcomes. Any disagreement between reviewers in SER selection, data extraction, or SER appraisal was resolved through discussion with a third reviewer (M.A.B.). The conflicting findings among SERs were resolved by consensus and by including the findings from a good SER over a fair SER.

RESULTS

Our search yielded 76,060 potential citations, out of which we identified 38 SERs meeting our inclusion criteria (Table 2). Figure 1 outlines our search strategy. Based on the USPSTF criteria, 22 SERs graded as good or fair provided the data to establish our review.

Figure 1

DISCUSSION AND CLINICAL IMPLICATIONS

Our study identified age, cognitive impairment, depression, and mepiridine use for analgesia as risk factors for delirium in surgical patients. Drugs with anticholinergic properties were implicated in delirium development in both medical and surgical patients. The CAM has the best available data to be used as a diagnostic tool for delirium. Multicomponent interventions to prevent delirium occurrence are effective in a non‐cognitively impaired population, and low‐dose haloperidol prophylaxis decreases delirium duration and severity without affecting delirium incidence in hip surgery patients. There is no advantage of using atypical antipsychotics over haloperidol in treating delirium, and low‐dose haloperidol is as effective as a higher dose without unwarranted extrapyramidal side effects. Delirium carries a poor prognosis with an increased risk of death, institutionalization, and dementia.

Hospitals may benefit from implementing multicomponent strategies, focusing on at‐risk elderly medical and surgical patients, administered by a multidisciplinary team to reduce delirium incidence. For ICU physicians and administrators, development of sedation guidelines minimizing the use of benzodiazepines will decrease the risk of delirium development.

A structured approach in diagnosing delirium is required to maximize identification. Use of the CAM, based on best available data is recommended. However, the length of time in doing the CAM (more than 10 minutes with the requisite mental status examination) and insensitivity in nonexpert hands suggest a need for alternative screening tools. Haloperidol should be the preferred first‐line pharmacological therapy for delirium, with atypical antipsychotics reserved for patients with contraindications to haloperidol or those who are refractory to therapy with haloperidol. Figure 2 delineates a clinical model for delirium management derived from the findings in the Results section.

Figure 2

FUTURE RESEARCH DIRECTIONS

We identified multiple areas without clear guidelines that could provide opportunities for future research. A role for routine delirium screening can be clarified through a well‐designed delirium screening trial investigating the benefits of delirium screening, coupled with a multicomponent intervention versus usual care. Use of pharmacotherapy in delirium prevention needs to be explored further in a large randomized trial, with 3 arms to compare typical antipsychotics, atypical antipsychotics, and placebo in patients at risk for delirium with a primary outcome of delirium incidence. In regard to delirium treatment, a large randomized trial to compare haloperidol with atypical antipsychotics, with a placebo arm focusing not only on delirium duration and severity, but also on long‐term outcomes such as rehospitalizations, institutionalization, cognitive impairment, and mortality, is warranted. Figure 3 points out potential areas for researchers to investigate hypotheses generated by our review and thereby improve delirium care.

Figure 3

To our knowledge, our SER presents the first summary of SERs in delirium. Prior to this review, Michaud et al9 and National Institute for Health and Clinical Excellence48 published delirium guidelines, but in both of these guidelines, evidence was collected from a multitude of studies ranging in methodology from scientific review and meta‐analysis to observational studies, and the majority of recommendations were based on expert opinion. On the contrary, our review was limited to rigorously conducted SERs; hence, we utilized the highest level, critically appraised evidence to provide guidance to clinicians and researchers.

Limitations include a diverse group of studies with a heterogeneous population of patients, preventing pooling of results. We did not review each individual study included in the 38 SERs. We excluded non‐English language SERs, studies evaluating delirium subtypes, alcohol or substance abuse‐related delirium, or delirium associated with psychiatric disorders. As we only reviewed SERs, some notable studies not included in the SERs may have been missed.

CONCLUSION

Delirium among hospitalized patients is a common syndrome with a significant burden to the healthcare system and society. The field of delirium has seen considerable advances in diagnosis, prevention, and treatment over the last decade. Even with this advancement, there are still areas of uncertainty, such as: the benefits and costs of delirium screening; the benefits and harms of single or combined pharmacological agents for delirium prevention and treatment; the development of a set of reliable biomarkers for delirium diagnosis, prognosis, and response to therapy; the long‐term effect of delirium‐specific therapeutics on patients' cognitive, physical, and psychological functions; and the relationship between delirium and the development of Alzheimer's disease. As our understanding of delirium's impact on patients and healthcare improves, delirium should be identified as an indicator of poor long‐term prognosis, and should prompt immediate and effective evidence‐based management strategies, like any other critical illness.