Current Geriatric Diagnosis & Treatment, 1st Edition

Section III - Common Disorders in the Elderly

10. Delirium

Lynn McNicoll MD, FRCPC

Sharon K. Inouye MD, MPH

DELIRIUM

ESSENTIALS OF DIAGNOSIS

  • Clinical diagnosis based on detailed history, cognitive assessment, and physical and neurological examination.
  • The pathognomonic feature is an acute change in baseline mental status developing over hours to days.
  • Fluctuating course with an increase or decrease in symptoms over a 24-h period; inattention, with difficulty focusing attention; disorganized thinking, such as rambling or incoherent speech; and altered level of consciousness (vigilant or lethargic).
  • Perceptual disturbances, such as hallucinations, or paranoid delusions.
  • Organic or physiological cause (eg, illness, drug related, or metabolic derangement).
  • Delirium is often misdiagnosed as dementia, depression, or psychosis.
  • Accepted delirium criteria provided by Diagnostic and Statistical Manual of Mental Disorders (fourth edition) as well as Confusion Assessment Method.

General Considerations

Delirium is an acute disorder of attention and cognitive function that may arise at any point in the course of an illness. It is often the only sign of a serious underlying medical condition, especially in frail older persons with underlying dementia.

The prevalence of delirium on admission can range from 10–40%. During hospitalization, it may affect an additional 25–50%. The rates of postoperative delirium are estimated at 10–52%. Even higher rates (70–87%) are seen in intensive care units (ICUs). In addition, 80% of terminally ill patients become delirious before death.

Three forms of delirium have been recognized: the hyperactive, hyperalert form; the hypoactive, hypoalert, lethargic form; and the mixed form, which combines elements of both. The hypoactive form is often unrecognized and is associated with a poorer overall prognosis. It is also the more common form in older hospitalized patients. The hyperactive, agitated, combative, and hallucinating delirious patient is rarely missed.

Delirium as a geriatric syndrome is inherently multifactorial. Delirium develops as a result of the interaction between predisposing factors in vulnerable older persons and noxious insults or precipitating factors. There is rarely only 1 factor or cause, and the effects of multiple factors appear to be cumulative. Thus, clinicians should not expect to address only 1 factor and observe resolution. Rather, it is imperative to identify and address all the potential predisposing and precipitating risk factors.

  1. RISK FACTORS

The major predisposing risk factor for delirium is preexisting cognitive impairment, specifically dementia, which increases the risk of delirium 2- to 5-fold. Other factors include advanced age, severe underlying illness, number and severity of comorbid conditions, functional impairment, chronic renal insufficiency, vision or

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hearing impairment, history of alcohol abuse, malnutrition, and dehydration. Virtually all chronic medical illnesses can predispose older persons to delirium.

  1. ASSOCIATED DISEASES

Specific diseases associated with delirium include neurological disorders involving the central nervous system (eg, Parkinson's disease, cerebrovascular disease, trauma, infections), systemic or non-neurological infections, metabolic alterations, as well as cardiac, pulmonary, endocrine, renal, and neoplastic diseases.

  1. PRECIPITATING FACTORS

The foremost precipitating factors are medications, immobilization, use of indwelling bladder catheters, use of physical restraints, dehydration, malnutrition, iatrogenic complications, organ insufficiency or failure (particularly renal or hepatic), infections, metabolic derangements, and illicit drug use or withdrawal. Environmental factors (eg, noise level) and psychosocial factors (eg, depression, pain) can also precipitate delirium. Occult infections are particularly common in older persons and may present only as delirium. Metabolic disorders may also contribute to delirium, such as hyper- or hyponatremia, hyper- or hypoglycemia, hypercalcemia, thyroid or adrenal dysfunctions, and acid-base disorders.

Medications are a contributing factor in more than 40% of cases. The medications most frequently associated with delirium are those with known psychoactive effects, such as sedative-hypnotics, opiates, H2 blockers, and drugs with anticholinergic effects (eg, antipsychotics, antihistamines, antiparkinsonian agents, antidepressants, antispasmodics). In addition, delirium risk increases in direct proportion to the number of medications prescribed. Herbal therapies have not been studied extensively with respect to delirium; however, these alternative therapies are being increasingly recognized as causing or contributing to delirium, especially when taken concurrently with a psychoactive medication. This is particularly true for psychoactive herbs, such as St. John's wort, kava kava, and valerian root.

Ely EW et al: Delirium in the intensive care unit: An under-recognized syndrome of organ dysfunction. Semin Respir Crit Care Med 2001;22:115. [PMID n/a] (Review of recent literature on delirium in critically ill patients, which presents delirium as an underrecognized form of organ dysfunction rather than an expected outcome of intensive care.)

Table 10-1. Risk factors for delirium and targeted interventions.

Risk factor

Intervention

Sleep deprivation

Nonpharmacological sleep protocol (back massage, relaxation music, decreased noise, warm milk or caffeine-free herbal tea)
Avoid using sedatives, especially diphenhydramine

Dehydration

Recognition of volume depletion and replenishment of fluids

Hearing loss

Proper hearing aids available and in use (either patient's own hearing aid or amplifier)

Vision loss

Provision of proper visual aids (patient's own glasses, magnifying lenses, or adaptive equipment)

Immobility

Ambulate as soon as possible (assistance or supervision when needed)
Active range-of-motion exercises if confined to bed

Cognitive impairment

Frequent reorientation to person, place, time. A large updated board in front of the patient is useful.
Avoidance of psychoactive medications.

Use of sedating or psychoactive medications

Use alternative and less harmful medications, avoid those with long half-lives, allow for impaired kidney and liver function. Use the lowest dose possible, taper and discontinue unnecessary

Prevention

Risk factors and targeted preventive interventions are shown in Table 10-1. Prevention of delirium by targeting vulnerable patients with predisposing or precipitating factors has been shown to be effective. In addition, proactive geriatrics consultation (daily geriatrician visits and targeted recommendations based on a structured protocol) is effective in vulnerable patients with preexisting dementia or functional impairments.

Inouye SK et al: The Hospital Elder Life Program: A model of care to prevent cognitive and functional decline in older hospitalized patients. J Am Geriatr Soc 2000;48:1697. [PMID: 11129764] (The practical implementation of a multicomponent targeted program to improve cognitive and functional outcomes in older hospitalized patients.)

Inouye SK et al: A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med 1999;340: 669. [PMID: 10053175] (Successful clinical trial of a multiple risk factor reduction strategy for the prevention of delirium in hospitalized older medical patients with 40% reduction in delirium.)

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Marcantonio ER et al: Reducing delirium after hip fracture: A randomized trial. J Am Geriatr Soc 2001;49:516. [PMID: 11380742] (Randomized controlled trial of proactive geriatric consultation, which successfully reduced occurrence of delirium in hip fracture patients by 36%.)

Clinical Findings

  1. SYMPTOMS & SIGNS

The initial evaluation of delirium is largely based on establishing a patient's baseline cognitive functioning and the clinical course of any cognitive change. Thus, a detailed history from a reliable informant, such as a spouse, child, or caregiver, is most important. The history should seek to clarify the acuity of any mental status changes and seek clues to the underlying cause.

The cardinal historical features of delirium are acute onset and fluctuating course, in which symptoms tend to come and go or increase and decrease in severity over a 24-h period. This is the major feature distinguishing delirium from dementia, which usually develops gradually and progressively over months to years. To fulfill the criteria of delirium, the change must occur in the context of a medical illness, metabolic derangement, drug toxicity, or withdrawal.

  1. Cognitive changes—Other features of delirium are usually determined through cognitive testing and, most importantly, close clinical observation of the quality of the patient's responses during cognitive testing. For example, a person may score correctly on the particular cognitive task, but during the task may demonstrate fluctuating attention, easy distractibility, rambling speech, or lethargy.
  2. Inattention—Inattention, or the inability or decreased ability to focus, maintain, and shift one's attention, is another key clinical manifestation of delirium. Patients will demonstrate difficulty maintaining or following a conversation, becoming easily distracted, or perseverating on a previous answer. Patients may require repetition of instructions or may struggle to follow instructions on cognitive tasks, such as simple repetition, digit span, or backward recitation of the months.
  3. Disorganized thinking—Disorganized thinking or speech is manifested as rambling and, at its extreme, incoherent speech. Problems with memory, disorientation, or language are frequent.
  4. Altered level of consciousness—Altered level of consciousness can range from agitated, vigilant states to lethargic or stuporous states.
  5. Other features—Other features commonly seen in delirious patients, but not essential for the diagnosis, are psychomotor agitation or retardation, perceptual disturbances (eg, hallucinations, illusions), paranoid delusions, emotional lability, and sleep–wake cycle disturbances.
  6. PHYSICAL EXAMINATION

A detailed physical examination is essential for evaluation of delirium. Delirium may often be the initial manifestation of serious underlying disease in an older person; thus, astute attention to early localizing signs on physical examination may allow early diagnosis of a precipitating insult. Assessment of vital signs is often helpful. A careful search for evidence of occult infections should be performed, including signs of pneumonia, urinary tract infection, acute abdominal processes, joint infections, or new cardiac murmur. A detailed neurologic examination with attention to focal or lateralizing signs is also crucial.

  1. SPECIAL TESTS
  2. Diagnostic and Statistical Manual of Mental Disorders–IV—The American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders–IVcriteria (Table 10-2) were developed based on expert opinion and remain the current standard for the definition and diagnostic criteria for delirium.
  3. Confusion Assessment Method—The Confusion Assessment Method (CAM) is a simple, validated tool that is currently in widespread use (Table 10-2). It has a sensitivity of 94–100%, specificity of 90–95%, and a negative predictive value of 90–100% for delirium. It has also been validated in patients with dementia.

In the intensive care setting, it is now feasible to perform cognitive evaluation and screen for delirium using the CAM for the ICU (CAM-ICU), a modification of the CAM for use in mechanically ventilated, restrained, or nonverbal patients. The CAM-ICU has been examined in ICU patients with probable dementia and uses the same 4 key delirium features for the diagnosis.

  1. Other instruments—Other instruments developed and validated for use in the identification of delirium include the Delirium Rating Scale, Delirium Severity Index, Memorial Delirium Assessment Scale, and Cognitive Test for Delirium.
  2. LABORATORY FINDINGS

The algorithm in Figure 10-1 provides a systematic approach to the diagnosis and evaluation of delirium in the older person. No specific laboratory tests exist that will positively identify delirium. Current research is focusing on using serum anticholinergic activity level or neurochemical tests, such as neuron-specific enolase or protein S-100, as potential markers for the presence or severity of the syndrome.

Laboratory tests that should be considered in the evaluation of any patient with delirium include determination

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of complete blood count, electrolytes (including calcium), kidney and liver function, glucose, and oxygen saturation. Furthermore, in searching for an occult infection, 2 sets of blood cultures, urinalysis, and urine culture may be useful. Other laboratory tests may be pursued if specific contributing factors have not been identified in a particular patient. These include thyroid function tests, arterial blood gas, vitamin B12 levels, drug levels, toxicology screens, ammonia or cortisol levels, and evaluation of the cerebrospinal fluid.

Table 10-2. Established diagnostic criteria for delirium.

DSM-IV diagnostic criteriaa

1. There is a disturbance of consciousness (ie, reduced clarity of awareness of the environment) with reduced ability to focus, sustain, or shift attention.

2. There is a change in cognition (memory deficits, disorientation, language disturbance) or the development of perceptual disturbances that are not accounted for by preexisting dementia.

3. The disturbance develops over a short period of time (hours to days) and tends to fluctuate (during the course of the day).

4. there is evidence from the history, physical examination, or laboratory findings that the disturbance is caused by the direct physiological consequences of a general medical condition or substance (drug of abuse, medication, or toxin exposure).

CAM diagnostic criteriab

5. Acute onset and fluctuating course. This feature is based on evidence from a family member or nurse of a positive response to the following questions:Is there evidence of an acute change in mental status from the patient's baseline? Did the (abnormal) behavior fluctuate during the day, that is, tend to come and go, or increase or decrease in severity?

6. Inattention. This feature is based on the observation of the presence of difficulty focusing attention, (eg, being easily distracted, or having difficulty keeping track of what was being said).

7. Disorganized thinking. This feature is based on the observation of the presence of disorganized thinking or incoherent speech, such as rambling or irrelevant conversation, unclear or illogical flow of ideas, or unpredictable switching from subject to subject.

8. Altered level of consciousness. This feature is based on the observation of the presence of a level of consciousness other than “alert.” This altered level of consciousness can be either vigilant (hyperalert) or various levels of hypoalert states, such as lethargy (drowsy, easily arousable), stupor (difficulty to arouse), or coma (unarousable).

The diagnosis of the delirium requires the presence of features 1 and 2 and either (3 or 4). DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edition, CAM, Confusion Assessment Method.
The ratings for the CAM should be completed after review of the medical chart, discussion with a family member or nurse, and a brief cognitive assessment of the patient (eg, using the Mini-Mental State Examination and Digit Span test).

  1. IMAGING STUDIES

In the evaluation of delirium, a chest radiograph to rule out occult pneumonia may prove revealing. Brain imaging with computed tomography (CT) or magnetic resonance imaging are indicated if a history or signs of a recent fall or head trauma, fever of unknown origin, new focal neurological symptoms, or no obvious cause has been identified. An electroencephalogram may be indicated if there is any suggestion of seizure activity. It can also be used in differentiating delirium from a nonorganic psychiatric disorder. No definitive evidence yet exists that functional nuclear medicine scans, such as positron emission tomography or single photon emission CT scans, provide any specific data in terms of diagnosis or cause.

American Psychiatric Association: Diagnostic and statistical manual of mental disorders, 4th ed. American Psychiatric Association, 1994. (Reference standard for definition of and diagnostic criteria for delirium.)

Elie M et al: Delirium risk factors in elderly hospitalized patients. J Gen Intern Med 1998;13:204. [PMID: 9541379] (Review of delirium risk factors emphasizing that advanced age, dementia, and severity of illness are the principal risk factors for the development of delirium in the hospital.)

Ely EW et al: Delirium in mechanically ventilated patients: Validity and reliability of the Confusion Assessment Method for the intensive care unit (CAM-ICU). JAMA 2001;286:2703. [PMID: 11730446] (Validation study of a new instrument for the detection of delirium in 3 subgroups of critically ill patients: mechanically ventilated, older, and potentially demented patients.)

Inouye SK et al: Clarifying confusion: The Confusion Assessment Method. A new method for the detection of delirium. Ann Intern Med 1990;113:941. [PMID: 2240918] (Validation study for the CAM instrument in hospitalized elderly and a subset of persons with dementia.)

Differential Diagnosis

The main diagnostic dilemma facing the clinician is differentiating delirium from dementia. This is especially difficult when knowledge of baseline cognitive function is missing or when there are known cognitive

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deficits and one must determine whether the current condition is due to underlying chronic cognitive impairment or to delirium. Thus, it is crucial to obtain a reliable history about baseline status from an informant. Inattention and altered level of consciousness are usually not features of mild to moderate dementia, and their presence supports the diagnosis of delirium. In patients with known dementia, a history that includes worsening confusion over and above the baseline cognitive impairment also suggests delirium.

 

Figure 10-1. Algorithm for the evaluation of suspected delirium in the older adult. MMSe, Mini-Mental State Exam; CAM, Confusion Assessment Method; OTC, over-the-counter; PRN, as needed; TFT, thyroid function tests; B12, vitamin B12; NH3, ammonia level; ABG, arterial blood gas; CSF, cerebrospinal fluid; EEG, electroencephalogram; PO, oral; IM, intramuscular; IV, intravenous. Adapted from Hazzard WR et al (editors): Principles of geriatric medicine and gerontology, fifth edition. McGraw-Hill, 2003. Used with permission.

Other important diagnoses that must be differentiated from delirium are depression, mania, and other nonorganic psychotic disorders, such as schizophrenia. These diseases do not typically arise in the context of a medical illness. Again, the history and clinical course can assist in providing important clues in differentiating these syndromes. Altered level of consciousness is not prominent in these other diseases. At times, the differential diagnosis can be quite difficult as a result of subtle symptoms or an uncooperative patient. Because of the potential life-threatening nature of delirium, one should err on the side of treating the patient as delirious until further information is available.

Fick D, Foreman M: Consequences of not recognizing delirium superimposed on dementia in hospitalized elderly individuals. J Gerontol Nurs 2000;26:30. [PMID: 10776167] (Delirium was less likely to be recognized in patients with dementia. These cases were also more likely to be readmitted to the hospital.)

Inouye SK et al: Nurses' recognition of delirium and its symptoms: Comparison of nurse and researcher ratings. Arch Intern Med 2001;161:2467. [PMID: 11700159] (Prospective study of nurse recognition of delirium: Nurses often missed delirium when present (70% of cases missed) but rarely identified delirium when absent. The recognition was enhanced with education of delirium and cognitive impairment.)

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Complications

Delirium is associated with increased morbidity, mortality, functional decline, and immobility and its attendant complications, including aspiration pneumonia, pressure ulcers, deep venous thrombosis, pulmonary emboli, and urinary tract infections. Moreover, delirium is associated with complications related to its underlying causes. All of these factors contribute to the poor long-term prognosis associated with delirium in older patients.

Inouye SK et al: Delirium: A symptom of how hospital care is failing older persons and a window to improve quality of hospital care. Am J Med 1999;106:565. [PMID: 10335730] (Considers delirium as a quality of care measure given the frequency of delirium and the correctable deficiencies in hospital care that can be implemented to reduce delirium. Provides in-depth discussion of the approaches to improving quality of care for hospitalized older persons.)

Rothschild RM et al: Preventable medical injuries in older patients. Arch Intern Med 2000;160:2717. [PMID: 11025781] (Includes delirium as one of the important preventable medical injuries in older hospitalized patients.)

Treatment

Two concurrent approaches are involved in the treatment of delirium (see Figure 10-1): (1) identification and treatment of the underlying medical cause and eradication or minimization of contributing factors of delirium; and (2) management of delirium symptoms. The first task involves the complete review of the medication history (including prescription, over-the-counter, as needed, and herbal medications) to identify potentially contributing medications that can be eliminated, converted to a less offending agent, or decreased in dosage. Drug interactions should be evaluated. Current kidney and liver function status should be assessed (eg, by estimation of the creatinine clearance) and medication dosage and frequency adjusted accordingly. A complete history and physical (including neurological) examination should be performed, along with selected laboratory and radiological screening tests. Occult infection should be evaluated. If no identifiable cause or contributor is identified, further testing should be pursued, as shown in Figure 10-1.

  1. NONPHARMACOLOGICAL STRATEGIES

In general, nonpharmacological strategies should be used in all delirious patients. These include reorientation (with visible and legible orientation boards updated regularly, clocks, and calendars), encouraging the presence of family members as a stabilizing presence, and transferring the patient to a private room or to a room closer to the nursing station for supervision. A skilled and sensitive staff can be vitally important in optimizing communication by using frequent verbal reorientation strategies, simple instructions and explanations, frequent eye contact, and involvement of patients in their care and in decision making. Sensory deficits should be corrected by ensuring that assistive devices (such as eyeglasses, hearing aids, listening devices) are available, functioning, and in use. All attempts should be made to minimize the use of physical restraints because they tend to worsen delirium and can aggravate or cause agitation. Instead, strategies for improving mobility, self-care, and independence should be encouraged.

Improving sleep in the delirious hospitalized older person is an important intervention. Feasible and effective nonpharmacological strategies for enhancing sleep in older people have been developed and tested and include back massage, a warm drink, relaxation techniques, soothing music, and, most importantly, uninterrupted periods of sleep with reduced light and noise level. Coordination of the timing of medications, vital signs, and procedures may be required to achieve the uninterrupted period of sleep.

  1. PHARMACOLOGICAL STRATEGIES

Pharmacological therapy for delirium should be reserved for severely agitated individuals whose behavior threatens to interrupt medically necessary care (such as mechanical ventilation) or poses a safety hazard. Given that all medications used in the treatment of delirium can also cause or worsen confusion, a general principle is to use the lowest dose possible and for the shortest period of time. The end point should be an awake and manageable patient, not a sedated patient. All too often, a neuroleptic is started for management of agitated delirium, but the medication is continued indefinitely, obscuring the ability to follow mental status on serial evaluation and putting the patient at significant risk for adverse drug reactions.

Neuroleptics are the preferred class of drugs in delirium management; haloperidol is the most widely used agent for agitation. It is available orally, intramuscularly, or intravenously, but the oral route remains optimal because of favorable pharmacokinetics. The parenteral routes are often medically necessary for emergent cases, but administration should be converted to oral as soon as possible. As noted in Figure 10-1, the recommended starting haloperidol dose is 0.25–1.0 mg, followed by a repeat dose every 20–30 min until the patient is manageable. The maximum dose should not exceed 3–5 mg. Vital signs should be monitored before each additional dose and frequently during active administration. Subsequently, after the loading dose, a maintenance dose is calculated by dividing the loading dose by 2 and administering this quantity in divided doses over the next 24 h and tapering over the next few days.

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Common and clinically relevant adverse effects of haloperidol include sedation, hypotension, acute dystonias, extrapyramidal effects, and anticholinergic effects (eg, dry mouth, constipation, urinary retention, and increased confusion). D2-dopaminergic receptors are saturated at low doses of haloperidol. Thus, theoretically, any additional haloperidol above 5 mg over a 24-h period is only likely to increase adverse events without providing additional clinical benefit.

New, atypical neuroleptics also used in the treatment of delirium include risperidone, olanzapine, and quetiapine; however, no trials have compared these agents with placebo or haloperidol. Haloperidol is the only agent that has been shown effective in the treatment of delirium. Olanzapine has greater anticholinergic properties but fewer extrapyramidal properties than haloperidol. Although it may be beneficial for greater sedation, it poses increased risk for worsening confusion.

Benzodiazepines remain the drugs of choice for the treatment of alcohol or sedative drug withdrawal, but they are not recommended in the primary treatment of delirium in older persons because they may cause oversedation and exacerbation of confusion. Among the benzodiazepines, lorazepam is the preferred agent in geriatric practice because of its shorter half-life, lack of active metabolites, and availability in parenteral form.

American Psychiatric Association: Practice guideline for the treatment of patients with delirium. Am J Psychiatry 1999;156 (5 suppl):1. [PMID: 10327941] (Clinical practice guidelines based on review of the literature and expert opinion.)

McDowell JA et al: A non-pharmacological sleep protocol for hospitalized older patients. J Am Geriatr Soc 1998;46:700. [PMID: 9625184] (Prospective study evaluating the effectiveness of a nonpharmacological approach to improve sleep in the hospital setting.)

Milisen K et al: A nurse-led interdisciplinary intervention program for delirium in elderly hip-fracture patients. J Am Geriatr Soc 2001;49:523. [PMID: 11380743] (Intervention focused on education of nursing staff, systematic cognitive screening, and geriatric assessment reduced the duration and severity of delirium after hip fracture. No effect was noted on incidence of delirium.)

Prognosis

Delirium is independently associated with adverse hospital and long-term outcomes, including poor long-term functioning, mortality, increased length of stay, increased need for formal home health care and rehabilitation services, new institutionalization, and increased costs of care. Delirium has traditionally been described as a reversible syndrome, implying that patients invariably return to their baseline cognitive and functional state. Evidence suggests, however, that long-term cognitive and functional deficits may persist as long as 2 years posthospitalization.

Patients who experience delirium are more likely to be diagnosed with dementia at a later date.

Ely EW et al: The impact of delirium in the intensive care unit on hospital length of stay. Intensive Care Med 2001;27:1892. [PMID: 11797025] (Delirium was independently associated with increased length of stay in mechanically ventilated adult ICU patients.)

Inouye SK et al: Does delirium contribute to poor hospital outcomes? A three-site epidemiological study. J Gen Intern Med 1998;13:234. [PMID: 9565386] (Delirium was independently associated with death and new institutionalization.)

McCusker J et al: Delirium predicts 12-month mortality. Arch Intern Med 2002;162:457. [PMID: 11863480] (This prospective case-control study confirmed that delirium was an independent marker of increased mortality in older hospitalized patients.)

O'Keeffe S, Lavan J: The prognostic significance of delirium in older hospital patients. J Am Geriatr Soc 1997;45:174. [PMID: 9033515] (Even after controlling for baseline and hospital factors, delirium was independently associated with multiple negative hospital outcomes.)

RELEVANT WORLD WIDE WEB SITES

American Psychiatric Association: A Patient and Family Guide: http://www.psych.org/clin_res/Delirium.pdf

American Psychiatric Association guidelines: http://www.psych.org/clin_res/pg_delirium.cfm

Hospital Elder Life Program: http://www.med.yale.edu/intmed/aging/elp

Systematic Reviews of delirium studies by Martin Cole and colleagues in the Cochrane Library, Database of Abstracts of Reviews of Effectiveness: http://www.cochranelibrary.com