Introduction: Methods, Commentary, and Summary

MICHAEL H. ALLEN, MD GLENN W. CURRIER, MD, MPH DANIEL CARPENTER, PhD RUTH W. ROSS, MA JOHN P. DOCHERTY, MD

Objectives. Due to inherent dangers and barriers to research in emergency settings, few data are available to guide clinicians about how best to manage behavioral emergencies. Key constructs such as agitation are poorly defined. This lack of empirical data led us to undertake a survey of expert opinion, results of which were published in the 2001 Expert Consensus Guidelines on the Treatment of Behavioral Emergencies. Several second-generation (atypical) antipsychotics (SGAs) are now available in new formulations for treating behavioral emergencies (e.g., intramuscular [I.M.] olanzapine and ziprasidone; rapidly dissolving tablets of olanzapine and risperidone). Critical questions face the field. The SGAs are significantly different from the FGAs and from each other and have not been studied in unselected patients as were the FGAs. Can the SGAs can be thought of as a class, do all antipsychotics have similar anti-agitation effects in different conditions, and, if equally effective, what limits might their safety profiles impose? Should antipsychotics be used more specifically to treat psychotic conditions, while benzodiazepines (BNZs) alone are used nonspecifically? Few data are available concerning combinations of SGAs and BNZs, and findings concerning the traditional combination of haloperidol plus a BNZ may not be relevant to combinations with SGAs. The culture is also evolving with more emphasis on patient involvement in treatment decisions. An international consensus has been developing that calming rather than sedation is the appropriate endpoint of behavioral emergency interventions. We undertook a new survey of expert opinion to update recommendations from the earlier survey. Method. A written survey of 61 questions (1,020 options) was mailed to 50 experts in the field, 48 (96%) of whom completed it. The survey sought to define level of agitation at which emergency interventions are appropriate, scope of assessment depending on urgency and patients ability to cooperate, guiding principles for selecting interventions, and appropriate physical and medication strategies at different levels of diagnostic confidence for a variety of provisional diagnoses and complicating conditions. A modified version of the RAND Corporations 9-point scale for rating appropriateness of medical decisions was used to score most options. Consensus was defined as a non-random distribution of scores by chi-square goodness-of-fit test. We assigned a categorical rank (first line/preferred, second line/alternate, third line/usually inappropriate) to each option based on the 95% confidence interval around the mean. Ratings were used to develop guidelines for preferred strategies in key clinical situations. This study received financial support from multiple sponsors, with the panel kept blind to sponsorship to reduce possible bias. Medication ratings were based on responses of only those respondents with direct experience with each drug. In reporting practice patterns, the panel was asked to respond based on actual data rather than estimates. Results. The expert panel reached consensus on 78% of the options rated on the 9-point scale. The responses suggest that physicians can make provisional diagnoses with some confidence and that pharmacological and nonpharmacological interventions are selected differentially based on diagnosis and other salient demographic and medical features. BNZs are recommended when no data are available, when there is no specific treatment (e.g., personality disorder), or when they may have specific benefits (e.g., intoxication). No single SGA emerges as a nonspecific replacement for haloperidol; instead, different SGAs are preferred in various circumstances consistent with current evidence.To the degree that haloperidol is recommended, it is almost always in combination with a BNZ; haloperidol alone is preferred only in the medically compromised. In contrast, the SGAs are more often recommended for use alone, and the panel would avoid combining BNZs with some SGAs. Oral risperidone alone or combined with a BNZ receives strong support in a variety of situations. Oral olanzapine was rated very similarly to risperidone, with slightly higher ratings than risperidone in situations where it has been studied (e.g., schizophrenia, mania) and slightly lower ratings where it has not been studied or safety may be a concern; there was less support for combining oral olanzapine with a BNZ. For oral treatment of agitation related to schizophrenia or mania, olanzapine alone, risperidone alone or combined with a BNZ, and haloperidol plus a BNZ are first line, with strong support also for combining divalproex with the antipsychotic for presumed mania. Oral ziprasidone and quetiapine generally received similar second-line ratings in most situations. If a parenteral agent is needed, I.M. olanzapine alone received somewhat more support than I.M. ziprasidone alone; however, there was more support for I.M. ziprasidone alone or combined with a BNZ than for I.M. olanzapine plus a BNZ, probably reflecting safety concerns. For example, for a provisional diagnosis of schizophrenia, first-line parenteral options are I.M. olanzapine or ziprasidone alone or I.M. haloperidol or ziprasidone combined with a BNZ. Neither of the new parenteral formulations received as much support as traditional agents (I.M. BNZs, I.M. haloperidol) when no data are available or the diagnosis involves medical comorbidity or intoxication. When initial intervention with risperidone, ziprasidone, or haloperidol is unsuccessful, the panel recommended adding a BZD to the antipsychotic. However, when initial treatment with olanzapine or quetiapine is unsuccessful, increasing the dosage is recommended. Perphenazine was consistently rated second line and droperidol and chlorpromazine received third-line ratings throughout. Conclusions. Within the limits of expert opinion and with the expectation that future research data will take precedence, these guidelines suggest that the SGAs are now preferred for agitation in the setting of primary psychiatric illnesses but that BNZs are preferred in other situations. (Journal of Psychiatric Practice 2005;11 [Suppl 1]:1108) KEY WORDS: behavioral emergency, agitation, psychosis, mania, expert consensus guidelines, antipsychotics, benzodiazepines, sedatives, restraints

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WHY A REVISION?
Behavioral emergencies are complex, dynamic situations. The diagnosis is often unknown or provisional at best. There is a sense of urgency, limited time for decision-making, and a need to intervene immediately despite limited data and change course rapidly as new information becomes available, including responses to prior interventions. Whether in the emergency room or inpatient psychiatric setting, immediate assessment and effective intervention can reduce danger to patients and staff and promote faster recovery. At the same time, any action or inaction may have serious adverse effects. Even an objectively good response may leave patients feeling traumatized and angered by the process. It is important for clinicians to remember they must first do no harm. Unfortunately, high-quality, empirical data on the most effective and appropriate methods of managing behavioral emergencies are limited. This is largely due to practical and ethical difficulties in performing controlled clinical trials in agitated patients in emergency settings. For example, it is often impossible or impractical to obtain consent for participation from severely agitated patients, and yet these are the very patients for whom information on appropriate treatments is most needed. It was for this reason that we undertook our original survey of expert opinion on behavioral emergencies, the results of which were published in 2001 in The Expert Consensus Guidelines on the Treatment of Behavioral Emergencies.1 Several new options for treating behavioral emergencies have become available since those guidelines were published. At the time of the first survey, only conventional antipsychotics (e.g., haloperidol, perphenazine) were available in intramuscular (I.M.) formulations, whereas two second-generation (atypical) antipsychotics (SGAs), olanzapine and ziprasidone, are now available in fast-acting I.M. formulations as well as fast dissolving tablets of risperidone (Risperdal M-Tab) and olanzapine (Zyprexa Zydis).2 In addition, agitation is still poorly understood. It has been described by Lindenmayer3 as a transnosological syndrome and agents that have historically been available, including first generation (conventional) antipsychotics (FGAs) and sedatives, have been used across disease states. In our previous survey, benzodiazepines (BNZs) were recommended when no diagnostic information was available. FGAs have been used somewhat more narrowly, not due to lack of efficacy in different states, but due to poor tolerability compared with BNZs. The FGAs have also been the treatment of choice for agitation associated with delirium. Not only is there evidence that both BNZs and FGAs are effective in multiple diseases but there is little evidence that one is superior to the other. However, the U. S. Food and Drug Administration (FDA) has been unwilling to accept a nonspecific pain and fever model of agitation. To do so, it would have to be demonstrated that symptoms of agitation are universally recognized, readily measured, have a well understood pathophysiologic basis, and respond similarly to symptomatic drug treatment, apart from the diverse disease states that

may lead to the symptom.4 Consequently, new drugs are studied in the context of particular diseases and are then said to be indicated for agitation associated with a particular disease entity such as schizophrenia or mania. Thus, new agents have been demonstrated effective only in well characterized and homogeneous populations. Of course, patients in emergency settings rarely present with a single, clearly defined diagnosis; instead, comorbid medical and substance use disorders are highly prevalent. Agitation may present in many different conditions, and treatments must be chosen based on limited data. Treatments must be safe enough to use in agitated patients who are assumed to have serious undiagnosed complications that can only be assessed after the agitation is successfully managed. In some fraction of cases, which varies by setting, agitation will later be determined to be associated with a primary psychiatric disorder for which antipsychotics might be indicated as a routine part of care. In those situations, using antipsychotic medication for agitation may speed recovery by a brief period. In other circumstances, antipsychotics may prove effective but unnecessary and will be discontinued. This situation raises questions as to whether the SGAs will be found to be effective in most forms of agitation and sufficiently benign that unnecessary exposure is of little consequence. If so, nonspecific use of antipsychotics may turn out to be the most efficient option, since treatment of patients who ultimately require antipsychotics will be hastened and others will not be harmed. However, the SGAs appear quite different from the FGAs in important ways, and their safety and efficacy have not been demonstrated in many relevant circumstances. While data are emerging that suggest there may be a cumulative risk of adverse health consequences with chronic exposure to some SGAs, the health consequences of a single dose in the context of p.r.n. use are completely uncharacterized. If the SGAs cannot be used nonspecifically, it is important to know what physical and psychiatric findings might be quickly identified on the basis of a limited examination to facilitate choice of a specific agent. Furthermore, if the newer agents are more tolerable, the rationale for combining an antipsychotic with a BNZ may be obviated. FGAs were often combined with BNZs to achieve sedation without use of excessive antipsychotic doses and to ameliorate side effects of the FGAs, principally haloperidol. This may be unnecessary and unwise with the SGAs. If the newer agents are in fact more tolerable, a better strategy may be to increase the dose of the SGA rather than risk combining these more pharmacologically complex agents with BNZs. Finally, there is the issue of the role of sedation in the management of agitation. An international consensus has been developing that calming rather than sedation is the appropriate endpoint of interventions for behavioral emergencies.57 Recent years have also seen a growing emphasis in both the clinical and lay literature on increasing patient involvement in treatment decisions for behavioral emergencies to the greatest extent possible, both through use of advance directives and input during the emergency.1,68 This would seem to further erode support for combinations with sedative medications.

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In order to update recommendations to reflect the rapid evolution and new concerns of the field, we undertook a new survey of expert opinion concerning the most appropriate goals of emergency interventions and best choice of specific agents.

Figure 2 shows Survey Question 6 as an example of our question format.

Composition of the Expert Panel

We identified 50 leading American experts in psychiatric emergency medicine from several sources: board certified members of the American Association of Emergency Psychiatry who have administrative responsibilities for a psychiatric emergency service (PES) as well as academic affiliations, individuals who have published research on emergency psychiatry or psychopharmacology, and emergency physicians recognized for their contributions to the treatment of patients with mental illness in general emergency settings. More than 90% of the panel were board certified and affiliated with academic institutions. We received responses from 48 (96%) of the 50 experts to whom the survey was sent, who practice in 17 different states. Of the respondents, 47 hold an MD degree and 1 a DO degree. 77% are male. The experts mean age was 48 years (SD 8.6, range 3169), with a mean of 17 years in practice (SD 8.6, range 345) and a mean of 16 years in emergency psychiatric care (SD 7.2, range 435). 100% reported that their practice involved clinical or research work with agitated patients. 65% reported spending at least half their work time seeing patients. 45% practice in a psychiatric (15%) or general hospital (30%) emergency service; 28% practice on an inpaFigure 1. The rating scale Extremely Inappropriate 123 456 789 Extremely Appropriate

EXPERT CONSENSUS AND PRACTICE GUIDELINES

The sheer number of possible combinations and sequences of available treatments for many diseases makes it difficult to provide comparative recommendations based entirely on clinical trial data.9,10 A method for describing expert opinion in a quantitative, reliable manner to help fill gaps in evidence-based guidelines has been developed and applied to a variety of psychiatric disorders.1125

Creating the Surveys

Based on a literature review and the 2001 survey results, we identified key decision points in the management of behavioral emergencies and feasible options for intervention, highlighting key clinical questions not adequately addressed or definitively answered in the literature.26 A written survey was developed with 61 questions (1,020 options) asking about types of assessments, most appropriate interventions, and tailoring selection of interventions to the most likely etiology of the behavioral dyscontrol. We also asked about next steps if there is an inadequate response to initial intervention as well as safety and tolerability issues, such as management of behavioral emergencies in children, the elderly, and patients with medical complications. The survey took 2 or more hours to complete, and we provided a $500 honorarium.

9 = Extremely appropriate: this is your treatment of choice

The Rating Scale

For 854 options in the survey, we asked raters to evaluate appropriateness by means of a 9-point scale slightly modified from a format developed by the RAND Corporation for ascertaining expert consensus.27 For the other questions, we asked respondents to fill in a blank (e.g., write in a dosage) or check a box endorsing one of several alternatives. We asked the raters to consider the best possible approach for the first few hours of intervention in order not to have a negative impact on the clinicians ability to diagnose and treat the disorder in continuing care. We asked the panel to draw on both their knowledge of the research literature (we did not provide a literature review) and their best clinical judgment in making their ratings, but not to consider financial cost. We instructed respondents to rate only those medications with which they had direct experience and to base their responses concerning practice patterns on actual data rather than estimates. In order to take as conservative an approach as possible, ratings of each medication were based on the responses of only those experts who had direct experience with that drug. We presented the rating scale to the experts with the anchors shown in Figure 1.

78 = Usually appropriate: a first-line treatment you would often use 46 = Equivocal: a second-line treatment you would sometimes use (e.g., patient/family preference or if first-line treatment is ineffective, unavailable, or unsuitable) 23 = Usually inappropriate: a treatment you would rarely use 1 = Extremely inappropriate: a treatment you would never use Figure 2. Sample survey question 6. Goals of emergency intervention. Assume you have decided to undertake an emergency intervention for a patient with clinically significant agitation. Please rate the following as appropriate goals for such an intervention. Calming the patient without sedation Mild sedation to the point of drowsiness but not sleep Sleep or heavy sedation 123 456 789 123 456 789 123 456 789

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tient service, either in a general or psychiatric hospital; and 28% practice in both emergency and inpatient services. 71% of the experts had participated in clinical research studies during the preceding 5 years. The respondents reported the following percentages of patients by diagnostic group: Mean SD Range % % % Psychotic disorder 31 18 180 Major depression 22 12 160 Bipolar disorder 16 9 140 Primary substance abuse 16 12 250 Dementia 8 14 175 Other Axis I disorder 8 7 132 Axis II disorder only 8 11 157 No psychiatric disorder, required social services 4 3 110 42% of the patients served by the experts services over the previous year had a secondary substance use disorder. 20% of their psychiatric emergency services evaluate fewer than 250 patients each month, 29% evaluate 250500 patients each month, and 51% more than 500 patients. The respondents reported that a mean of 36% of patients in their services were treated involuntarily. The authors acknowledge that many panel members were drawn from urban academic medical centers, which may affect the applicability of their recommendations for rural settings.

the numerical values are given in the table on the right, including the number of experts who rated each option.

The Ratings
First-line treatments are strategies that received highest ratings when the experts responses to the survey were statistically analyzed. These are options the panel feels are usually appropriate as initial treatment for a given situation. Treatment of choice, when it appears, is an especially strong first-line recommendation (rated 9 by at least half the experts). In choosing between several first-line recommendations, or deciding to use a first-line treatment at all, clinicians should consider the overall clinical situation, including the patients prior response to treatment, side effects, general medical problems, and patient preferences. Second-line treatments are reasonable choices for patients who cannot tolerate or do not respond to the first-line choices. A second-line choice might also be used for initial treatment if the firstline options are deemed unsuitable for a particular patient (e.g., because of poor previous response, history of side effects, general medical contraindication, potential drug interaction, or if the experts do not agree on a first-line treatment). To differentiate among second-line options, we label items whose CIs overlap with the first-line category high second line. Third-line treatments are usually inappropriate or used only when preferred alternatives have not been effective. No consensus. For each item in the survey, we used a chisquare test to determine whether the experts responses were randomly distributed across the 3 categories, which suggests a lack of consensus, indicated by an unshaded bar in the survey results. Statistical differences between treatments. While we did not perform tests of significance for most treatments, the reader can readily see whether CIs overlap (roughly indicating no significant difference between options by t-test). The wider the gap between CIs, the smaller the p value would be (i.e., the more significant the difference). In some questions there are important differences within levels that we point out. However. differences within levels are often not significant from a statistical perspective. Also, there are sometimes no statistical differences between choices at the bottom of first line and those at the top of second line.

Financial Support
This survey study was supported by grants from multiple sponsors: AstraZeneca Pharmaceuticals LP, Janssen Pharmaceutica Products LP, and Pfizer, Inc. The experts were kept blind to the sponsorship of the survey in order to reduce any possible bias.

Data Analysis for Options Scored on the Rating Scale

For each option, we first defined the presence or absence of consensus as a distribution unlikely to occur by chance by performing a chisquare test (p < 0.05) of the distribution of scores across the 3 ranges of appropriateness (13, 46, 79). Next we calculated the mean and 95% confidence interval (CI). A categorical rating of first, second, or third line was designated based on the lowest category in which the CI fell, with boundaries of 6.5 or greater for first line, and 3.5 or greater for second line. Within first line, we designated an item as treatment of choice if at least 50% of the experts rated it as 9.

From Survey Results to Guidelines Displaying the Survey Results

The results of Question 6 (Figure 2) are presented graphically in Figure 3. The CIs for each option are shown as horizontal bars and After the results were analyzed and ratings assigned, the experts recommendations were used to develop user-friendly guidelines. Two levels of recommendations are presented: first-line/preferred and high

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Figure 3. Results of survey question 6

95% CONFIDENCE INTERVALS Third Line Second Line First Line Calming the patient without sedation Mild sedation to the point of drowsiness but not sleep Sleep or heavy sedation 1 2 3 4 5 6 7 8 9 N 48 48 48 Tr of 1st 2nd 3rd Avg (SD) Chc Line Line Line 8.4(1.3) 6.8 (1.4) 3.7(1.8) 75 17 0 % 92 54 10 % 8 46 31 % 0 0 58 %

second line/alternate. When the guideline gives more than one treatment in a rating level, they are listed in order of mean scores. For example, results of question 6 above appear on page 63 and are used in Guideline 2D: Goals of Emergency Intervention. (p. 30). As indicated by the black box with the asterisk in the results and bold italics in the guideline, calming without sedation was the goal of choice, being rated 9 by more than 50% of the panel. Mild sedation to the point of drowsiness but not sleep was high second line, while sleep or heavy sedation was not endorsed as an appropriate goal (third line).

Degree of Consensus
Of the 854 options rated on the 9-point scale, consensus was reached on 663 options (78%) as defined by the chi-square test. When there is no first-line recommendation, the highest rated second-line option is presented as the preferred treatment in the guideline.

RESULTS AND COMMENTARY

The clinical problem addressed in these guidelines differs from others for which these methods have been used.1125 Most treatment algorithms on which previous expert consensus guidelines were based began with a diagnosis and assumed a typical physician-patient relationship. However, behavioral emergencies are defined by disruption in the physician-patient relationship with resulting deficiencies in assessment and patient participation. Many questions involve forced decisions based on assumptions about urgency, cooperation, amount of available information, diagnostic confidence, and individual risk factors. In a sense, the goal of these interventions, a confident diagnosis and informed consent, is the starting point of other guidelines. In the following sections, we summarize key recommendations from the guidelines on management of behavioral emergencies and discuss how the recommendations relate to available research and how they have changed since the first survey. Complete survey data appear on pages 60108 and the guidelines based on those data are presented on pages 2659.

lowing as central to the concept of clinically significant agitation requiring intervention in the emergency setting: abnormal and excessive verbal, physically aggressive, or purposeless motor behaviors, heightened arousal, and clinically significant disruption of the patients functioning. In the first survey, the panel gave increasing support to the use of an emergency intervention (involuntary medication or physical restraint) as patient behavior suggests an increased potential for violence, with 100% indicating that it would almost always be appropriate for a patient who is directly threatening or assaultive, while the majority did not consider such intervention appropriate for a patient who displays only a refusal to cooperate with unit routine or intense staring.1 In the current survey, to help define the syndrome of agitation and further clarify indications for emergency intervention, we provided a list of target behaviors (taken from the literature and various rating instruments for agitation) and asked the experts to select 10 features they considered most typical of clinically significant agitation requiring emergency intervention. The following 7 behaviors were endorsed by 60% or more of the panel: explosive and/or unpredictable anger; intimidating behavior; restlessness, pacing, or excessive movement; physical and/or verbal self-abusiveness; demeaning or hostile verbal behavior; uncooperative or demanding behavior or resistance to care; and impulsive or impatient behavior or low tolerance for pain or frustration. Of note, 5 of these 7 are among the 14 items on Corrigans Agitated Behavior Scale.28

Goals of Emergency Intervention

The panel strongly endorsed calming the patient without sedation as the most appropriate goal of emergency intervention (rated first line by 92%) and gave high second-line ratings to mild sedation to the point of drowsiness but not sleep. They did not endorse sleep or heavy sedation as an appropriate goal of intervention (rated third line by a majority) These recommendations are consistent with the Clinical Guideline on Schizophrenia from the National Institute for Clinical Excellence (NICE) in the United Kingdom, which states that the aim of drug treatment in such circumstances is to calm the person and reduce the risk of violence and harm and that an optimal response would be a reduction in agitation or aggression without sedation, allowing the service user to participate in further assessment and treatment.5

Defining Clinically Significant Agitation

We presented the panel with a number of putative definitions of agitation based on the literature, from which they identified the fol-

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Patient Involvement in Care

In the first survey,1 the panel stressed the importance of collaboration between patient and clinician whenever possible in achieving the best short- and long-term outcomes. They also emphasized the importance of safety concerns in the short-term (e.g., control of aggressive behavior and protecting the patient and community). These ratings agree with findings in a recent survey/focus group study of consumers, which reported that consumers place great emphasis on being treated with respect and being allowed to participate in decisions about their treatment to the greatest extent possible.8 This can be accomplished by suggesting that the patient might feel better if he or she took some medication and asking if there is a medication he or she would prefer. Failing that, the patient can be offered a choice between two medications or, as a last resort, can simply be asked to assent to a medication (e.g., Would you be willing to take?).

Initial Assessment
The goal in a behavioral emergency is to facilitate resumption of a more typical physician-patient relationship, obtain informed consent if possible, and promote the best possible long-term treatment outcome. Acute agitation interferes with assessment and treatment at a time when immediate intervention appears needed because of dangerous behavior or warning signs of such behavior, and yet assessment plays a critical role in selecting the most appropriate intervention. Recommendations for assessment based on the expert surveys are summarized below. Medical assessment. In the first survey, the panel indicated that a key step in initial evaluation is identifying any medical conditions that might be causing or contributing to agitation. This is especially important because available data suggest that delirium, in particular, should be managed based on its underlying etiology if it can be identified. The earlier panel also indicated that it is most important in the initial medical evaluation to obtain vital signs and a medical history, perform a visual examination of the patient, a urine toxicology screen, a cognitive examination, and a pregnancy test if the patient is a woman of childbearing age.1 There was somewhat less support for more complete physical examinations, possibly reflecting constraints on time and availability of personnel. The level of examination will depend on the patients specific signs and symptoms, with more complete evaluations indicated in some circumstances or later in treatment. We asked some additional questions in the current survey to refine these recommendations. The panel in the current survey stressed the importance of assessing the following in the initial assessment: head trauma, respiration, heart rhythm, color, smell of alcohol, diameter/reactivity of pupils, lacerations, nuchal rigidity, and fractures; they would also obtain glucometry and urine for toxicology. Despite the interest in toxicology, they did not endorse nystagmus, reflexes, and tongue fasciculations although these may provide evi-

dence of intoxication or withdrawal. The panel endorsed the MiniMental State Examination29 as the preferred tool for assessing cognitive function in the emergency setting, with the Clock Drawing Test30 and the Confusion Assessment Method (CAM)31 second-line options. Methods of cognitive screening have been reviewed elsewhere.32,33 These recommendations generally agree with evidence-based clinical policies being developed by the American College of Emergency Physicians (ACEP) (with the participation of two of the authors of these guidelines) for assessment and management of psychiatric patients in emergency departments.7 The ACEP policy endorses the CAM for cognitive assessment and indicates that diagnostic evaluation should be directed by the history and physical examination, which should be used to identify patients at risk. Routine testing is not recommended; in fact, no procedures are recommended in the absence of indications from the history and physical examination. The ACEP clinical policy committee specifically addressed breath alcohol concentration and urine toxicology; they recognized that urine toxicology may be important for psychiatric diagnosis and disposition but found no evidence that it would alter emergency medical care and felt it should not delay transfer to a more appropriate setting. The current expert panel, of whom 10% were emergency physicians, did indicate that substance use would alter the management of a behavioral emergency, though there are no studies that compare different strategies for agitation in the setting of substance use. Psychiatric assessment. In the first survey, we ascertained that a brief assessment leading to a general category of diagnosis is adequate for managing agitation. We tested this by asking the panels in both surveys how they would manage an agitated patient in need of immediate treatment but with no data available to guide the decision. In this survey, we also presented vignettes typical of actual situations encountered in emergency settings. We then asked the panel to rate the most appropriate interventions based on available information to determine if they could form a provisional diagnosis and if that diagnosis would influence or determine their approach to treatment or if they would pursue the same course regardless of available information. If the same treatments emerged consistently regardless of differing presentations, this might suggest the existence of a nonspecific approach. Alternatively, differences between strategies used in different situations might suggest more specificity in treatment selection.

Interventions When No Information Is Available

There are situations in which immediate intervention is needed to assess the patient or to ensure safety of patient and others but insufficient data are available on which to base even a provisional diagnosis (i.e., the only sign or symptom entering the decision-making process is agitation). This seems to fit the definition of nonspecific treatment rather than chemical restraint, as indicated in the first survey.1 To proceed safely with assessment when no additional information is available but the patient is willing to take oral medication, the

10

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panel recommended lorazepam as agent of choice, with risperidone another first-line option, and olanzapine, haloperidol, and quetiapine high second line. If I.M. medication is required before an assessment can be done, I.M. lorazepam is again agent of choice, with I.M. ziprasidone, olanzapine, and haloperidol other first-line options. This preference is unchanged from 2001 when an oral or I.M. BNZ alone was preferred if one must intervene with medication to manage agitation when insufficient information is available to make even a provisional diagnosis. BNZs are also preferred when there is no specific pharmacologic treatment (e.g., conduct disorder, stimulant intoxication), presumably because the goal is to achieve time-limited sedation while avoiding undue risk of extrapyramidal symptoms (EPS) and other side effects associated with antipsychotic drugs. (BNZs are also recommended for alcohol-related agitation.)

ziprasidone alone or combined with a BNZ, or I.M. haloperidol or an I.M. BNZ alone. The experts clearly preferred to use an antipsychotic, either alone or combined with a BNZ, for a patient who appears to have a psychotic disorder. We then asked the panel to assume that they had established that Patient 1 has a diagnosis of schizophrenia, had prescribed what they consider the usual maximum dose of an antipsychotic, and that the patient has calmed down somewhat but is still moderately agitated. If additional medication is needed to control the agitation and the patient is now willing to take oral medication, the experts recommended giving an oral BNZ. Giving another dose of the same antipsychotic was a second-line option. The experts did not recommend using divalproex or a different antipsychotic (both third line) as adjunctive oral agents for residual agitation. Patient 2: The patient, a 19-year-old college freshman, is brought to the emergency room by his parents because of agitation and unusual behavior. He has no psychiatric history, but there is a family history of major depression. The patient is highly agitated, pacing, displaying pressured speech and marked grandiosity, and bragging about his artwork. The patient insists that there is nothing wrong with him. The family reports that the patient has not been sleeping. The patient refuses to follow directions and begins to shout at staff. His thought processes are difficult to follow. At times he appears to be responding to internal stimuli and hallucinating. The experts strongly endorsed (89%) a diagnosis of mania for this patient, with the majority fairly or very confident in the diagnosis. As in the previous case, when the panelists are able to make a fairly specific diagnosis, they indicate that this will influence or determine their treatment selection. For a patient with presumed bipolar mania, the experts would always recommend including an antipsychotic in the initial treatment, preferably in combination with a BNZ, although they would also consider using the antipsychotic alone or in combination with a mood stabilizer. There was less support for a mood stabilizer alone or combined with a BNZ as initial treatment (both second line), presumably because of the need to calm the patient as rapidly as possible. If it is possible to use an oral antipsychotic, the experts rated olanzapine and risperidone first line for a patient with presumed bipolar mania, with quetiapine, ziprasidone, and haloperidol high second line. These ratings may reflect the fact that olanzapine and risperidone were the first two SGAs to obtain an indication for bipolar mania as well as a desire to use an agent with more sedating properties such as olanzapine. If it is decided to include a traditional mood stabilizer in the initial regimen, divalproex was agent of choice. This recommendation agrees with responses from a survey of emergency psychiatrists, which found that, if a mood stabilizer is needed in this setting, 90% would use divalproex/valproate, while only 8% would choose lithium and only 2% another mood stabilizer.34 The experts supported using divalproex loading doses in all types of manic episodes, probably reflecting the fact that lithium is not generally used in the emergency setting and that loading doses of divalproex may help stabilize the

Interventions Selected Based on Limited Information

We presented several case vignettes and asked what provisional diagnosis the panel would make based on the information given, how much confidence they would have in this diagnosis, how much the diagnosis would guide treatment selection, and what initial nonpharmacologic interventions and medications they would recommend. Patient 1: The patient, a young white male who appears to be in his early 20s, presents to the PES in a highly agitated state. He is directly threatening, throwing the food tray and yelling. He is paranoid about staff poisoning him and appears to be responding to internal stimuli. The patient is unable to converse with staff at all. No data or history are available, but the patient clearly poses a risk to staff and self. Two-thirds of the panel endorsed a diagnosis of a psychotic disorder (either schizophrenia or psychosis not otherwise specified [NOS]), with a majority somewhat to very confident in the diagnosis. The experts indicated that the diagnosis of a psychotic disorder would determine or at least influence their treatment selection. Thus, when the experts are at least fairly confident they are dealing with a psychotic disorder, they will treat more specifically. Throughout the survey, for patients who appear to have a primary psychiatric disturbance, the experts strongly endorsed beginning with the least invasive interventions possible consistent with ensuring safety of patient and others (see algorithms, pp. 43 and 45). Even though the description specified that the patient posed a clear risk to staff and self, the experts still endorsed beginning with a show of force and trying verbal intervention before using involuntary medication or restraints. If restraints are needed, the panel did not recommend using them alone but with concomitant medication. We asked the experts to assume that Patient 1 was not able or willing to take oral medication and that, based on the initial assessment, they had decided to intervene with parenteral medication to treat the agitation before further medical intervention. In this situation, the panel recommended beginning with I.M. haloperidol plus an I.M. BNZ, or I.M. olanzapine alone, but would also consider I.M.

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patient quickly.35 As in 2001, the panel favored strategies that employ higher doses of divalproex rather than usual titration (e.g., beginning with 250 mg tid and titrating as tolerated). Whereas a 20 mg/kg/day initiation strategy was preferred in 2001, there was a slight preference in the current survey for beginning with a loading dose of 30 mg/kg/day for 2 days and then reducing the dose to 20 mg/kg/day, despite inclusion of emergency physicians presumably less familiar with this approach to mania. The experts also preferred delayed- over extended-release divalproex for emergency use. If an I.M. treatment is needed for a patient with presumed bipolar mania, the experts endorsed olanzapine alone or the traditional combination of haloperidol plus a BNZ. The preference for I.M. olanzapine over ziprasidone here may reflect the length of time olanzapine has had an indication for mania, findings from the I.M. olanzapine study in agitated patients with bipolar mania by Meehan et al.,36 and the desire to use a more sedating agent. Patient 3: A 60-year-old man with a history of alcohol abuse and diabetes presents to the emergency department with agitation and confusion. He is mildly diaphoretic with mild tachycardia but is afebrile. The patient is cheerful but tries to wander and is difficult to redirect. He asks the same questions repeatedly and picks at his skin. Two-thirds of the panel endorsed a diagnosis of delirium, with 86% somewhat to very confident in this diagnosis. A third endorsed a diagnosis of alcohol withdrawal, with 81% somewhat to fairly confident in this diagnosis. A majority indicated that these diagnoses would determine their treatment selection, while nearly all the rest said that the diagnosis would at least influence treatment selection. If an older patient is delirious or suffering alcohol withdrawal, the experts are much less likely to use show of force to avoid making the patient feel threatened or increasing his or her confusion (see treatment algorithm p. 48). When an organic basis for the problem is strongly suspected, the panel emphasized the need to gather as much data as possible from collateral sources before intervening with medication that might cloud the clinical picture. The experts did not generally endorse use of restraints in this situation. The panel recommended monotherapy for this patient and rated a BNZ alone first line. This choice probably reflects concern about the role of alcohol in the presentation and the limited evidence for haloperidol or other antipsychotics in this type of patient. The experts ratings may also reflect warnings concerning potential for cerebrovascular accidents (CVAs) in elderly patients with dementia treated with SGAs,3742 although recently published reports have indicated that this risk appears to be no different than in patients taking FGAs,43,44 and the reports involved chronic rather than acute treatment. Patient 4: A 14-year-old boy with a history of behavior problems is brought by police from school where he threatened a teacher. The boy is loud and profane in the emergency department. He is hostile to the nurses and demands immediate discharge. A member of the school staff who accompanies him reports that the school records show no medical history

beyond the usual childhood diseases and immunizations but that the boy does have a history of many previous behavior problems The panel strongly endorsed (85%) a diagnosis of conduct disorder, with 74% somewhat to very confident in the diagnosis, which a majority said would influence their treatment selection. The experts clearly indicated a reluctance to medicate a child in the absence of a clear Axis I psychiatric disorder (see algorithm p. 50). They gave priority to talking to the patient and family and using nonpharmacological means to try to calm the patient. Not surprisingly, given the reluctance to use medication, no agents were rated first line and a BNZ alone was the only medication rated high second line. The experts would avoid combining medications in this patient (all combinations except I.M. haloperidol plus a BNZ were rated third line). Note that the panel was not recruited for expertise in child psychiatry. Patient 5: A patient has been treated in the PES or acute inpatient service for a behavioral emergency characterized by significant agitation. The underlying condition has been adequately treated and the patient has calmed down. The patient has a history of insomnia with restlessness and racing thoughts before sleep and it is decided to leave p.r.n. orders for the nursing staff in case the patient has difficulty at bedtime. None of the sedating agents we asked about were rated first line, probably reflecting lack of data concerning the most appropriate sedatives for use in agitated patients. The panel gave high second-line ratings to lorazepam, zolpidem, trazodone, and temazepam. The support for lorazepam may reflect the perception that the sleep problems represent residual agitation. None of the antipsychotics, including quetiapine, received significant support in this situation.

Selecting Medications Based on an Established Diagnosis

In the next part of the survey, we eliminated any ambiguity about diagnosis and asked the panel about treatments for agitation in the context of specific diagnoses, both if the patient was willing to take oral medication or if it was necessary to use a parenteral agent. General medical etiology. The experts would avoid using medication if possible if the agitation appears due to a general medical condition (e.g., delirium, agitation in dementia), probably because of concern about inducing profound somnolence or clouding the sensorium and interfering with medical assessment. Available data suggest delirium should be managed according to its underlying etiology if this can be identified. If a medication is needed to treat agitation in a patient with a medical condition such as delirium and the patient is able and willing to take oral medication, the experts prefer to use haloperidol or risperidone alone. If a parenteral medication is needed, the experts would start with I.M. haloperidol alone and would also consider I.M. olanzapine or I.M. ziprasidone alone. It is interesting to examine changes in recommendations since the first survey. In choosing a medication for agitation related to a general medical etiology, oral or I.M. haloperidol alone, the highest

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rated option in 2001, continued to be preferred in the current survey. However, whereas oral or parenteral BNZs alone or combined with haloperidol were the next choice in 2001, oral or I.M. SGAs were the next choice in the current survey. Among the oral SGAs, the experts preferred risperidone (43% first line in 2001 and 60% in current survey) and olanzapine (19% first line in 2001 and 44% in current survey) for agitation related to a general medical etiology. If a parenteral medication is needed, the next choices after haloperidol were I.M. olanzapine or ziprasidone. These ratings reflect the fact that delirium due to a general medical etiology has usually been treated with high-potency FGAs, although evidence to support this is very limited. Breitbart et al.45 found that the FGAs were superior to lorazepam in efficacy and side effects in a group of prospectively defined patients with AIDS delirium, although the generalizability of these findings to other types of delirium is questionable. The 1998 Expert Consensus Guidelines for the Treatment of Agitation in Older Persons with Dementia14 also recommended high potency FGAs for delirium due to a general medical etiology (e.g., congestive heart failure, urinary tract or upper respiratory infections) in patients with dementia, with risperidone high second line. The increased support for using an SGA rather than a BNZ alone or combined with an FGA in the current survey reflects the growing research base on the efficacy and safety of the SGAs. A number of recent studies have found risperidone as effective in managing agitation in delirium as haloperidol but with less risk of EPS.4649 Similar but more limited findings have been reported for olanzapine.50,51 Risperidone was also the preferred antipsychotic for treatment of delirium in elderly patients in the 2004 Expert Consensus Guidelines on Using Antipsychotics in Older Patients.23 The warning concerning the possibility of CVAs in older patients now in the labeling for the SGAs3842 does not seem to have influenced the experts choice of agents for use in acute emergency settings, probably because reports of CVAs have all involved chronic rather than acute exposure and recent reports have indicated that the risk appears no different than with FGAs.43,44 Substance or alcohol intoxication. Just as in the earlier survey, a BNZ alone is the preferred oral or parenteral agent for a patient with stimulant intoxication (and alcohol intoxication if a medication must be used). For stimulant intoxication, the next choice would be a BNZ plus a high-potency FGA. A report by van Harten et al.52 suggested that individuals who abuse stimulants may be more prone to EPS, which may be why the experts prefer BNZs in this situation (i.e., antipsychotics are not likely to have any special benefits for this population but may be more likely to cause EPS). Cocaine toxicity may also involve seizures, and the experts may prefer BNZs to antipsychotics for their protective effect in this situation. In both surveys, the experts had no first-line recommendations for treatment of agitation due to alcohol intoxication, but did rate a BNZ alone high second line. The slight preference for BNZs for patients intoxicated with alcohol may reflect the fact that a component of withdrawal may be contributing to the agitation for which the BNZ

may be specifically indicated. The American Psychiatric Association Guideline for the Treatment of Substance Use Disorders53 recommends BNZs for alcohol withdrawal. A meta-analysis of 9 prospective controlled trials demonstrated that sedative-hypnotic agents are more effective than antipsychotics in reducing duration of alcohol withdrawal delirium and mortality.54 A 2001 bulletin from the Centers for Medicare and Medicaid Services (CMS [formerly the Health Care Financing Administration])55 mentions use of BNZs for behavioral disturbances associated with alcohol withdrawal as appropriate use of medication for purposes of treatment rather than chemical restraint. Primary psychiatric disturbances. If the clinician can tentatively make a more specific Axis I psychiatric diagnosis, the experts prefer to provide treatment that is likely to be effective for the underlying condition and would generally use an antipsychotic. If the provisional diagnosis is schizophrenia or bipolar mania and the patient is willing to take oral medication, first-line options are olanzapine or risperidone alone or risperidone or haloperidol plus a BNZ. Another first-line option for bipolar mania is divalproex plus an antipsychotic. Comparing recommendations from 2001 with the current survey, it is clear that the general trend to choose an SGA as initial treatment for psychotic and bipolar disorders22,24,56 is reflected in responses to the current survey. In the first survey, the first-line recommendation for acute oral treatment of a patient with a provisional diagnosis of schizophrenia or bipolar mania was a BNZ combined with either an FGA or an SGA. Of the three SGAs available at the time of the previous survey (olanzapine, quetiapine, and risperidone), monotherapy with oral risperidone and olanzapine was only rated high second line for schizophrenia (risperidone 65%, olanzapine 49% first line) and mania (olanzapine 45%, risperidone 41% first line). In contrast, in the current survey, there was much more support for the use of monotherapy with SGAs, with oral olanzapine rated first line by 87% and oral risperidone rated first line by 84% for a provisional diagnosis of schizophrenia, and oral olanzapine rated first line by 78% and oral risperidone rated first line by 67% for mania. Quetiapine and ziprasidone received high secondline ratings for schizophrenia (rated first line by 58%) and quetiapine was also rated high second line for mania (49% first line). None of the SGAs was available in a parenteral formulation at the time of the earlier survey, but there was strong support for the SGAs in the current survey when a parenteral medication is needed. For a patient with a provisional diagnosis of schizophrenia who requires parenteral medication, the panel gave first-line ratings to I.M. olanzapine alone, I.M. haloperidol plus a BNZ, and I.M. ziprasidone alone or combined with a BNZ. For a patient who appears to have mania, the experts gave first-line ratings to I.M. olanzapine and to I.M. haloperidol plus a BNZ and high second-line ratings to I.M. ziprasidone alone or combined with a BNZ, possibly because they are considering continuation treatment if needed. In summary, there is increasing support for the use of SGAs, both oral and parenteral, in emergency settings to treat patients with a

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provisional diagnosis of schizophrenia or mania. Nevertheless, the experts also gave more support to the use of haloperidol, usually combined with a BNZ, than is generally seen in other treatment settings, probably reflecting extensive experience with this agent in emergency care. However, use of haloperidol alone is rarely recommended, while there is less support for combining SGAs with BNZs. For psychotic depression and personality disorder in a patient willing to take oral medication, there was no consensus on first-line agents in either survey, probably reflecting lack of data on emergency treatment of these conditions. However, the panel in the current survey was more likely to use an SGA alone to treat agitation in a patient with psychotic depression or a personality disorder than the 2001 panel, probably reflecting findings on the possible efficacy of SGAs in these conditions in nonemergency treatment.22,5761 If parenteral medication is needed to manage agitation in a patient with a provisional diagnosis of psychotic depression, I.M. olanzapine alone was first line, with ziprasidone or haloperidol alone or combined with a BNZ high second line. This contrasts with the first survey where the panel gave first-line ratings to an FGA plus a BNZ, with a BNZ alone high second line. As in the first survey, an I.M. BNZ alone was preferred for agitation associated with a personality disorder requiring I.M. medication, with I.M. haloperidol plus a BNZ high second line. In the current survey, I.M. olanzapine was also high second line.

Use of Emergency Medications: General Strategies

Most important factors in medication selection. The following factors were rated most important in selecting initial emergency medication: acute (immediate) effect on behavioral symptoms, speed of onset, availability of I.M., liquid, or rapidly dissolving formulation, patients history of response to the medication, limited liability for side effects, patient preference, and ease of administration (no need for laboratory tests and simple dosing requirements). The panel would also consider the medications safety in overdose and likelihood of promoting long-term adherence to treatment. Just as in the first survey,1 the experts placed less emphasis on continuity with the next phase of treatment than on managing acute symptoms and did not consider cost a significant factor in initial medication selection. Medication characteristics. Treatment of agitation may be directed solely at managing the current state or may also represent initiation of a continuing treatment. We thus asked the panel to assess medications in terms of their perceptions of how calming (reducing agitation without inducing sleep) or sedating (reducing agitation by inducing sleep) they are and how likely they are to be effective for the underlying condition (e.g., a psychotic disorder). The following agents were rated most calming (without putting the patient to sleep): lorazepam, olanzapine, risperidone, and haloperidol, while chlorpromazine, lorazepam, quetiapine, and droperidol were rated most sedating. In terms of effectiveness for the underlying condition, risperidone, olanzapine, ziprasidone, haloperidol, and perphenazine were first line.

Lorazepam is viewed as potentially calming or sedating but not as effective for the underlying condition. This survey was conducted before publication of findings on perphenazine from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE).62 In both surveys, haloperidol and lorazepam were first line for decreasing acute agitation. However, support for using SGAs to treat acute agitation has increased since 2001, when they were rated high second line. In the current survey, olanzapine and risperidone were first line for being calming but not sedating, while risperidone, olanzapine, and ziprasidone were first line for being effective for the underlying condition. In the first survey, droperidol (an FDA-approved butyrophenone available only for parenteral administration and used primarily in anesthesia) was rated most effective for decreasing agitation but dropped to high second line in the current survey, probably due to the black box warning concerning prolongation of the QTc interval and risk of torsade de pointes.63 Although recent analyses failed to find evidence of a relationship between droperidol and cardiac events,6466 there has been a dramatic decrease in its use and availability in emergency settings.67 Despite use as an antipsychotic in Europe, droperidol was rated here as ineffective for treating an underlying psychosis, reflecting inexperience with its use in the United States. Since the experts indicated that the preferred goal of emergency intervention for acute agitation should be to calm the patient without sedation, we examined the rank ordering of the medications in terms of combinations of characteristics. The highest combined mean scores for being both calming and effective for the underlying condition went to risperidone, olanzapine, haloperidol, and ziprasidone in that order. The highest combined mean score for being calming plus effective minus the mean rating for sedation went to risperidone, ziprasidone, olanzapine, and haloperidol, in that order. Time to onset is also important. In managing agitated and potentially violent patients, faster onset may reduce the chance of injuries and the need for, or time in, restraints. For speed of onset, the panel gave highest ratings to intravenous (I.V.) medication of any class; however, the panel in the first survey did not give strong support to making I.V. access available in the PES, probably because it would require a different staffing pattern. The next highest ratings (first line) for speed of onset went to I.M. formulations of lorazepam, haloperidol, olanzapine, ziprasidone, and chlorpromazine. The main change between the surveys was that the two SGAs now available in I.M. formulations, olanzapine and ziprasidone, which were not included in the first survey, received first-line ratings for speed of onset in the current survey. This is consistent with clinical trial data showing that olanzapine separates from haloperidol at 15 and 30 minutes after injection, after which haloperidol catches up. The majority of the panel indicated they would not generally use the following as initial treatment for a behavioral emergency: oral aripiprazole, chlorpromazine, and perphenazine and I.M. droperidol or perphenazine. Data have recently been presented concerning an I.M. formulation of aripiprazole, which was found to be similar to haloperidol in clinical trials for agitation at a dose of 7.5 mg.68

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Route of administration. We asked which formulations the panel preferred to use if a patient is willing to take oral medication, taking into account feasibility and convenience of use by nursing staff as well as intrinsic properties. Rapidly dissolving formulations received the highest ratings with strong support also for liquid concentrate or tablets. Although I.M. medications are clearly needed in some situations, the panel in the first survey1 indicated that they prefer to use oral medication if possible, probably due to concern about possible adverse effects of I.M. medication in this situation, such as mental or physical trauma to patient, compromising the patient-physician relationship, and effects on long-term adherence. The experts recommendations are consistent with responses to a survey of approximately 50 PES directors, in which the majority advocated use of oral medication whenever possible, with liquid formulations preferred to tablets because of more rapid onset and ease of verifying compliance.34 In that survey, the medical directors estimated that only 1 in 10 patients in their PESs requires an injection. It has been reported elsewhere that most agitated patients will assent to oral medications.69 Although we did not repeat the question in the current survey, the earlier panel was asked what percentage of patients in their services were likely to require emergency interventions (restraints, seclusion, parenteral medication), and the 19 who responded indicated that more than 80% of patients are managed without these interventions. CMS interim rules70 specify that chemical restraint be considered a last resort, suggesting that oral medication should be offered to patients first if possible. These recommendations are reinforced by findings from a consumer survey in which respondents expressed a strong preference for oral medication.8 In that survey, the consumers also indicated that they preferred anti-anxiety medications (e.g., lorazepam) over combinations of antipsychotics and anti-anxiety agents. Among the antipsychotics, the consumers appeared to prefer an SGA over an FGA. (Results of three questions from the consumer survey are presented on p. 108.) Use of combination treatment. An ideal drug for emergency treatment of agitation would have a wide therapeutic index, be both safe and effective at high doses, and could be used nonspecifically in all conditions. However, medications that have historically been available are not well tolerated in high doses. Two strategies to deal with this problem have been used: repeated administration or use of drug combinations. The most common medication strategy in the PES has been combining I.M. haloperidol (usually 5 mg) and lorazepam (usually 2 mg) in the same injection.71 The rationale for this widely used combination is that haloperidol is often poorly tolerated and lorazepam helps achieve adequate sedation while reducing the side effects that might occur with higher doses of haloperidol. Although this strategy is generally considered safe and effective, research concerning it is very limited. Two randomized, controlled studies72,73 found the combination more effective than the component agents alone early in treatment; however, the results were confounded by unequal dosing.73 Differences also tended to disappear in 24 hours,

perhaps because of additional doses given in the interval or passage of time. The panel in the first survey indicated that the most important potential benefits of a BNZ and antipsychotic combination were greater efficacy, faster onset of action, and reduced side effects. The limited literature is inconclusive as to whether combinations produce these benefits, but it appears to support the advantage of using lower doses of each of the component medications, thus reducing the liability for side effects, especially from haloperidol.74 Given their recent introduction, even fewer data are available on combining SGAs with BNZs in management of acute agitation. Two studies75,76 compared haloperidol plus lorazepam with risperidone plus lorazepam and found both combinations equally efficacious. However, because the SGAs have more complex mechanisms of action and varying side effects, the risk-benefit ratio of combinations may vary significantly from one SGA to another. To the extent that the newer SGAs have more benign side-effect profiles than the FGAs, the rationale of adding BNZs to reduce side effects by using a lower antipsychotic dose may not apply. To the extent that the SGAs have a rapid onset of action, the rationale for using a BNZ to achieve more rapid calming is eliminated. However, tolerability at high doses has been demonstrated only for ziprasidone.77 We thus asked the panel to rate the safety of combining different antipsychotics with lorazepam and for which antipsychotics there might be a therapeutic advantage in adding lorazepam instead of using higher doses of the antipsychotic alone (i.e., where clinical benefits of the combination outweigh potential adverse effects). The panel indicated they would base these decisions on the differing pharmacological properties of the various antipsychotics and that, as elsewhere, they would consider each SGA separately, rather than viewing these agents as a homogeneous class. Haloperidol and perphenazine. The panel felt that the widely used combination haloperidol plus lorazepam is likely to be more beneficial than haloperidol monotherapy and gave high second-line ratings to the therapeutic benefits of combining I.M. or oral perphenazine with lorazepam. The majority felt these combinations are safe. Risperidone, ziprasidone, and aripiprazole. Among the SGAs, the panel felt there was therapeutic benefit in combining oral risperidone with lorazepam and gave high second-line ratings to combining oral aripiprazole and oral or I.M. ziprasidone with lorazepam, probably because these agents are less sedating and have lower hypotensive liability (although the majority would not use oral aripiprazole in emergency settings). The majority rated these combinations generally safe. Chlorpromazine, olanzapine, and quetiapine. The panel suggested caution when combining oral or I.M. chlorpromazine, I.M. olanzapine, or oral quetiapine with lorazepam. The panel felt that it was generally safe to combine oral olanzapine with lorazepam. In terms of benefit, the panel did not give strong support to combining oral or I.M. olanzapine or quetiapine with a BNZ, probably because these agents are viewed as adequately sedating without the addition of a BNZ. The experts did not believe that there was therapeutic benefit in combining I.M. or oral chlorpromazine with lorazepam and would avoid this combination (third line). The ratings of chlorpromazine

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and I.M. olanzapine probably reflect concern about the potential for excessive sedation and cardiorespiratory depression when these agents are combined with I.M. BNZs. The editors note that the current survey was completed before the release of information about adverse events associated with co-administration of I.M. olanzapine and I.M. lorazepam. As noted in the current labeling for olanzapine, Concomitant administration of intramuscular olanzapine and parenteral benzodiazepine has not been studied and is therefore not recommended. If use of intramuscular olanzapine in combination with parenteral benzodiazepines is considered, careful evaluation of clinical status for excessive sedation and cardiorespiratory depression is recommended.39 The caution about quetiapine and BNZs probably reflects similar concerns about overlapping side-effect profiles. Strategies when no response to initial medication. Until the introduction of the SGAs, only a limited number of options were available if the first treatment tried produced an inadequate response. We asked the panel what strategy they would use if, after 60 minutes, they had not achieved an adequate response to monotherapy with an oral or I.M. antipsychotic or to the combination of an antipsychotic and lorazepam. The experts rejected switching to a different antipsychotic in any of these situations (rated third line in nearly every case). Instead they recommended giving another dose of the same antipsychotic at the same or higher dose, giving a dose of lorazepam, or using (or repeating if one started with it) a combination of the same antipsychotic and lorazepam. The order in which they would try these options reflects the recommendations for combinations described above. Thus, they are more likely to add a BNZ or give a dose of the combination if they started with haloperidol, ziprasidone, or risperidone, but more likely to give another dose of the antipsychotic alone if they started with olanzapine or quetiapine. If they began with a combination, they would generally repeat the same combination again and would also consider giving a single dose of the same antipsychotic or lorazepam. We did not ask about combinations of I.M. olanzapine and lorazepam because the package insert for I.M. olanzapine indicates this combination is not recommended. We asked the panel in the first survey1 how long they would recommend waiting before changing medication strategies (e.g., switching to a different agent or agents, using a combination of agents if they had started with monotherapy) if a patient was not responding, assuming that the goal is to get to the point where the patient is sufficiently improved to be able to converse with caregivers and take oral medication. If the initial treatment was monotherapy, the experts recommended changing strategies after 2 or more doses of medication had been totally ineffective or 3 or 4 doses had been only partially effective. If the initial treatment involved a combination of medications (e.g., an antipsychotic plus a BNZ), the experts recommended changing strategies after 3 or more doses of the combination had been totally ineffective or 4 or more doses had been only partially effective. These ratings reflect a willingness to continue treatment longer when the initial treatment involved a combination of

medications, reflecting the more limited options available at this point. It is interesting that even with more options available, the panel seemed to assume that issues of poor response are better addressed by increasing dosage than switching compounds. Dosage and frequency. The experts recommendations concerning dosing levels and intervals between doses are summarized in Guideline 7 (p. 42) and are generally consistent with data from the few fixed dose studies available as well as recommendations in the drugs labeling. The following medications were considered appropriate for use in a behavioral emergency by 90% or more of the panel at the following minimum and maximum doses: oral lorazepam (13 mg), I.M. lorazepam (0.53 mg), oral or I.M. haloperidol (2.510 mg), oral risperidone (13 mg), oral olanzapine (520 mg), I.M. olanzapine (510 mg), and I.M. ziprasidone (1020 mg). Although few dose-response studies have been done to determine optimal doses for emergency use, a few studies have compared different doses of medication for agitation. Three studies looked at dosing of haloperidol.7880 Baldessarini et al.81 subsequently combined the results of these studies and produced a dose-response curve. Their results suggest that a single dose of 7.510 mg of haloperidol might be expected to produce the most benefit possible with fewest side effects, and that higher doses associated with an increased incidence of side effects are not likely to produce much additional benefit. These findings are consistent with our panels recommendations. Brier et al.82 compared I.M. olanzapine 2.5, 5.0, 7.5, or 10.0 mg with haloperidol 7.5 mg and placebo and found the 10 mg dose most effective and equivalent to haloperidol. However, this study did not indicate whether a higher dose might be more effective than haloperidol or whether it would have sufficient tolerability. Baker et al.83 compared a new approach to olanzapine dosing involving rapid initial dose escalation (RIDE) up to 40 mg/day with standard dosing of olanzapine plus lorazepam and found that the RIDE strategy may offer superior efficacy in rapidly and effectively controlling agitation without causing excessive sedation. Clinicians are always seeking to strike a compromise between effectiveness and tolerability. Since data are limited and there is no way to predict the best dose for a specific patient, clinicians have historically begun with a moderate dose. There is some controversy in the literature, which is very limited, as to the most appropriate dose of BNZs with which to initiate treatment for agitation in a behavioral emergency, although most published studies have used a dose of 2.0 mg lorazepam. Bienek et al.73 discussed the use of a higher initial dose of 34 mg.

Agents Not Available in the United States

We did not include agents not available in the United States in this survey. Regional differences in management of agitation are quite dramatic even in the United States, where there are distinct clinical cultures that favor different pharmacologic approaches to agitation, and this is even more true transnationally. A number of issues under-

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lie this variation in practice, one of the most contentious of which is the appropriate endpoint of the intervention. If one considers U.S. expert consensus, as presented in our 2001 guidelines1 and the current publication, and the NICE guidelines from the United Kingdom,5 it might appear that among large blocks of Englishspeaking psychiatrists, there is a consensus on goals (i.e., calming without sedation) so as to permit patient participation in assessment and care decisions. However, this view is not universal. It derives from some tolerance for disturbed behavior and the value attached to a collaborative rather than authoritarian physician-patient relationship. However, published guidelines in some countries, the continued use of sleep as an endpoint in some studies,84 the continued popularity of cocktails, and the unpublished opinions of many practitioners reflect a preference for sleep as an endpoint. With this in mind, there are a large number of sedatives available with a great deal of history and considerable anecdotal but very limited experimental support. Medications are also regulated and funded very differently around the world and economic reasons can lead to great variation in the medications available and preferred in different regions. Levomepromazine, a phenothiazine not used by U.S. psychiatrists, is popular in Japan for its sedative effects.85 Loxapine is popular in France.86 Chlorpromazine still has proponents. Barbiturates, despite their safety limitations, are still used in some areas. Promethazine is combined with haloperidol in Brazil and India.87 Zuclopenthixol, available as both an acute and a relatively short-acting depot preparation, is promoted in some European countries although the depot formulation is not thought to be appropriate for acute agitation according to NICE. Flunitrazepam is a BNZ that was marketed in the United States as Rohypnol (known here as roofies).88 It is still used elsewhere but was removed from the U.S. market amid reports of date rape.89 To establish a more global consensus on best practices for the management of behavioral emergencies will require more convergence on the relative value of participation versus sedation and, as Huf et al.87 noted in a recent Cochrane Review, cost will still impose significant differences between developed and developing countries.

was unlikely to be effective for long-term symptomatic treatment or was likely to cause significant EPS or if the patient expressed a preference for a different medication. They would also consider the potential for substance abuse or side effects (e.g., weight gain, sedation, nausea, or dizziness) in deciding whether to switch to a different agent. We asked the experts which agent they would use if continuation treatment with an oral antipsychotic is indicated following initial treatment with an I.M. antipsychotic. If the initial medication was I.M. haloperidol (or perphenazine or droperidol), the experts recommended using oral risperidone, with one of the other SGAs a high second-line option. If the initial medication was I.M. ziprasidone or olanzapine, the experts treatment of choice was to continue with the same agent in an oral formulation. Switching from I.M. olanzapine to oral risperidone was another first-line option.

Research Findings Concerning Choice of Medications

First generation antipsychotics. The literature provides little evidence of differential effectiveness among the FGAs that is not accounted for by dosage levels or pharmacokinetics. The majority of studies have been done with haloperidol,78,79 although some studies that have looked at other antipsychotics (e.g., thiothixene,90 molindone,91 loxapine92,93) have found comparable effectiveness with haloperidol. Although chlorpromazine is often mentioned for behavioral emergencies because of its sedative side effects, haloperidol has been found superior at usual doses.80,94 Second generation antipsychotics. Although SGAs are recommended as first-line agents for treatment of schizophrenia and bipolar disorder,15,22,95,96 they have not up to now been as widely used as FGAs in emergency settings. Their advantages in schizophrenia have been thought to be related to differences in their relative activity at serotonin and dopamine receptors. One of the putative advantages of the SGAs has been thought to be reductions in hostility relative to the FGAs. For example, in the 3-year Intercontinental Schizophrenia Outpatient Health Outcomes (IC-SOHO) study of 7,655 schizophrenia patients who initiated or changed to monotherapy with clozapine, olanzapine, quetiapine, risperidone, or haloperidol, the researchers assessed the presence or absence of verbal or physical hostility/aggression retrospectively for the 6 months before enrollment and prospectively in the first 6 months of the study.97 They found that hostile/aggressive behavior was reduced during treatment, with olanzapine and risperidone significantly superior to haloperidol and clozapine in reducing aggression, even when results were adjusted for baseline imbalances in age, gender, age of onset, and substance abuse. However, it is not clear that this effect is relevant to conditions other than schizophrenia or in the time frame of an emergency, and acute serotonin antagonism could be problematic. The relative tolerability of the SGAs is also dependent on doses and titration schedules that are not pertinent to emergency settings. Until very recently, none of

Transition to Oral Continuation Medication

Nearly all the experts (> 90%) agreed that the ideal medication for managing a behavioral emergency may not be ideal for continuing care and that there are circumstances when it may be advantageous to switch to an oral formulation of a different antipsychotic for longterm treatment. Over 80% of the panel did not believe that there is any significant disadvantage to switching within 24 hours to an oral formulation of a different antipsychotic; however, 44% of the panel indicated that there may be some minor disadvantages in making such a switch. The panel indicated that the most important factors that would lead them to switch to a different medication for ongoing treatment (from one that had successfully managed a patients agitation early in an episode of care) were that the initial medication

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the SGAs was available in an I.M. formulation. Unlike studies of FGAs and other agents which were performed in heterogeneous populations using a pain and fever approach, recent studies of I.M. antipsychotics have examined agitation in particular conditions, thus limiting their generalizability. Oral risperidone. A study compared the relative efficacy, safety, and tolerability of oral risperidone plus oral lorazepam (2 mg of each given to patients willing to take oral medication) with 5 mg of I.M. haloperidol plus 2 mg of I.M. lorazepam (given to patients who refused oral medication).75 The subjects were a convenience sample of 60 psychotic patients (30 in each treatment group) admitted to a large PES who required emergency medication to control agitation and/or violence. Both treatment groups showed improvement over time, with no significant differences between the groups. One patient in the haloperidol group developed a dystonic reaction; there were no adverse reactions in the risperidone group. In a more recent randomized study conducted at 24 sites in the United States, Currier et al.76 compared the same two combinations and doses in 162 patients exhibiting agitation associated with active psychosis and found that a single dose of oral risperidone plus lorazepam (n = 83) was as effective as I.M. haloperidol plus lorazepam (n = 79) for rapid control of agitation and psychosis and that both treatments were well tolerated. Thus, these studies indicate that oral treatment with risperidone plus lorazepam is a tolerable and comparable alternative to the traditional combination of I.M. haloperidol and lorazepam for short-term treatment of agitated psychotic patients in the emergency setting who are willing to take oral medications. I.M. ziprasidone. Several studies have looked at the use of I.M. ziprasidone in hospital settings. In a randomized, open-label study, Brook et al.98 compared the efficacy and tolerability of I.M. ziprasidone (n = 90) and I.M. haloperidol (n = 42) for 3 days followed by oral treatment to day 7 in hospitalized patients with acute psychotic agitation. I.M. ziprasidone was significantly more effective in reducing the symptoms of acute psychosis and was associated with a lower incidence of EPS than I.M. haloperidol. The transition from I.M. to oral ziprasidone was effective and well tolerated. A post hoc analysis of data from the Brook et al. study demonstrated that ziprasidone or haloperidol combined with lorazepam were similarly effective but ziprasidone alone was superior to haloperidol alone.99 In a 24-hour, double-blind, fixed dose trial, Lesem et al.100 evaluated the efficacy and tolerability of I.M. ziprasidone in inpatients with psychosis and acute agitation. Patients received up to 4 injections (q 2 hr p.r.n.) of 2 mg (n = 54) or 10 mg (n = 63) of I.M. ziprasidone, with 2 mg used as a control dose. I.M. ziprasidone 10 mg rapidly reduced acute agitation and was significantly more effective than the 2 mg dose. Patients were calmed but not excessively sedated and no acute dystonia or behavioral disinhibition was reported; one patient in the 10 mg group developed akathisia. Daniel et al.101 performed a very similar 24-hour, double-blind, fixed dose study comparing I.M. ziprasi-

done 2 mg (n = 38) and 20 mg (n = 41) in the acute management of agitated psychotic patients. The 20 mg dose of I.M. ziprasidone substantially and significantly reduced symptoms of acute agitation in patients with psychotic disorders, was well tolerated, and produced no dystonia or akathisia. It is usually not possible to perform controlled trials in the type of severely agitated patients seen in emergency settings because of the need to obtain informed consent. However, Preval et al.102 recently examined use of I.M. ziprasidone (n = 77) in a naturalistic study in a PES. Subjects were all sufficiently agitated to require restraint as opposed to the majority of previous clinical trial subjects. They found that I.M. ziprasidone was well tolerated and appeared effective in decreasing agitation in patients with severe agitation, including agitation associated with alcohol or substance intoxication. A review of clinical experience based on the first 2 years of postmarketing experience with I.M. ziprasidone was recently published.103 As of July 2005, there had been no published reports of sudden cardiac death or death from any cause associated with ziprasidone and changes in QTc interval associated with I.M. ziprasidone at peak serum concentrations were modest and comparable to those seen with I.M. haloperidol. One case of sudden cardiac death was published in March 2005,104 which was not considered attributable to drug treatment. Serial EKGs for this patient showed some increases in QTc interval but always within normal limits (baseline of 377 ms, highest level during treatment 429 ms). The patient also had multiple cardiac risk factors (low high density lipoprotein, overweight, heavy smoker) and autopsy revealed significant occlusion of all three coronary arteries. There is also one case report in press105 of a brief, asymptomatic episode of torsades de pointe associated with ziprasidone in a patient with multiple medical problems. I.M. olanzapine. A number of studies have been done with I.M. olanzapine. In a double-blind, randomized, 24-hour study, Meehan et al.36 compared the efficacy and safety of one to three injections of I.M. olanzapine (10 mg for the first two injections, 5 mg for the third), lorazepam (2 mg for the first two injections, 1 mg for the third), and placebo (placebo for the first two injections, olanzapine 10 mg for the third) in 201 agitated patients with bipolar mania and found that I.M. olanzapine was safe and effective in reducing acute agitation in these patients. At 2 hours after the first injection, I.M. olanzapine produced significantly greater reduction in agitation than lorazepam or placebo; there was no statistical difference between lorazepam and olanzapine 24 hours after the first injection but both were superior to placebo. Another double-blind, randomized study by Meehan et al.106 compared the efficacy and safety of I.M. olanzapine (2.5 or 5.0 mg), I.M. lorazepam (1.0 mg), and placebo in acutely agitated patients with dementia and found that both active treatments produced significant improvement in agitation compared with placebo but did not differ from placebo in sedation or adverse effects, including orthostasis. In a double-blind, placebo-controlled, dose-response study, Brier et al.82 compared one to three injections of I.M. olanzapine (2.5, 5.0, 7.5, or

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10.0 mg), haloperidol (7.5 mg), or placebo in the treatment of acute agitation in 270 recently hospitalized patients with schizophrenia. They found that olanzapine exhibited a dose-response relationship in reducing agitation and had a lower incidence of treatment-emergent parkinsonism than I.M. haloperidol. Wright et al.107 performed a 24hour, double-blind study comparing one to three injections of I.M. olanzapine (10 mg), I.M. haloperidol (7.5 mg), and I.M. placebo in the treatment of acutely agitated hospitalized patients with schizophrenia. I.M. olanzapine reduced agitation significantly more than I.M. haloperidol at 15, 30, and 45 minutes after the first injection; however, both I.M. olanzapine and haloperidol reduced agitation significantly more than placebo and were similar to each other at 2 and 24 hours after the first injection, indicating that olanzapine starts out faster but that haloperidol subsequently catches up. No patients in the I.M. olanzapine group experienced acute dystonia, while 7% of those in the I.M. haloperidol group did. In a follow-up double-blind, randomized study, Wright et al.108 assessed the efficacy and safety of olanzapine (n = 131) and haloperidol (n = 126) versus placebo (n = 54) during a 4-day transition from I.M. to oral therapy and found that reductions in agitation were sustained with both study drugs throughout the oral treatment period, but patients in the haloperidol group experienced significantly more dystonia (4.5% vs. 0%) and akathisia (4.3% vs. 0%) than those in the olanzapine group. Although the SGAs are distinguished from the FGAs by reduced EPS, other side effects are also relevant. There are no published reports of vital sign measurements with I.M. olanzapine, but an FDA Psychopharmacological Drugs Advisory Committee briefing document cites a prevalence of 11.9% for a 20 mm Hg drop in systolic blood pressure in clinical trial subjects.109 Monitoring of vital signs for orthostasis is recommended if repeated administration of olanzapine is contemplated. Concomitant use of I.M. olanzapine with BNZs has not been studied and is not recommended by the manufacturer.39 Safety findings based on the first year of post-marketing experience with I.M. olanzapine were recently presented,110 which indicated that, worldwide, patient exposure to I.M. olanzapine in the first year was 278,600 with 91 spontaneous adverse events reported and 15 fatalities. Of the 62 adverse event reports in which patients were known to have received concomitant medications, 38 received BNZs in proximity to treatment with I.M. olanzapine. Most of the fatalities involved multiple concomitant medications, mainly BNZs or other antipsychotics. Of the 15 fatalities, 8 were treated with BNZs within 24 hours of death. Other contributing factors identified in the reports of fatalities were age (4/15 were 60 years of age), overweight or obesity (5/15), metabolic issues, such as diabetes, hyperlipidemia, hyperglycemia (3/15), cardiac comorbidities (3/15), respiratory conditions (5/15), and vascular conditions (4/15). Benzodiazepines. Studies concerning the use of BNZs in psychiatric emergencies suggest that they are at least as effective as haloperidol alone. Most of the studies have been done with lorazepam,7274,111113 but controlled data have also been published concerning midazo-

lam,114,115 clonazepam,116 and flunitrazepam.88 Studies comparing 5 mg of haloperidol with 2 mg of lorazepam found that the 2 agents were equal on some measures,72,74,112 but that 2 mg of lorazepam was superior on measures of aggression74 and clinical global improvement.112 Flunitrazepam 1 mg was compared with haloperidol 5 mg and found to be superior using the Overt Aggression Scale as a measure of outcome.88 Midazolam 5 mg was reported to be superior to haloperidol 10 mg in its effect on a measure of motor agitation.114 Battaglia et al.72 found lorazepam used alone to be more sedating than haloperidol used alone. A recent randomized, prospective doubleblind study by Nobay et al.115 compared midazolam with lorazepam and haloperidol in the management of 111 violent and severely agitated patients in the emergency department and found that midazolam had a significantly shorter time to onset of sedation and a more rapid time to arousal than lorazepam or haloperidol, with all three drugs appearing to have similar efficacy. These studies suggest that BNZs used at doses typical in emergency settings may be more effective than haloperidol.

Selecting Medications in Special Situations

Medical comorbidity. The panel gave first-line ratings to lorazepam for patients with cardiac arrhythmias or conduction defects, to risperidone for patients with delirium or dementia, to lorazepam, haloperidol, or ziprasidone for patients with diabetes or hyperglycemia, and lorazepam for obese patients. They did not give first-line ratings to any agent for patients with alcohol intoxication, but recommended using a BNZ rather than an antipsychotic if a medication is needed, probably reflecting concern about withdrawal syndromes and the risk of seizures. Note that BNZs may be initiated even while alcohol is still present in the patients system. Although concerns have been raised on theoretical grounds about the risk of respiratory depression when BNZs are used in combination with alcohol or other sedatives and about the possibility of behavioral disinhibition with BNZs, these concerns are not reflected in the high ratings the BNZs generally received throughout the survey nor are they supported by research findings.117 The experts did not recommend the use of droperidol or chlorpromazine as treatments for behavioral emergencies and thus they received third-line ratings in every situation, even when these agents would not be expected to pose any particular safety risks. In keeping with findings concerning the different agents adverse-effect profiles, the experts would avoid olanzapine in patients who have diabetes or hyperglycemia or who are obese and would avoid ziprasidone in patients with cardiac arrhythmias or a conduction defect. The results of the CATIE study,62 which compared olanzapine, perphenazine, quetiapine, risperidone, and ziprasidone, were published after the survey was completed. The CATIE findings confirmed that olanzapine was associated with greater weight gain and increases in measures of glucose and lipids than other agents in the study but did not find any QTc problems with ziprasidone. There was little support for using BNZs in patients with delirium or dementia, probably

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because of concern about sedation, gait problems, and the possibility of falls. Risperidone is preferred for delirious patients, perhaps because some of the other newer antipsychotics have anticholinergic properties that might increase confusion and cause excessive sedation. Elderly patients. The panel preferred to avoid antipsychotics or BNZs in frail elderly patients. If medication is needed, risperidone, haloperidol, and olanzapine were preferred (high second line). The preference for risperidone and olanzapine may reflect the larger number of studies done with these agents in geriatric populations (in agitated patients with dementia and elderly patients with psychotic disorders) compared with other newer SGAs as well as the recently published Expert Consensus Guidelines on use of antipsychotics in elderly patients23 and patients with dementia.25 SGAs may be associated with an increased risk of death (due to cardiovascular or infectious causes) in chronic treatment of elderly patients with dementia-related psychosis and should be used cautiously in elderly patients with dementia or at risk for cerebrovascular disease,3741 although recent studies indicate that this risk appears no higher than with FGAs.43,44 Children. The panel would prefer to avoid using antipsychotics or BNZs in children. However, if medication is needed for a child, risperidone and lorazepam are preferred (high second line), probably reflecting the larger number of studies with risperidone in this population.118 Mental retardation. If the patient has mental retardation, risperidone is the preferred agent, reflecting the fact that the largest number of studies with antipsychotics in this population have been done with this drug.119,120 The preference for SGAs in patients with mental retardation agrees with recommendations in the Expert Consensus Guidelines on the Treatment of Psychiatric and Behavioral Problems in Mental Retardation, in which SGAs were strongly preferred over FGAs for treatment of agitation, aggression, or self-injurious behavior.18,120 Pregnancy. We did not repeat questions about pregnant women in the current survey. In 2001, when asked about medication strategies for a pregnant woman who is agitated, psychotic, and unresponsive to direction and for whom immediate medical intervention is judged necessary to prevent harm to the mother or fetus or to reduce the deleterious effects that the stress of agitation may have on the maternal-fetal system, the panel preferred a high-potency FGA (rated first line by 76%),1 probably reflecting the much larger database concerning and lack of teratogenicity reported for high-potency FGAs.121 These recommendations agree with those for treating psychotic depression in pregnant women in the Expert Consensus Guidelines on the Treatment of Depression in Women 2001.19 While the FDA rates the FGAs and SGAs similarly in their Use-in-Pregnancy ratings (category C: risk cannot be ruled out), the 2001 expert panel was less willing to endorse the use of SGAs, presumably because of less experience with these agents in pregnant women. For a discussion of psychotropic agents in pregnancy, readers are referred to a recent review by Jain and Lacy.122

Other complicating problems. We asked the panel which medications were most appropriate for an agitated aggressive patient with a history of various complicating problems. Their recommendations reflect findings concerning the adverse-effect profiles of the different agents. They would avoid using BNZs if possible in patients with a history of drug abuse or dependence, while BNZs are preferred for patients with a history of seizures (e.g., because of substance or alcohol abuse). If a patient has a history of akathisia or other EPS, tardive dyskinesia, or neuroleptic malignant syndrome, the panel recommended choosing agents with the least liability for causing EPS (e.g., a BNZ, an SGA other than risperidone) and would generally avoid antipsychotics that are more likely to cause EPS (e.g., risperidone, especially at higher doses, and high potency FGAs). If a patient has a history of amenorrhea or galactorrhea, the experts would choose a prolactin-sparing medication.

Summary of Medication Recommendations

Although the differences are slight and in many cases not statistically significant, it is of some interest to compare the available drugs, particularly in terms of changes since the last survey. Benzodiazepines alone are still favored in situations when there is no information, for which no specific treatment is available (e.g., personality disorders), or when they may have specific benefits (e.g., intoxication). BNZs are not recommended for use alone in psychotic conditions. Haloperidol. Although haloperidol alone is usually thought to be appropriate, in the current survey it received second-line ratings for agitation in several circumstances. Its use alone is favored over other choices only in medically compromised patients and, even in that context, risperidone received very similar ratings. The traditional combination of haloperidol plus a BNZ was never the most highly rated alternative, but it was a first-line option for schizophrenia, mania, and psychosis NOS (although not for psychotic depression). Risperidone. Among the SGAs, risperidone, alone or combined with a BNZ, received strong support and was the second or third choice in almost every situation. In the current survey, risperidone alone received higher ratings than haloperidol alone except for the medically compromised patient, and the combination of risperidone plus a BNZ received higher ratings than haloperidol plus a BNZ for acute treatment of agitation related to primary psychiatric disturbances. For example, for mania, risperidone plus a BNZ was rated first line by the highest percentage of experts (80%), although the combination of divalproex and an antipsychotic was most frequently rated treatment of choice (42%). Oral risperidone is also recommended following parenteral use of haloperidol, perphenazine, or droperidol. Taken together, the ratings suggest that risperidone may now be viewed somewhat as haloperidol was in the pastas a safe utility drug, alone or combined with a BNZ, in many situations.

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Oral olanzapine, consistent with findings in other settings, received high ratings for agitation in a variety of conditions. It generally received ratings very similarly to risperidone, with slightly higher ratings in areas where it has been tested (e.g., schizophrenia, mania) and slightly lower ratings in situations where it has not been studied and safety may be an issue. Even before publicity concerning potential problems with combinations of olanzapine plus a BNZ, such combinations received less support. Thus, even when olanzapine alone is top rated, olanzapine plus a BNZ was rated second line. Oral ziprasidone and quetiapine generally received similar second-line ratings. Quetiapine received the strongest support in personality disorders, where it was ranked fourth. The combination of oral ziprasidone plus a BNZ sometimes outranked ziprasidone alone (e.g., in mania); in contrast, the combination of quetiapine plus a BNZ was consistently rated lower than monotherapy with quetiapine. Parenteral formulations. The biggest change since the first survey was the advent of new parenteral agents. In primary psychiatric conditions (schizophrenia, mania, psychotic depression, personality disorder), I.M. olanzapine alone and I.M. ziprasidone alone were more highly rated than I.M. haloperidol alone. I.M. olanzapine received slightly more support than I.M. ziprasidone, even though the latter has been available longer. I.M. olanzapine was first line and top rated in schizophrenia, mania, and psychotic depression. I.M. ziprasidone alone was generally rated slightly higher than I.M. ziprasidone plus a BNZ, but both are first line in schizophrenia. The experts made a greater distinction between using I.M. olanzapine alone and combined with a BNZ. Thus, although I.M. olanzapine alone usually received somewhat higher ratings than I.M. ziprasidone, I.M. ziprasidone plus a BNZ was generally rated more highly than I.M. olanzapine plus a BNZ. Neither of the new parenteral formulations received as much support as traditional agents (I.M. haloperidol, I.M. BNZ) when there is no diagnosis or the diagnosis involves a medical condition or intoxication. Other agents. As in the first survey, chlorpromazine received consistently low ratings from the current panel. Although there is controversy over its role, droperidol was also rated third line throughout. Positive results for perphenazine in the CATIE trial62 had not been published at the time of the survey and perphenazine generally received lower ratings than SGAs except aripiprazole. Data concerning I.M. aripiprazole may influence perceptions of this agent in the future.

(e.g., intoxication, psychosis) is usually adequate to create a plan of care (a more comprehensive assessment leading to a specific diagnosis was also supported but may be impractical for various reasons). Use of physical restraints. The current survey did not repeat questions about the use of restraints, since no significant change in responses was anticipated. The 2001 panel considered use of physical restraints a last resort, agreeing with the CMS interim rules,70 which specify that use of restraints for managing behavioral emergencies is allowed only when all less restrictive measures have failed and unanticipated severely aggressive or destructive behavior places the patient or others in imminent danger They considered restraints extremely or usually appropriate when patients pose an acute danger to other patients, bystanders, staff, or themselves and sometimes appropriate to prevent an involuntary patient from leaving prior to assessment or transfer to a locked facility, but did not consider use of physical restraints appropriate in other situations, such as a patient who has a history of previous self-injury or aggression but does not appear to pose any immediate risk at the moment, when adequate resources are not available to supervise the patient adequately, to maintain an orderly treatment environment, or to prevent a voluntary patient from leaving prior to assessment. Use of medications in conjunction with restraints. If a patient becomes calmer when put in restraints, the experts were divided between using no medication or only oral medication, but did not generally recommend parenteral medication in this situation. However, if a patient continues to be violent and extremely agitated while in restraints, the experts strongly supported the use of parenteral medication in combination with the restraints, but would also consider oral medication in this situation. They did not consider it appropriate to leave such a patient unmedicated in restraints. Overall, the responses indicate that the goal in this situation is to use medication to reduce time in and complications of restraints. Feasibility of reducing use of restraints. In the current survey, we did ask the panel if they consider elimination of the use of physical restraints a feasible goal. Only 36% of the experts believed that restraint is a form of treatment. These respondents agreed that it may be overutilized but did not feel that it should be eliminated. Another 40% did not consider restraint a form of treatment but believed that its advantages as a security measure outweigh its disadvantages. The remaining 24% of the experts felt that the disadvantages of restraint outweigh the advantages, but were divided as to whether it would be possible to reduce or eliminate the use of restraint in their treatment settings.

Use of Restraints
The concept of chemical restraint. According to the CMS interim final rules,55,70 the distinction between what is considered a chemical restraint and a treatment appears to hinge on whether medication is given as part of a plan of care or merely to control the patients behavior. The panel in the first survey indicated that a brief assessment leading to determination of a general category of presentation

Minimizing Negative Impact and Preventing Future Crises

The majority of the experts felt that involuntary treatment is likely to have a negative impact on a patients willingness to seek care in the

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future, although a third did not think it would have an effect, and about 10% felt that it would have a positive effect. These responses reinforce the results of a consumer survey which found that consumers of emergency care put great emphasis on the importance of being allowed to express a preference concerning their treatment.8 We asked the experts which interventions were most important for staff to undertake after a crisis but before the person leaves the emergency setting to minimize negative impact on the therapeutic alliance or the persons willingness to seek out mental health care in the future, and more than 60% said is is essential to encourage patients to discuss the experience and ask questions, provide medical monitoring as needed, and give patients (and family) information about the medication the person is being discharged on and its side effects. These ratings reflect findings that emergency interventions are less likely to be effective and promote positive long-term outcomes if patients do not understand what happened and why they received the treatment they were given. We then asked about interventions to reduce risk of future psychiatric crises. More than 80% of the panel said it is essential to arrange an outpatient follow-up visit before discharge. This reflects findings that merely telling the person to call for an appointment is ineffective and that the best outcomes are obtained when an appointment soon after the emergency intervention is scheduled for the patient before discharge.123

afterward may bring improvement in this area. The inclusion of consumer perspectives in the training of providers should help to sensitize providers and peer counselors. Advocates and families can also give providers proxy data that might help avoid or shorten episodes.

LIMITATIONS AND ADVANTAGES OF EXPERT CONSENSUS GUIDELINES

These guidelines can be viewed as an expert consultation, to be weighed in conjunction with other information and in the context of each individual patient-physician relationship. The recommendations do not replace clinical judgment, which must be tailored to the particular needs of each clinical situation. We describe groups of patients and make suggestions intended to apply to the average patient in each group. However, individual patients will differ greatly in their treatment preferences and capacities, history of response to previous treatments, family history of treatment response, and tolerance for different side effects. Therefore, the experts first-line recommendations certainly will not be appropriate in all circumstances. We remind readers of several other limitations of these guidelines: 1. The guidelines are based on a synthesis of the opinions of a large group of experts. From question to question, some of the individual experts would differ with the consensus view. 2. We have relied on expert opinion precisely because we are asking crucial questions that are not yet well answered by the literature. One thing that the history of medicine teaches us is that expert opinion at any given time can be very wrong. Accumulating research will ultimately reveal better and clearer answers. Clinicians should therefore stay abreast of the literature for developments that would make at least some of our recommendations obsolete. We hope to revise the guidelines periodically based on new research information and on reassessment of expert opinion to keep them up-to-date. 3. The guidelines are financially sponsored by the pharmaceutical industry, which could possibly introduce biases. Because of this, we have made every step in guideline development transparent, reported all results, and taken little or no editorial liberty. 4. These guidelines are comprehensive but not exhaustive; because of the nature of our method, we omit some interesting topics on which we did not query the expert panel. Despite the limitations, these guidelines represent a significant advance because of their specificity, ease of use, and the credibility that comes from achieving a very high response rate from a large sample of the leading experts in the field.

CONCLUSIONS AND DIRECTIONS FOR FUTURE RESEARCH

Even as tremendous strides are made in the treatment of psychiatric illness, behavioral emergencies continue to pose a challenge because they tend to occur in the context of incomplete information. This remains a difficult and controversial area of practice because it involves limitations on patient autonomy and control, although it is hoped that better practices will lead to improvement in this area. This guideline, like the previous one, is dedicated to a new climate of increased respect and an effort to move from control to care. Other core problems in a behavioral emergency are the perceived need to do something immediately and the lack of agreement between the individual at the center of the emergency and those responsible for managing it. This guideline is an effort to reach agreement among providers. But how do we facilitate agreement between patients and providers? Strategies with a narrow focus on the technical issues that determine short-term outcome may do so at the cost of relationship issues that influence long-term outcome. Although the attitudes and behaviors that foster autonomy and respect are difficult to incorporate into guidelines, it is important to take into account available information concerning consumer preferences in choosing the most appropriate interventions.8 Available data suggest that consumers understand the need for emergency interventions but often feel frightened and abandoned in the midst of them. In this respect, recent regulations that stress continuing contact with the patient during the episode and debriefing

FINAL WORD
Advances in public health do not always require technological breakthroughs or long periods of waiting for new data. Immediate gains can be made by increasing the speed with which best practices are implemented. Guidelines offer a rapid means for communicating a

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distillate of expert opinion. When reaching a clinical decision point, practitioners and patients can use guidelines to generate a menu of reasonable choices and then select the option that is judged best for each individual. This process drives the next round of expert opinion and the next round of empirical studies.

References
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