Category: Commentaries

Haloperidol for psychosis-induced aggression or agitation (Rapid Tranquillisation)

Dott. Paolo Balzaretti
 
S.C. Medicina e Chirurgia d’Accettazione e d’Urgenza, A.O. “Ordine Mauriziano”, Torino
 

What we already know about this topic

Even though it is one of the most difficult clinical situations to manage in the Emergency Department, good evidence for optimal treatment of acute agitation due to psychosis is still lacking. As a consequence, documents from Scientific Societies disagree about which drug employ to quickly sedate the agitated patient, as synthetized in table 1.
 
Scientific society
Recommendations for pharmacological tranquillisation
AAEP 2012 (1)
First choice: i.m. ziprasidone or i.m. olanzapine Second line: benzodiazepine such as lorazepam.
NICE 2015 (2)
i.m. lorazepam, i.m. haloperidol + i.m. promethazine Prefer i.m. lorazepam if there is insufficient information to guide the choice or the patient has not taken antipsychotic medication before.
NSWH 2015 (3)
First choice: droperidol, Second choice: Benzodiazepines, ketamine.
ACEP 2017 (4)
Ketamine is one option for immediate sedation of the severely agitated patient who may be violent or aggressive. (Consensus recommendation)
 
Table 1. These documents refer primarily to “acute agitation” or “acute behavioral disturbances” in the Emergency Department, and only a part of them addresses specifically psychosis-induced acute agitation. Abbreviations: AAEP, American Association for Emergency Psychiatry; NICE, National Institute for Health and Care Excellence; NSWH, New South Wales Ministry of Health; ACEP, American College of Emergency Physicians, im: intramuscolar
 
For this reason, more evidence is needed to clarify which pharmacological agent is to prefer in such a clinical situation. Haloperidol is a typical, first generation, anti-psychotic and today still represents one of most employed drugs to treat acute manifestations of psychosis. Which is its efficacy in controlling acute psychosis-induced agitation? The work from the Cochrane Collaboration we look at try to answer this question, summarizing the evidence from the published randomized controlled trials confronting haloperidol with placebo or other active pharmacological agents.

The Cochrane review

Title: Haloperidol for psychosis-induced aggression or agitation (rapid tranquillisation).
Authors: Ostinelli EG, Brooke-Powney MJ, Li X, Adams CE.
Bibliographic citation: Cochrane Database of Systematic Reviews 2017, Issue 7. Art.No.: CD009377.
Objective: to examine whether haloperidol, administered orally, intra-muscolarly or intravenously, is effective for the treatment of psychosis-induced aggression or agitation.
Included studies: randomized controlled trials.
Primary outcome: not tranquil o asleep by up 30 minutes; repeated need for rapid tranquillisation.
Secondary outcomes: there were 72 secondary endpoints, grouped in 11 categories (tranquillisation or asleep, specific behavior, global outcomes, service outcomes, mental state, adverse effects, leaving the study early, satisfaction with treatment, acceptance of treatment, quality of life, economic outcome).
Number of included studies: 41
Quality of included studies:the vast majority of the studies have high or unclear risk of bias for more than half of the methodological aspects evaluated.
Number of patients: 4933
Results:
 
                                                         Haloperidol vs. placebo

 

Outcome
No. of studies / No. of patients
Risk Ratio
(95% C.I.)
Quality of evidence
Not asleep at 2 hours
2 / 220
0,88 (0,82 – 0,95)
Very low
Needing additional injection within 24 hours
4 / 660
0,51 (0,42 – 0,62)
Low
One or more drug related adverse events over 24 hours
2 / 395
1,64 (1,22 – 2,20)
 
Dystonia during 24 hours
2 / 207
7,49 (0.93 – 60,21)
 
Risk ratio below 1 favors haloperidol
 
                                                   Haloperidol vs. chlorpromazine 
 
Outcome
No. of studies / No. of patients
Risk Ratio
(95% C.I.)
Quality of evidence
Not asleep at 2 hours
1 / 39
1,93 (1,04 – 3,60)
Very low
Needing additional injection within 24 hours
1 /30
1,07 (0,89 - 1,28)
Very low
One or more drug related adverse events over 24 hours
Not available
 
 
Extra-piramidal adverse effects
2 / 69
2,07 (0,28 – 15,15)
 
Risk ratio below 1 favors haloperidol 
                                       
                                        Haloperidol vs. haloperidol + promethazine
 
Outcome
No. of studies / No. of patients
Risk Ratio
(95% C.I.)
Quality of evidence
Not asleep at 20 minutes
1 / 316
1,60 (1,18 – 2,16)
Moderate
Needing additional injection within 24 hours
2 / 376
0,78 (0,43 – 1,41)
Very low
One or more drug related adverse events over 24 hours
2 / 376
2,01 (1,07- 3,80)
 
Acute dystonia
1 / 361
 19,48 (1,14 – 331,92)
Low
Risk ratio below 1 favors haloperidol
                                                     
                                                       Haloperidol vs. lorazepam
 
Outcome
No. of studies / No. of patients
Risk Ratio
(95% C.I.)
Quality of evidence
Not asleep at 3 hours
1 / 60
1,05 (0,76 – 1,44)
Very low
Needing additional injection within 24 hours
1 / 66
1,14 (0,91 – 1,43)
Very low
One or more drug related adverse events over 24 hours
Not available
 
 
Dystonia during 24 hours
1 / 66
3,54 (0,42 – 30,03)
Very low
Risk ratio below 1 favors haloperidol
 
                                                       Haloperidol vs. midazolam
 
Outcome
No. of studies / No. of patients
Risk Ratio
(95% C.I.)
Quality of evidence
Not asleep at 3 hours
Not available
 
 
Needing rescue drug
1 / 84
1,14 (0,46 – 2,87)
 
One or more drug related adverse events over 24 hours
1 / 84
5,0 (0,25 – 101,11)
Low
Apnoea
1 / 84
3,0 (0,13 – 71,61)
 
Risk ratio below 1 favors haloperidol
 
                                           Haloperidol vs. haloperidol + lorazepam
 
Outcome
No. of studies / No. of patients
Risk Ratio
(95% C.I.)
Quality of evidence
Not asleep at 3 hours
1 / 67
1,83 (1,11 – 3,02)
Very low
Needing additional injection within 24 hours
1 / 67
1,05 (0,87 – 1,27)
Very low
One or more drug related adverse events over 24 hours
1 / 67
1,16 (0,62 – 2,18)
Very low
Dystonia during 24 hours
1 / 67
8,25 (0,46–147,45)
 
Risk ratio below 1 favors haloperidol
 
                                            Haloperidol vs. haloperidol + midazolam
 
Outcome
No. of studies / No. of patients
Risk Ratio
(95% C.I.)
Quality of evidence
Not asleep at 2 hours
Not available
 
 
Needing additional injection within 24 hours
1 / 60
0,88 (0,69 – 1,13)
Very low
One or more drug related adverse events over 24 hours
Not available
 
 
Dystonia during 24 hours
Not available
 
 
Risk ratio below 1 favors haloperidol

Comment and conclusions

The modest relevance of the results of the present systematic review reflects the scarcity of data regarding the treatment of acute agitation in patients with psychosis. Indeed, most of the proposed comparisons are based on just one study, frequently with a small sample. Moreover, quality of the included studies is low (above all because of a high prevalence of bias in blinding procedures and of a substantial risk of selective reporting). For these reasons quality of evidence has been correctly labeled as low or very low.
Apart from some general recommendations shared by most of the available guidelines, namely to use drugs only if nonpharmacological strategies of tranquillisation failed (1,3), and to avoid complete sedation favoring simply the reaching of a drowsiness (1,3), much uncertainty is still present in this clinical field. Haloperidol appeared more effective than placebo at the cost of increased risk of adverse effects, mainly extrapyramidal ones. No firm conclusions can be drawn regarding the efficacy and safety of haloperidol with respect to benzodiazepines, alone or as an association.
Bibliography
  1. Wilson MP, Pepper D, Currier GW, Holloman GH, Jr, Feifel D. The Psychopharmacology of Agitation: Consensus Statement of the American Association for Emergency Psychiatry Project BETA Psychopharmacology Workgroup. West J Emerg Med. 2012;13(1): 26–34. 
  2. NICE, National Institute for Health and Care Excellence. Violence and aggression: short-term management in mental health, health and community settings. NICE guideline (NG 10). Published: 28 May 2015. Available at: www.nice.org.uk/guidance/ng10
  3. New South Wales Ministry of Health. Management of patients with Acute Severe Behavioural Disturbance in Emergency Departments. Document n.°:  Published: 10 August 2015.
  4. American College of Emergency Physicians Clinical Policies Subcommittee (Writing Committee) on the Adult Psychiatric Patient. Clinical Policy: Critical Issues in the Diagnosis and Management of the Adult Psychiatric Patient in the Emergency Department. Ann Emerg Med. 2017;69:480-498.

Notes: doses and modes of administration of cited drugs

Drug
Dose as indicated by Italian regulatory Agency (AIFA)
Range of doses employed in cited studies
Haloperidol
5 mg i.m.; repeat dose every hour until symptom relief or a total dose of 20 mg has been reached over 24 hours.I.v. administration is not allowed
1 to 7,5 mg (mainly 5 mg)
Counterindications as indicated by the Italian Regulatory Agency (AIFA)
·       Hypersensitivity to the drug
·       Coma, or CNS depression due to alcohol or other psychotropic substances. ·       Parkinson’s disease
·       Diseases of basal ganglia
·       Significant cardiac disease (e.g., recent acute myocardial infarction, acute
        heart failure, treatment with class IA o III anti-arrhythmic drugs)
·       Prolonged QTc interval
·       Concomitant use of QTc interval prolonging drugs
·       Patients with family history of arrhythmia or Torsade de Point
·       Hypopotassemia

 

Drug
Dose as indicated by Italian regulatory Agency (AIFA)
Range of doses employed in cited studies
Chlorpromazine 
25 mg i.m.; repeat administration if necessary. 
25 to 100 mg (over 24 hours)
Counterindications as indicated by the Italian Regulatory Agency (AIFA)
·       Hypersensitivity to the drug
·       Coma, especially caused by CNS depression due to alcohol or other
        psychotropic substances
·       Patients with known sub-cortical cerebral pathology
·       Major depression
·       Severe blood dyscrasias
·       Hepatic or kidney diseases
·       early childhood
·       Pheochromocytoma, Myasthenia Gravis and not-treated epilepsy
·        Breastfeeding (and pregnancy)

 

Drug
Dose as indicated by Italian regulatory Agency (AIFA)
Range of doses employed in cited studies
Lorazepam
2-4 mg i.v. o i.m. If necessary, administration can be repeated after 2 hours.  I.v. administration route is preferred.Intra-arterial administration is counter indicated. 
2 to 4 mg 
Counterindications as indicated by the Italian Regulatory Agency (AIFA)
·       Hypersensitivity to the drug or other benzodiazepines
·       Sleep apnea syndrome
·       Severe respiratory failure
·       Severe hepatic failure
·       Myasthenia Gravis
·       Angle-closure glaucoma
·       Pregnancy and breastfeeding
·       Childhood

   

Drug
Dose as indicated by Italian regulatory Agency (AIFA)
Range of doses employed in cited studies
Midazolam
Initial dose: 2 - 2,5 mgFollowing doses: 1 mgMaximum allowed dose: 3,5–7,5 mg
5 mg
Counterindications as indicated by the Italian Regulatory Agency (AIFA)
·       Hypersensitivity to the drug or other benzodiazepines
·       For conscious sedation, severe respiratory failure or acute depression of
        respiratory function

 

Drug
Dose as indicated by Italian regulatory Agency (AIFA)
Range of doses employed in cited studies
Promethazine
25-50 mg i.m. (maximum dose: 100 mg)
25 – 50 mg
Counterindications as indicated by the Italian Regulatory Agency (AIFA)
·       Hypersensitivity to the drug
·       During treatment with monoamino-ossidases
·       Asthma
·       Glaucoma
·       prostatic hypertrophy
·       Pregnancy and breastfeeding
·       Childhood (age less than 2 years)

 

 

 

 

 

 

 

 

 

 

 

 

 

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