Pipamperone and Delirium: a Preliminary Evaluation of Its Effectiveness in the Management of Delirium and Its Subtypes
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Original article | Published 24 July 2017 | doi:10.4414/smw.2017.14471 Cite this as: Swiss Med Wkly. 2017;147:w14471 Pipamperone and delirium: a preliminary evaluation of its effectiveness in the management of delirium and its subtypes Boettger Soenkea, Knoepfel Silvanaa, Schubert Mariabd, Garcia Nuñez Davidc, Plichta Michael Martine, Klaghofer Richarda, Jenewein Josefa a Department of Psychiatry and Psychotherapy, University of Zurich, University Hospital Zurich, Switzerland b Centre of Clinical Nursing Science, University of Zurich, University Hospital Zurich, Switzerland c University Basel, University Hospital Basel, Switzerland d Directorate of Nursing/MTT, Inselspital, University Hospital Bern, Switzerland e Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Goethe University, Frankfurt, Germany Summary Key words: haloperidol, pipamperone, antipsychotics, delirium, subtypes, effectiveness INTRODUCTION: Delirium has been recognised as an underdiagnosed and undermanaged syndrome with sub- Introduction stantial prevalence rates and potentially deleterious con- sequences in the medically ill population. Despite its fre- Delirium is a neuropsychiatric syndrome characterised by quent administration in the management of delirium, the an abrupt onset and fluctuating disturbances in conscious- effectiveness of pipamperone has not yet been evaluated. ness and cognition, as well as a range of noncognitive domains including disturbances in motor behaviour, emo- METHODS: In this retrospective, descriptive cohort study tionality and sleep-wake cycle, caused by an underlying of 192 patients, pipamperone as monotherapy and as an aetiology [1, 2]. adjunct to haloperidol, haloperidol alone, or atypical an- Delirium is a common occurrence over the course of hos- tipsychotics were compared with respect to their effective- pitalisation, depending, among other factors, on the age ness in the management of delirium and its subtypes over and gender of the patient, previous episodes of delirium, the course of 20 days. pre-existing dementia and severity of illness [3–5]. Across RESULTS: In this elderly patient population, pipamperone the hospital, including the medical, surgical or general set- alone and as an adjunct to haloperidol was as effective tings, delirium rates vary between 10 and 60% [5] and in as haloperidol or atypical antipsychotics in the manage- the intensive care setting varies between 60 and 82% [4–7]. ment of delirium. Management with low-dose pipamper- If not managed appropriately, delirium can exert a very ad- one monotherapy achieved delirium resolution in 70% of verse effect on clinical outcomes. This can include short- patients, over a mean of 6.4 (2–20) days. With pipam- term consequences such as increased morbidity and mor- perone as an adjunct to haloperidol, delirium resolved in tality, and prolonged hospitalisation, as well as long-term 59% of patients, over a mean of 7.4 (2–20) days. When consequences such as increased rates of cognitive decline, haloperidol or atypical antipsychotics (risperidone, olan- deterioration in functionality and institutionalisation [8, zapine or quetiapine) were used, the delirium resolution 9]. Another factor contributing to worsened delirium out- rates were 72 and 67%, over a mean of 5.2 (2–11) and 6.4 comes has been identified as delirium severity, with more (2–20) days, respectively. The addition of pipamperone to severe episodes associated with worse outcomes [10, 11]. haloperidol decreased the requirement for lorazepam. Pi- In particular, persistent delirium has been recognised to pamperone proved to be equally effective in all delirium predict worse outcomes. Such persistence of delirium has subtypes – hypoactive, hyperactive and mixed. Nonethe- been documented as long as 3 and 6 months after hospital less, potential bias could not be excluded in this observa- discharge, leading to the conclusion that delirium may be tional design. much less transient than previously assumed [12–14]. Per- Correspondence: sistent delirium is also associated with a greater risk of Soenke Boettger, MD, Uni- CONCLUSION: From these initial results, low-dose pi- death [15, 16]. In contrast, delirium symptoms resolving versity of Zurich, University pamperone was as effective as haloperidol or atypical an- within 2 weeks have been associated with excellent func- Hospital Zurich, Depart- tipsychotics in the management of delirium and its sub- ment of Psychiatry and Psy- tional recovery [12], and resolved delirium with decreased chotherapy, Ramistrasse types, and was benzodiazepine-sparing when used as an mortality [15]. 100, CH-8091 Zurich, adjunct to haloperidol. As a result of its different psychomotor representations, Switzerland, soenke.boettger[at]usz.ch delirium has been further characterised into hypoactive, Swiss Medical Weekly · PDF of the online version · www.smw.ch Page 1 of 9 Published under the copyright license “Attribution – Non-Commercial – No Derivatives 4.0”. No commercial reuse without permission. See http://emh.ch/en/services/permissions.html. Original article Swiss Med Wkly. 2017;147:w14471 hyperactive and mixed subtypes. The hypoactive subtype of hypoactive delirium was haloperidol, starting with a is characterised by decreased activity, apathy, decreased dose of 0.5 to 2 mg and increasing to a maximum of 10 mg speed of activity and speech, decreased volume of speech, daily, plus pipamperone 20 mg up to a maximum of 80 mg decreased alertness, and withdrawal; the hyperactive sub- daily in those patients with anxiety, distress or restlessness. type by increased activity, loss of control of activity, rest- The mainstay of management of the hyperactive and mixed lessness, and wandering; and the mixed subtype by the subtypes was pipamperone, starting at 20 to 40 mg, in- occurrence of both hypoactive and hyperactive features creasing up to a maximum of 80 mg daily. When delusions within a given day [17]. or perceptual disturbances were present, haloperidol was Due to its adverse short- and long-term consequences [8, initiated at 0.5 to 2 mg, up to a maximum of 10 mg daily. 9], delirium prevention strategies [18, 19] and, once detect- When agitation occurred, lorazepam 0.5 to 2.5 mg, up to ed, management strategies have been devised. The man- a daily maximum dose of 7.5 mg, was added throughout agement approach to delirium relies on eliminating the un- the daytime and at night. Haloperidol was administered derlying aetiology, providing environmental interventions throughout the day, whereas the focus of pipamperone ad- like hearing and visual aids, frequent reorientation and, if ministration was the night-time in order to reinforce or necessary, pharmacological management [2]. Haloperidol restore the sleep-wake cycle pattern. Once clinical im- remains the gold standard [2],but an increasing number of provement was evident, the delirium management sched- studies are supporting the administration of other, atypical ule recommended reducing the doses of administered med- antipsychotics. Altogether, delirium studies indicate remis- ications by 50%. sion rates from 40 to 90% [20, 21]. In addition, patients were also managed with risperidone, Pipamperone, a low potency antipsychotic and an antago- olanzapine and quetiapine for delirium. nist of 5HT2A-C-, D2-4- and α1-2-receptors with much higher In total, 192 patients were retrospectively enrolled. Inclu- activity against the D4 and 5HT2A than D2 receptor and in- sion criteria were the presence of delirium, active man- significant activity against histamine1 and muscarinic-an- agement of delirium with psychotropic medication, and ticholinergic (mACh) receptors [22], is recommended for DOS recordings for more than three days. Exclusion crite- the management of delirium [23, 24]. However, to date the ria were the absence of delirium, an insufficient duration effectiveness of pipamperone for this purpose has not yet of DOS recordings, and transfer to other facilities shortly been evaluated at all. Thus, in this study, the effectiveness after initiation of the delirium management schedule. of pipamperone alone and as an adjunct to haloperidol was Once patients were included in this study, sociodemo- compared with that of haloperidol alone, as well as atypical graphic variables like age and gender, medical or surgical antipsychotics, in the management of delirium, both over- variables, as well as psychiatric diagnoses were collected. all and its various clinical subtypes. These psychiatric diagnoses were classified as cognitive The aim of this study was to assess the effectiveness of pi- disorders including dementias, addictive, psychotic and af- pamperone alone and as an adjunct to haloperidol in the fective disorders, or other. Among management variables, management of delirium versus the gold standard haloperi- psychotropic medications administered were recorded in dol or atypical antipsychotics such as risperidone, olanza- daily doses, including all psychotropic medications in the pine and quetiapine. delirium management protocol, as well as other antipsy- chotics and lorazepam. Methods Because of the nature of the protocol, various combina- tions of medications were possible. For the purposes of This study was approved by the ethics committee of the analysis, these were grouped into four categories: (1) pi- Canton of Zurich (KEK-ZH-Nr. 2012-0263). pamperone monotherapy; (2) pipamperone as an adjunct to haloperidol; (3) haloperidol alone accepted as the gold Patients and procedures standard; and (4) atypical antipsychotics, including