Hope-icu trial

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List of Abbreviations

ACh Acetylcholine/Cholinergic

AE Adverse event

APACHE Acute Physiological and Chronic Health Evaluation

CAM-ICU Confusion Assessment Method-ICU

CI Chief Investigator

CLRN Comprehensive Local Research Network

CONSORT Consolidated standards of reporting trials.

CPAP Continuous Positive Airways Pressure

CRF Case Report Form

CTU Clinical Trials Unit

DMEC Data Monitoring and Ethics Committee

DSM-IV Diagnostic and Statistical Manual of Mental Disorders

ECG Electrocardiogram

EQ-5D EuroQol 5 dimension questionnaire

EPS Extrapyramidal Symptoms

HRQoL Health Related Quality of Life

ICNARC Intensive Care National Audit and Research Centre

ICU Intensive Care Unit

IMV Intermittent Mandatory Ventilation

IQCODE Informant Questionnaire on Cognitive Decline in the Elderly

MHRA Medicines and Healthcare products Regulatory Agency

MIND Modifying the Incidence of Delirium Trial

NICE National Institute for Health and Clinical Excellence

NSTS NHS Strategic Tracing Service

PACU Post anaesthetic care unit – the “recovery” area in the operating theatre

PerLR Personal Legal Representative

PIS Patient Information Sheet

ProfLR Professional Legal Representative

QTc Corrected QT time

RASS Richmond Agitation and Sedation Score

R&D Research and Development

SAE Serious adverse event

SOP Standard Operating Procedure

SUSAR Suspected unexpected serious adverse reaction

TICS-M Telephone Interview of Cognitive Status – modified.

TSC Trial Steering Committee

VFD Ventilator free days

WHHT West Hertfordshire Hospitals NHS Trust

1. Lay Summary

Does haloperidol prevent and/or treat delirium in critically ill ventilated patients?

Many circumstances, e.g. severe infection or accident results in a person becoming critically ill. Patients with critical illness often develop impaired brain function – “delirium”. This common condition affects up to 2 out of every 3 patients in Intensive Care Units (ICU), results in a longer ICU and hospital stay and a higher risk of death. Importantly, even after recovery from the initial illness, patients frequently experience impaired memory, a lower quality of life, e.g. many are unable to return to work or even look after themselves, essentially a mild or accelerated “dementia”. There is no proven effective treatment for delirium. This study will investigate if the drug haloperidol, commonly used in the management of delirium, is safe and effective. Our study is a “randomised placebo controlled trial”, widely accepted to be the best way to find out if a treatment really works or not. There will be 2 groups of 71 patients who will be given either haloperidol or a dummy drug (placebo). The group that a patient is in will be decided at random, the only difference between the 2 groups will be the treatment. We will count the number of days a patient has delirium, how fast they recover and how well their brain functions at 6 months using an approved telephone questionnaire. Haloperidol may reduce the time patients spend in ICU. Demand for ICU exceeds supply; a treatment that reduced use of ICU resources would result in increased capacity and improved access to appropriate facilities for critically ill patients. Furthermore delirium is associated with serious adverse outcomes; the potential impact of an effective treatment is considerable. This study is funded by a Research for Patients Benefit grant and run in partnership with the Alzheimer’s Society.

2. Background

2.1 Terminology

Delirium is a clinical syndrome – an acute confusional state. Hippocrates was credited with the first description. The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) define it as a disturbance of consciousness with inattention, changes of cognition developing over a short time period caused by direct physiological consequences of a medical condition.¹ Four groups of causes identified are a general medical condition, substance intoxication, substance withdrawal or delirium due to multiple aetiologies. There are three subtypes, hyperactive, hypoactive and mixed. Hypoactive delirium is more common in elderly patients and associated with worse outcomes than the familiar hyperactive type.² Hypoactive delirium is categorised by decreased alertness and motor activity, sparse or slow speech, staring and apathy. Numerous risk factors for patients developing delirium have been identified in non-ICU populations of which ICU patients have an average of 11 risk factors.³ Delirium will be overlooked unless a screening tool is used such as the Confusion Assessment Method – ICU (CAM-ICU).⁴ In mechanically ventilated patients, using the CAM-ICU, the incidence is 55 – 69% in the UK. Data demonstrate an incidence up to 65% in the population to be recruited to this study.⁵

2.2 Pathophysiology

The pathophysiology of delirium remains poorly understood. Neurotransmitter imbalance is the leading hypothesis in delirium – an imbalance in the cholinergic and dopaminergic neurotransmitter system resulting in a relative cholinergic deficient state with excess dopamine. Neurotransmitter imbalance can come about from a number of causes, direct or indirect, which result in oxidative stress. The proposed mechanisms include cell membrane stability, oxygen supply and utilisation, imbalance of one, two or many neurotransmitters, false transmitters, stress hormones, cytokines, inflammation, blood supply, functional connection disruption and thalamic dysfunction.^6,7 Given the nature of delirium it is likely that several mechanisms contribute to delirium development in patients. Because of its multifactorial nature it has been thought that delirium from different causes may have different mechanisms and/or involve different parts of the brain. But it has been suggested there is always a final common pathway – in other words ultimately particular neural pathways are always involved resulting in the core symptoms.⁸ The neural pathways that may constitute the final common pathway are the prefrontal cortices, anterior and right thalamus and the right basilar mesial temporoparietal cortex. Delusions and visual hallucinations in delirium are likely to be related to dysfunction of frontal and/or temporo-occipital circuits.

Acetylcholine plays an extensive role in attention and consciousness. Extensive evidence supports the role of a central cholinergic (ACh) deficiency in delirium.⁹ The ACh hypothesis cannot be separated from the dopamine excess hypothesis because they interact so closely with each other in the brain. Dopamine excess itself has been linked to simultaneous cholinergic deficiency. Dopamine, norepinephrine and serotonin have roles in arousal and the sleep/wake cycle, mediating responses to stimuli where the responses are modulated by the cholinergic pathway. There are several metabolic pathways that lead to significant increases of dopamine under impaired oxidative conditions. Anatomically the dopaminergic and cholinergic pathways overlap significantly.

As part of the aging process there is a decrease in the volume of acetylcholine (ACh) producing cells and a decrease in cerebral oxidative metabolism. Both factors lead to a normal decline in ACh synthesis, which be the reason increasing age is a risk factor for developing delirium. These normal processes may then be aggravated by even mild hypoxia as a result of illness, which also further inhibits ACh synthesis and release.

2.3 Outcomes

Delirium during hospitalisation is a strong independent marker of high risk of mortality not just in hospital but for at least 11 months after admission. Among older medical patients delirium means a doubling of the risk of dying by 12 months.¹⁰ The risk is increased in the first month, and consistently throughout the next 12 months. Each additional day an ICU patient spends in delirium is associated with a 10% increased risk of death.¹¹

Delirium is linked to poor cognitive outcomes in a variety of patient populations. Incident delirium has been shown to accelerate the trajectory of cognitive decline in hospitalised patients with Alzheimer disease such that over 12 months they will experience a decline that would otherwise have taken 18 months but for the delirium.¹²

Delirium is associated with worse functional outcomes, it is not necessarily an accelerated decline but at a lower level than patients who do not become delirious.¹³ While it can be sustained this is not always the case. How completely a patient recovers functional status depends on how completely the patient recovers from delirium, how long the episode lasted and whether it recurs.

Delirium has been shown to be a predictor of patients being discharged to an institution other than home in several patient groups including critically ill patients.¹⁴ Delirium has been shown associated with longer lengths of stay; in some ICU patients it is the strongest independent determinant of length of hospital stay. ¹⁵ In the original delirium and mortality study by Ely and colleagues this translated to an additional 10 days in hospital for patients who developed delirium.¹⁶ Regarding ICU stay this is consistently increased in ventilated and non-ventilated patients.

2.4 Rationale for using haloperidol in delirium

2.4.1 Delirium Treatment:

Antipsychotics are the mainstay of drug therapy when treating patients with delirium; the one most commonly used is haloperidol. The rationale for using these drugs is that an imbalance of neurotransmitters, a central cholinergic deficiency and a relative excess of dopamine cause delirium. D2 receptor blockade plus the associated enhanced acetylcholine release restore the imbalance of neurotransmitters in the brain. Antipsychotics are used in a range of severe psychiatric disorders including the short term treatment of acute psychotic, manic and psychotic-depressive disorders as well as agitated dementia and the long-term treatment of chronic psychotic disorders including schizophrenia.

Its main action is via dopamine antagonism in the central nervous system.¹⁷ It exhibits partial selectivity for dopamine 2 receptors particularly in the corpus striatum. It is this action that is thought to be responsible for its antipsychotic properties. It also acts on some alpha adrenoreceptors (α-1), opioid, muscarinic cholinergic, histamine and serotonin receptors. Its actions on 5-HT2 (serotonin) receptors occur at high doses.

2.4.2 Lack of evidence:

Haloperidol has been used in tens of thousands of patients throughout the world for years. The evidence regarding the use of haloperidol in delirium is almost entirely based on case series and case reports. There has been one trial reported in 175 elderly Chinese patients; 29 patients received placebo compared with 72 patients who received haloperidol 2.5mgs to 10mgs im.¹⁸ This demonstrated a significant reduction in delirium severity. The study is difficult to assess for validity because it is not reported according to CONSORT guidelines. There have been no placebo-controlled trials in critically ill patients powered for clinical outcomes. Two recent Cochrane systematic reviews concluded that further trials in the prevention and treatment of delirium were needed as data on effectiveness of treatment to prevent and treat delirium were limited.^{19, 20} Two clinical studies were identified which used haloperidol to prevent delirium in surgical patients and found haloperidol decreased the incidence and duration of delirium.^{21, 22} These studies did not involve critically ill patients. A retrospective study concluded the use of haloperidol in mechanically ventilated patients was associated with lower mortality. ²³ These studies support the concept that haloperidol may improve outcomes in mechanically ventilated patients at risk of delirium.

Research evaluating the association between the use of typical and atypical antipsychotics, adverse events and mortality has been published.^{24, 25} The findings have been mixed due to differences in data source, methodological approach, sample size and geographical variation in treatment practices. Although some have detected a positive association between antipsychotic use and mortality, other studies report that antipsychotics have no effect – or even a protective effect – on mortality.^{26, 27} The difficulty these studies have is controlling for confounding factors, in particular the patient’s functional status was not taken into account in the large cohort studies.

2.4.3 Potential benefits in ICU patients:

Haloperidol has sedative sparing effects and so may decrease the amount of sedative drugs ventilated ICU patients are given, which are thought to be potentially deliriogenic. Furthermore haloperidol has potentially beneficial immunomodulatory effects inhibiting the release of proinflammatory cytokines that may reduce multiple organ dysfunction and improve survival.²⁸ Also as haloperidol improves cognitive function, it may reduce cognitive impairment and ICU accelerated dementia. ²⁹ Haloperidol is the first-line drug recommended to treat delirium in any guideline drawn up nationally or internationally. In a UK survey of intensive care consultants, 74% use haloperidol as first-line treatment for hyperactive delirium and of those who treat hypoactive delirium pharmacologically 80% use haloperidol.³⁰ As more delirium is recognised in our critically ill patients it is expected that haloperidol will be used in increasing amounts.³¹

A randomised placebo-controlled trial pilot study (MIND) demonstrated that haloperidol was safe as well as confirming the feasibility of a placebo-controlled trial of haloperidol for the management of delirium in mechanically ventilated patients.³²
2.4.4 Rationale for haloperidol to prevent delirium:

If antipsychotics work to help prevent/treat delirium, they could very well increase the number of patients who emerge from coma into a normal cognitive state rather than delirium. All mechanically ventilated patients experience coma at least transiently due to their disease and/or iatrogenically administered medications. Patients who experience coma and delirium have been shown to have even worse outcomes in terms of mortality than those who have delirium alone.¹⁶ If short term use of these agents is met with a good safety profile, and the patients who would never have developed delirium can be exposed to less of the other classes of drugs (benzodiazepines and narcotics), the investigation may show improved clinical outcomes both acutely and with respect to long-term cognitive impairment.

2.4.5 The intervention is simple and cheap:

Haloperidol is available in generic form and the intervention is cheap £1.20 per day.

2.4.6 Acceptable tolerability and side effects:

Haloperidol is generally considered to be a safe drug to be used in critically ill patients. It has limited respiratory depressant and haemodynamic effects, with variable but usually mild sedation. A randomised placebo-controlled trial pilot study (MIND) demonstrated that haloperidol was safe as well as confirming the feasibility of a placebo-controlled trial of haloperidol for the management of delirium in mechanically ventilated patients.³²

Hypotension – usually mild, can occur with haloperidol, arterial blood pressure monitoring is routine in ventilated ICU patients. If the blood pressure falls it will be treated with fluids and/or vasopressors. Other causes for a fall in blood pressure will be looked for and treated accordingly.

Extrapyramidal side effects (EPS) – parenteral haloperidol causes fewer EPS than enteral haloperidol. All study patients will be monitored by EPS using a modified Simpson-Angus scale.³³ EPS often is seen as twitching around the mouth and a fine tremor in the hands and is reversible unless the drug is continued for several weeks. It is treated by reducing or stopping haloperidol or benztropine if it persists.

Akathisia is a motor restlessness that may be confused with agitation. Akathisia will be monitored clinically.

QT interval prolongation – torsades de pointes has been reported with the use of haloperidol. This is a life threatening multiforme ventricular arrhythmia that frequently degenerates into ventricular fibrillation. All patients who receive haloperidol need an ECG in order to determine the corrected Q-T time, the QTc, normally 450 msecs or less. The patient’s QTc interval will be recorded daily on the case report form (CRF). Torsades de pointes usually develops after large doses of haloperidol; a patient who already has QTc prolongation is thought to be at higher risk.³⁴

Neuroleptic malignant syndrome is a rare and serious side effect of haloperidol. This idiosyncratic drug reaction is characterised by high temperature, muscle rigidity, metabolic acidosis and autonomic instability. All of these will be monitored in the ICU. The treatment is ICU support as necessary and it is self-limiting once the drug has been stopped.

2.4.7 Dosing regimen:

The dosing regimen is based on current clinical practice for managing ICU delirium amongst UK consultant intensivists as conducted by the Intensive Care Society in 2008. In the pilot feasibility study MIND patients in the haloperidol group received a median dose of 15.0 mg/day (interquartile range10.8-17.0 mg/day). While the majority of doses were given enterally, the bioavailability of haloperidol is 60%. This dosing schedule resulted in plasma haloperidol levels predicted to achieve effective D2 receptor antagonism for clinical effect.³⁵

2.4.8 Need for a trial:

Two research groups have demonstrated that duration of ICU delirium is associated with mortality up to one year after admission even after adjusting for important potential confounders. Each day of delirium in the ICU increases the hazard of mortality by 10%. In two studies the presence of delirium and severity, as measured by number of days of delirium, were independently associated with increased ICU days and hospital costs. It is not known if decreasing the duration of ICU delirium improves patient outcomes or decreases length of stay.

Routine screening for delirium in ICU patients is recommended in draft guidelines for delirium management by the National Institute for Clinical Excellence and from the Intensive Care Society. It has been demonstrated that the implementation of a screening tool for delirium in the ICU increases the number of patients who are given haloperidol. Local data has shown an increase in the amount of haloperidol used in Watford critical care unit since the introduction of routine CAM-ICU screening. It is to be expected that as clinicians recognise delirium in their patients that they will use more haloperidol. Those clinicians who do not treat delirium pharmacologically, the main reason is likely to be lack of high quality evidence to support the use of haloperidol.
2.5 Rationale for plasma -amyloid measurement

Plasma -amyloid measurement has emerged as a promising biomarker to identify elderly persons at risk of developing dementia.³⁶ Lower -amyloid 42 and 42/40 levels have been associated with increased risk of developing Alzheimer’s Disease. A recent study suggests that older adults without dementia and with lower -amyloid 42/40 levels have an increased rate of cognitive decline over 9 years compared with those with higher levels.³⁷ It may be that plasma -amyloid 42/40 levels may be a predictor of those patients who are most at risk of developing cognitive impairment following ICU delirium.

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