Clinical manifestations, outcome and management of delirium in critically ill patients

Department of Critical Care Medicine, Harrison International Peace Hospital, Hengshui, Hebei, China.
Chunmanze Wang, Critical Care Medicine, Wang Jinrong, Translation Group of Critical Care Travelers Abstract: Delirium is the most common clinical manifestation of brain dysfunction in critically ill patients
.

The duration of delirium is an independent factor predicting ICU survival rate, length of hospital stay, nursing cost, and acquired dementia
.

There are many hypotheses about its mechanism, such as neurotransmitter, functional or damaging causes, and there are different opinions
.

If effective evaluation methods are not used, delirium may be misdiagnosed (diagnostic evidence is insufficient, but it may also be overdiagnosed and ignored), so it should be routinely monitored
.

The most commonly used bedside screening methods for ICU are CAM-ICU and ICDSC, both of which can detect subclinical delirium
.

Although both tools have some limitations in patients with nerve injury, they can still provide important information even when the sequelae of the primary injury becomes a baseline problem for the new injury
.

It is well known that the current antipsychotic drugs and other neuroactive drugs cannot reliably improve the brain function of patients with critical delirium
.

The ICU team should comprehensively screen for susceptibility and predisposing factors, including circulatory/respiratory failure or sepsis, metabolic disorders caused by psychotropic drugs (hypoglycemia, hyponatremia, uremia and ammoniaemia), and long-term bed rest.
Sensory loss, uncorrectable vision and hearing impairment, poor sleep quality, and separation from relatives are common factors during the COVID-19 pandemic
.

The ABCDEF (A2F) clustering strategy can facilitate the implementation of the 2018 ICU (PADIS) guidelines
.

Among more than 25,000 patients in nearly 100 hospitals, the A2F clustering strategy showed dose-effect dependence characteristics (such as higher compliance, better results), which can improve survival rate, shorten hospital stay, shorten the duration of coma and delirium, Save treatment costs and reduce the number of ICU reentry
.

Knowledge points Delirium is a common problem in ICU.
If you do not use effective tools for screening, it is usually impossible to diagnose
.

It is an independent predictor of important outcomes, including increased medical costs, ICU time and hospital stay, mortality, and long-term cognitive impairment
.

Evidence shows that the best way to solve the problem is not a specific medicine, but the use of ABCDEF (A2F) clustered non-drug safety progressive measures
.

A2F focuses on managing the cause of delirium, reducing sedation/mechanical ventilation/braking, returning to the family, and humane monitoring measures
.

Preface and basic theory Delirium is a clinical manifestation that is generally ignored in ICU organ dysfunction
.

It is usually not monitored and is not mentioned in the medical record
.

The ICU team believes that it is incapable of delirium and is already treating the major disease, or that cognitive impairment after sedation seems to be normal
.

In addition, I feel that the patient "needs" sedation and is very ill and cannot get out of bed anyway
.

On the one hand, sedatives can ensure the normal progress of mechanical ventilation, but on the other hand, it can further aggravate delirium
.

In addition, critically ill patients may live in ICU wards with no windows or no direct view of the outside.
Disorientation in time and space occurs, which is often considered a normal state of sedation for several days and nights
.

These reasons cause people to be indifferent to this form of brain dysfunction, which leads to long-term pain after being transferred from the ICU.

.

Delirium increases the risk of death and burdens families and family members
.

Objectives In this narrative review, the aim is to summarize measures that can improve the diagnosis, prevention, and treatment of delirium
.

As ICU personnel, the daily management of critically ill patients must consider the importance of delirium prevention and treatment
.

As the patient's sensitivity increases and the complexity of care increases, it is necessary to find ways to avoid excessive sedation and prolonged immobilization in order to improve the quality of life of patients
.

Definition and Epidemiology According to the "Diagnostic and Statistical Manual of Mental Disorders DSM-5", delirium is defined as a cognitive impairment that occurs within a short period of time and cannot be explained by other reasons.
It is not an existing or developing cognitive impairment, and it should be recognized The cognitive disorder does not occur when the level of arousal is severely reduced; and evidence from medical history, physical examination, or laboratory examination cannot show that the disorder is caused by other causes such as drug poisoning or withdrawal
.

If the evidence for diagnosing delirium is insufficient, then the diagnosis of subclinical delirium is similar to that of delirium, but it is also important to differentiate from the following diagnoses, such as alcohol withdrawal syndrome, which manifests as hallucinations before the well-known “delirium tremor” appears.
And delusions; patients with mental illness who stopped using antipsychotics; hallucinations associated with opioid use; and sleep deprivation common in the ICU, often manifested as isolated hallucinations without cognitive impairment
.

Historical data found that 60-80% of mechanical ventilation in ICU and 20-50% of mild patients will have delirium
.

More and more people around the world use professional diagnostic tools, which have been translated into more than 30 languages ​​(see the translation on https://cibs.
webflow.
io/medical-professionals/downloads/resource-language-translations )
.

By adjusting the daily management of the ICU to reduce excessive sedation and immobilization, the prevalence of delirium in many ICUs has dropped by about 25%
.

According to reports, including a prospective study of 21 large research centers, the prevalence of delirium was 48%, and the data only included patients with mechanical ventilation and shock
.

In the past 15 years, this population has been evaluated using the same method, showing that the prevalence of delirium has been around 75%
.

ICU delirium can be manifested as excitement (restlessness and restlessness), depression (easy mood, apathy, lethargy, decreased response) or a mixture of the above two states, and the patient's state fluctuates between
.

Inhibitory delirium is the hardest to find.
Unless you use effective screening tools, you may miss the diagnosis because its manifestations are mistaken for fatigue or depression
.

Inhibitory delirium heralds more dangerous consequences
.

In addition, delirium is classified as a rapidly reversible type related to sedation, which is manifested as delirium that occurs when sedation is stopped within 2 hours during the spontaneous arousal test (SAT)
.

12% of 102 patients developed rapidly reversible delirium, and 75% of these patients had persistent delirium (delirium lasted more than 2 hours after sedation was interrupted)
.

Therefore, patients are continuously evaluated two days before and after the SAT to better evaluate the mental state
.

If delirium persists after SAT, or SAT cannot be performed for some reason, screening and analysis of all causes of delirium (except for analgesia and sedation) should be performed
.

In two parallel studies of BRAIN-ICU and MIND-ICU, a multicenter, prospective cohort analysis was performed on adult medical and surgical ICU patients with respiratory failure and/or shock.
Month and 12th month, observe the relationship between the duration of delirium and the neuropsychological status score (RBANS).
The RBANS scale is a tool to assess the overall cognitive function of adults
.

The clinical phenotype of delirium is defined as delirium associated with hypoxia, sepsis, sedation, or metabolism (hepatic dysfunction of the kidneys)
.

Sedation-related delirium is the most common delirium phenotype, occurring in 2634 delirium days (63%) (Figure 1)
.

After adjusting for covariates, the longer the duration of sedation-related delirium, the worse the overall RBANS cognitive score after 12 months (the difference in score between 3 days and 0 days: -4.
03, 95% CI-7.
80 to-0.
26)
.

Hypoxic delirium (− 3.
76, 95% CI − 7.
16 to − 0.
37), septic delirium (− 3.
67, – 7.
13 to − 0.
22) and unclassified delirium (− 4.
70, − 7.
16 to-2.
25) duration The longer, the worse the cognitive function at 12 months
.

However, the duration of metabolic delirium does not predict cognitive function at 12 months (1.
14, −0.
12 to −3.
01)
.

"Diagnosing or excluding delirium: To diagnose any organ dysfunction, it is necessary to determine the status, severity and cause of this dysfunction
.
The
CAM-ICU or ICDSC tools are usually used to screen for delirium for brain dysfunction
.

But it is necessary to assess whether the patient is You can concentrate, such as falling asleep during the conversation or omitting the details of the conversation; then ask the patient to raise two fingers of one hand and repeat the action with the other hand
.

The inability to perform these simple tasks is characteristic of delirium, and the next step is to find out the cause of brain dysfunction
.

"2018 PADIS delirium screening guidelines recommend the use of CAM-ICU or ICDSC to ICU adult patients for routine delirium monitoring, this guide uses a rigorous assessment of psychological measurement
.

CAM-ICU originally at Vanderbilt University Medical Center (USA) Validated in 96 adult patients in internal medicine or coronary ICU
.

Intensive professional nurses conducted 471 evaluations and compared them with the evaluations conducted by experts using the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders
.

Compared with the diagnostic criteria for delirium, The sensitivity of CAM-ICU is 100% and 93%, the specificity is 98% and 100%, and its reliability is high (κ = 0.
96; 95% CI, 0.
92-0.
99)
.

CAM-ICU can be used in Complete the test within 1 minute, including patients with speech communication disorders.
The method has been modified and verified in pediatrics, emergency departments, and neuro-intensive care patients, and translated into more than 30 languages
.

CAM-ICU knows delirium and delirium during the test.
NO
.

should be assessed once, should be performed if possible, change awareness (such as sedation stops before and after) occurs at a time when every shift
.

CAM-2014 released an updated version of the ICU, the use strict and standard neuropsychological The scientific evaluation criteria were validated against the fifth edition of DSM-5
.

ICDSC was initially validated in 93 patients at Hôpital Maisonneuve-Rosemont in Montreal, Quebec, Canada
.

Compare psychiatric assessment with ICU physician assessment methods
.

The ROC curve was used to evaluate the sensitivity and specificity of ICDSC
.

The area under the ROC curve is 0.
9017; the predictive sensitivity of ICDSC is 99%, and the specificity is 64%
.

ICDSC is ideal for patients who are not good at communicating, including data obtained during routine bedside care throughout the care shift
.

Both CAM-ICU and ICDSC can identify patients with subdelirium syndrome (that is, there are some abnormal characteristics in the evaluation of delirium, but they do not meet all the criteria for the diagnosis of delirium)
.

A recent systematic review of ICU patients using CAM-ICU showed that the comprehensive sensitivity was 80% and the specificity was 96%, while the comprehensive sensitivity of ICDSC was 74% and the specificity was 82%
.

However, compared with researchers, bedside staff will be much less sensitive when implementing these two tools, which highlights the importance of training and learning
.

These two tools are widely used in all types of intensive care units (ie internal medicine, surgery, neurology and cardiology) around the world
.

Finally, a few tools can quantify the severity of delirium, which can increase mortality and the need for home care
.

Although it is mainly used in the ICU population, the delirium severity score has been used in clinical and outside ICU settings
.

The Delirium Rating Scale (DRS), CAM-S and CAM-ICU-7 are three tools to assess the severity of delirium
.

DRS is designed for research, while CAM-S can be used in general internal medicine and elective non-cardiac surgery
.

CAM-ICU-7 is adapted from CAM-ICU and has been verified in 518 adults in internal medicine, surgery and transitional ICU in three medical research centers
.

The patients received CAM-ICU and RASS assessments twice a day
.

The patients were evaluated using CAM-ICU and the revised version of the Delirium Rating Scale (DRS-R)-98
.

7 points out of 0-7 points are responses to CAM-ICU and RASS assessments
.

It is found that CAM-ICU-7 and DRS-R-98 have high internal compatibility (Cronbach's alpha = 0.
85) and good correlation (correlation coefficient = 0.
64)
.

After adjusting the auxiliary factors, it was found that CAM-ICU-7 had high predictive power for in-hospital mortality and low predictive power for discharge rate (OR = 0.
8; 95% CI = 0.
72–0.
9)
.

The increase in ICU hospital stay is also associated with a higher CAM-ICU-7 score (p = 0.
001), and further research on this tool is needed to determine whether the severity of delirium can be associated with long-term complications
.

In addition, the tool should be compared with other methods of measuring the severity of delirium, and it needs to be validated in various critically ill populations before it is used in the clinic
.

Delirium prediction model (PRE-DELIRIC), early delirium prediction model (E-PRE-DELIRIC) and Lanzhou model, these three models can help clinicians prevent or treat delirium
.

PRE-DELIRIC includes 10 predictive factors [age, APACHE II score, admission group (internal medicine, surgery, trauma, nervous system), emergency admission, infection, coma, sedation, morphine use, urea level and metabolic acidosis], E -PRE -DELIRIC includes 9 predictors [age, history of cognitive impairment, history of alcoholism, blood urea nitrogen, admission group (internal medicine, surgery, trauma, neurology), emergency admission, mean arterial pressure, use of corticosteroids, and breathing Failure], the Lanzhou model includes 11 predictors (age, APACHE II score, mechanical ventilation, emergency surgery, coma, multiple injuries, metabolic acidosis, history of hypertension, history of delirium, history of dementia, and use of dexmedetomidine)
.

A prospective observational study of 455 ICU patients validated these prediction models in routine clinical practice.
PRE-DELIRIC showed an area under the ROC curve of 0.
79 (95% CI, 0.
75-0.
83), and E-PRE-DELIRIC showed a curve.
The area under the curve is 0.
72 (95% CI, 0.
67-0.
77), and the area under the curve shown by the Lanzhou model is 0.
77 (95% CI, 0.
72-0.
81)
.

However, the results of these models are often untrue and limit the practical application of clinicians, especially for patients who live in ICU for more than 24 hours
.

It can be used to screen high-risk patients before delirium clinical trials and/or to compare the baseline characteristics of these patients
.

The role of magnetic resonance imaging (MRI) in the assessment and management of delirium is unclear
.

MRI may be able to provide diagnostic information for structural problems such as stroke or abscess to guide treatment
.

MRI can also provide prognostic information about long-term cognitive function
.

In elderly patients with postoperative delirium, diffusion imaging revealed structural abnormalities in the deep, white matter, and thalamus before surgery
.

White matter hyperintensity (WMH) and atrophy were seen in 6 of the 8 patients who underwent MRI
.

Young patients have a smaller WMH
.

Six patients underwent a 3-month neuropsychological follow-up, and the results showed that they all had memory, executive function, and attention deficits
.

MRI has no obvious effect in standard delirium treatment because MRI examinations increase the burden on the patient, use a lot of resources, and may produce motion artifacts
.

However, if delirium persists after dealing with all potential causes, MRI can be used to look for any brain damage that cannot be seen on CT of the head (small-scale ischemic stroke, hemorrhage, encephalitis, etc.
)
.

In contrast, MRI is an excellent method as a research tool for delirium
.

Electroencephalogram (EEG) is a potentially effective tool for assessing delirium
.

Inflammatory mediators cross the blood-brain barrier and increase vascular permeability leading to changes in EEG
.

A prospective cohort study of unintubated patients was evaluated for delirium using 3D-CAM within 1 hour after EEG examination
.

EEG found that widespread theta or delta wave slowing is most closely related to delirium (OR 10.
3, 95% CI 5.
3-20.
1)
.

The prevalence of delirium severity is related to the overall severity of delirium (R 2 = 0.
907) and each indicator of CAM individual characteristics
.

After adjusting for the presence or severity of delirium, slower EEG is associated with longer hospital stays, worse recovery of brain function, and increased mortality
.

However, a larger study is needed to confirm
.

EEG can also be used to rule out nonconvulsive seizures that may be related to delirium, especially in ICU patients with sepsis
.

ICU delirium and prognosis "Delirium is a manifestation of brain dysfunction: the longer the patient’s organ dysfunction, the greater the possibility of long-term and irreversible damage
.

Delirium can also be regarded as a sign of acute brain dysfunction
.

"Delirium in hospitalized patients is an important independent predictor of death, increased length of hospital stay, readmissions, long-term cognitive impairment, and increased cost of care
.

A prospective cohort study of 275 adult medicine and cardiology ICUs sought to determine the effect of delirium on mortality and length of stay
.

During ICU hospitalization, 183 (81.
7%) patients developed delirium
.

After adjusting for age, disease severity, comorbidities, coma, and use of sedatives or analgesics, delirium was associated with a higher 6-month mortality rate (adjusted hazard ratio [HR], 3.
2; 95% confidence interval [CI ], 1.
4 –7.
7; p = 0.
008), longer hospital stay (adjusted HR, 2.
0; 95% CI, 1.
4–3.
0; p <0.
001), longer hospital stay after ICU (adjusted HR, 1.
6; 95% CI, 1.
2–2.
3; p = 0.
009) independently correlated
.

Other studies have evaluated the true attributable risk of death from delirium, especially the different severity of the disease before the onset of delirium, proving that delirium and mortality are not accidentally related
.

The study found that there is a real risk of death from delirium in the ICU for more than 2 days
.

This research reveals the difference between association and causality
.

Causality requires the following criteria: strength of association, consistency, timeliness, biological gradient, rationality, and finally, experiments are needed to prove that the treatment of delirium can reduce mortality
.

In addition, a recent study evaluated the risk of death from delirium in 1495 critically ill adults.
Delirium events and days of delirium were not significantly associated with mortality, and days of coma, delirium, or coma were significantly associated with death
.

A retrospective cohort study of 6323 ICU patients evaluated the association between delirium subtypes and 90-day mortality after adjusting for covariates, and found that only mixed delirium was associated with 90-day mortality [1.
57 (95% CI: 1.
51) –2.
14)], and there is no significant correlation between hyperactivity, hypoactivity or rapidly reversible delirium
.

A large, multi-center, prospective observational cohort study (BRAIN-ICU study) reveals the risk factors and incidence of neuropsychological dysfunction in ICU survivors.
The study evaluated 821 patients with respiratory failure, cardiogenic or infectious Adult medical and surgical ICU patients in shock were studied to determine the prevalence of long-term cognitive impairment after severe illness
.

Three months after discharge, 26% of patients had RBANS scores similar to Alzheimer's disease, and 40% of patients had scores similar to moderate traumatic brain injury (Figure 2)
.

Both young and old patients, with or without comorbidities, have experienced these brain damages
.

These damages still existed at 12 months in 24% and 34%
.

A subgroup analysis of 402 patients who had undergone anesthesia surgery found that at 3 and 12 months, even during hospitalization or after adjusting for baseline covariates, the overall cognitive scores were similar to those of no surgery
.

Delirium was the strongest independent predictor of cognitive impairment in this cohort study
.

Delirium does not always occur before cognitive impairment.
So far, there has been no randomized clinical trial to prove that treatment of delirium can improve long-term cognitive impairment
.

The cost of treatment for delirium is also high
.

In the subgroup analysis of the BRAIN-ICU study, due to the high utilization of ICU delirium resources, the average cumulative 30-day treatment cost was US$17,838 (95% confidence interval, US$11,132-23,497)
.

If it were not for the early deaths associated with delirium in some patients to reduce the cost of care by US$4,654 (95% confidence interval, US$2056-7869), this cost would have been even higher
.

Assuming that 20% of elderly patients who are hospitalized each year develop delirium, the 1-year direct medical costs associated with delirium are estimated to be between 143 billion and 152 billion U.
S.
dollars
.

Prevention and management of ICU delirium "No drug can prevent delirium: no drug can prevent the brain dysfunction characterized by delirium
.
It
is necessary to actively monitor delirium and pay attention to the risk factors that may allow patients to develop delirium
.

" ICU delirium The hypothesis of drug prevention neurotransmitter has promoted the research of the efficacy of antipsychotic drugs on delirium
.

Haloperidol mainly acts by blocking dopamine.
Atypical antipsychotics block serotonin, dopamine, alpha-1 adrenergic receptors and histamine
.

Many studies have been conducted on this hypothesis and other central nervous receptors, but none of the studies have shown that neurotransmitters are significantly reduced in patients with delirium
.

Therefore, the PADIS guidelines recommend against the use of haloperidol, atypical antipsychotics, dexmedetomidine, statins, or ketamine to prevent delirium in all critically ill adult patients
.

The main studies supporting this proposal are described below
.

A double-blind placebo-controlled randomized trial (HOPE ICU) studied the effect of haloperidol in preventing delirium
.

If patients receive mechanical ventilation within 72 hours of admission, they are randomly given intravenous haloperidol 2.
5 mg or 0.
9% normal saline, every 8 hours
.

The number of days of survival for non-delirium and coma patients was similar in the two groups (median 5 days [IQR 0-10] and 6 days [0-11] days; p = 0.
53)
.

The prophylactic use of haloperidol in patients with high-risk delirium (REDUCE) is a randomized, double-blind, placebo-controlled study involving 1789 patients receiving prophylactic haloperidol 1 mg, haloperidol 2 mg or placebo treatment Of critically ill patients
.

The 1mg group was stopped early due to ineffectiveness
.

Compared with the placebo group, there was no difference in the median survival time of 28 days in the 2 mg group (95% CI, 0–0; p = 0.
93), and the HR was 1.
003 (95% CI, 0.
78) – 1.
30; p = 0.
82)
.

There was no statistical difference in the 15 secondary results among the three groups
.

These results include the incidence of delirium (mean difference 1.
5%; 95% CI, -3.
6% to 6.
7%), delirium-free and coma-free days (mean difference 0 days; 95% CI, 0-0 days) and mechanical ventilation time, ICU and length of hospital stay (mean difference is 0 days; 95% CI, all three indicators are 0-0 days)
.

There were no differences in adverse events between the groups
.

A randomized, double-blind, placebo-controlled study to observe the effect of risperidone on delirium after cardiac surgery
.

126 patients were randomized to receive 1 mg risperidone or placebo.
As a result, the incidence of postoperative delirium was lower in the risperidone group (11.
1% vs.
31.
7%, p = 0.
009, RR = 0.
35, 95% CI = 0.
16–0.
77 )
.

A randomized, double-blind, placebo-controlled trial was conducted in two tertiary hospitals in China.
700 elderly patients who were admitted to the ICU after non-cardiac surgery were randomly given right after entering the ICU on the day of surgery to 8 hours on the first day after surgery.
Medetomidine or placebo treatment
.

Compared with the placebo group (79 of 350 patients [23%]), the dexmedetomidine group (32 of 350 patients [9%]) significantly reduced the incidence of delirium at 7 days after surgery, ( 95% CI 0.
22–0.
54; p <0.
0001)
.

A multicenter, double-blind, placebo-controlled trial randomly assigned 100 critically ill patients without delirium to the night-time dexmedetomidine or placebo group
.

Compared with placebo [27 of 50 patients (54%)], there was a higher proportion of dexmedetomidine that did not develop delirium during ICU hospitalization (dexmedetomidine [40 of 50 patients ( 80%)]; RR is 0.
44; 95% CI, 0.
23–0.
82; p = 0.
006)
.

The authors of the PADIS guidelines believe that the incidence and duration of delirium, the duration of mechanical ventilation, the length of hospital stay in the ICU, and the mortality rate are the most critical outcomes
.

Although the incidence of delirium continues to decline, the PADIS Guidelines Committee believes that none of the other important clinical results in a study are statistically different
.

In addition, the severity of disease in surgical patients in many studies was lower than that of medical patients
.

Given that there is a strong correlation between delirium and disease severity, and many critically ill patients may develop delirium when they are admitted to the ICU, further research is needed to evaluate the preventive effects of delirium medications
.

Three cohort studies confirmed that there is an association between discontinuation of statins during critical illness and an increase in the incidence of delirium
.

In contrast, a randomized study of patients undergoing cardiac surgery found that preoperative use of atorvastatin did not reduce the incidence of delirium
.

Similarly, in a large randomized study, after a single dose of ketamine, the incidence of delirium in the elderly after major surgery did not decrease
.

However, a randomized double-blind controlled study in 162 patients (26% surgery) used ketamine and placebo to reduce the dose of remifentanil used for analgesia and sedation (primary outcome).
The results showed that the ketamine group The incidence and duration of delirium were significantly reduced, but there were no other differences in patient outcomes, which is worthy of further study
.

Drug treatment of ICU delirium "There is no drug that can treat delirium: no drug can treat delirium
.

However, clinicians need to pay attention to delirium susceptibility factors and non-drug strategies
.
In
some cases, drugs may be needed to control patients with delirium.
You must be aware that it is not a treatment for delirium
.

” Similar to the ICU delirium prevention data, no large-scale trial has shown that any drug can treat ICU delirium.
Therefore, the PADIS guidelines recommend against the routine use of haloperidol, non-classical antipsychotics, or Statins treat delirium
.

The guidelines do emphasize that in some cases, these drugs may be needed to manage hyperactive behaviors or stress symptoms (anxiety, hallucinations, delusions, fear, etc.
) in patients with delirium, but it must be realized that this is not a treatment
.

If antipsychotics are chosen in these situations, the smallest dose and the shortest duration should be used
.

It is also important to pay attention to the limitations of the concept in real life.
It is very challenging to distinguish between delirium prevention and delirium treatment
.

The MIND study is a randomized, double-blind, placebo-controlled trial in 101 ICU patients receiving mechanical ventilation with haloperidol, ziprasidone, or placebo every 6 hours for up to 14 days
.

Results The survival time of the three groups without delirium or coma was similar (14 days, 15 [9.
1-18] days, 12.
5 [1.
2-17.
2])
.

The MIND USA study is a multicenter, randomized, placebo-controlled study involving 566 patients with acute respiratory failure or shock, comparing haloperidol, ziprasidone, and placebo in the treatment of delirium
.

The median survival days after correction for delirium or coma in the placebo group was 8.
5 days (95% CI, 5.
6–9.
9), compared with 7.
9 (95% CI, 4.
4–9.
6) in the haloperidol group and ziprasidone 8.
7 days (95% CI), 5.
9–10.
0), p = 0.
26
.

In this study, 60% of patients had hypoactive delirium at some point in the study, and 40% of patients had hyperactive delirium
.

Compared with placebo, there were no differences between the two groups in terms of mechanical ventilation time, ICU or hospital stay, days of reentry to the ICU, 30-day death or 90-day death
.

The incidence of arrhythmia, Parkinson's syndrome (extrapyramidal symptoms), antipsychotic malignant syndrome, study drug withdrawal, and other safety issues were extremely low in all three groups
.

However, in a European multinational cohort study (AID-ICU study) by Collet et al.
, which included 1,260 patients from 99 ICUs in 13 countries, the study showed that haloperidol was the most common intervention for subtype delirium
.

In this study, patients received haloperidol 24 hours after admission to the ICU [aOR 1.
2 (0.
5–2.
5); p = 0.
66] and within 72 hours after admission to the ICU [aOR 1.
9 (1.
0–3.
9); p = 0.
07], It has nothing to do with the increase in mortality at 90 days, but after 72 hours of admission to the ICU, the use of haloperidol is related to the need for circulatory support [aOR 2.
6 (1.
1-6.
9)]
.

Antipsychotics are still feasible in the short-term control of severe agitation in patients to prevent patients from removing ICU equipment on their own, falling or aggressive behavior towards ICU team members, and dangerous diseases that need to avoid respiratory depression (such as heart failure, COPD, or asthma).
Or have characteristic symptoms of delirium such as hallucinations or delusions
.

If antipsychotics are used, a low starting dose should be considered, and daily review of drug interactions, adverse reactions, dose titrations, and antipsychotics needs should be carried out
.

In addition to antipsychotics, other drugs for the treatment of delirium have also been studied, such as statins and dexmedetomidine
.

In a randomized, double-blind placebo-controlled trial involving 142 patients, patients in the high-dose simvastatin (80 mg per day) group without delirium and coma did not increase their 14-day survival time (mean difference 0.
4 days, 95% CI-1.
3 –2.
1; p = 0.
66), 5.
7 days (SD 5.
1) in the simvastatin group, 6.
1 days (5.
2) in the placebo group
.

Although the PADIS guidelines do not recommend the use of statins for patients with delirium, dexmedetomidine is recommended because agitation prevents extubation or discontinuation of the ventilator
.

The Dexmedetomidine Reduction ICU Restlessness (DAHLIA) study is a double-blind placebo-controlled trial conducted in 15 ICUs in Australia and New Zealand.
Of these, 39 patients were randomized to receive dexmedetomidine and 32 received a placebo
.

Compared with placebo, the use of dexmedetomidine for 7 days was associated with a slight increase in offline time (median, 144.
8 hours vs.
127.
5 hours, 95% CI 4–33.
2 hours, p = 0.
01)
.

Dexmedetomidine does not affect the length of stay in the ICU or the length of hospital stay and discharge plan
.

Patients usually do not receive opioid therapy, and there are no reports of withdrawal
.

Future research needs to evaluate the role of dexmedetomidine in intubated patients with suppressive or agitated delirium, as well as in patients without intubation
.

Future studies evaluating drug treatments for delirium need to focus on long-term cognitive and functional outcomes
.

In addition, drugs such as valproic acid are only included in small studies, which require further detailed evaluation in prospective randomized trials
.

Non-drug prevention and management Although no drugs have been shown to have a significant effect on delirium, non-drug treatment clustering strategies have become an important part of ICU management
.

When considering different causes of delirium, please remember the mnemonic DR.
DRE, which is Disease Remediation, Drug Removal (screening for drug-related delirium and withdrawal syndrome) and environment Factors (Environment) composition
.

This helps to find the most common risk factors, and may be particularly useful for communication with the entire treatment team (medical, nursing, physical therapy, pharmacy)
.

However, the use of mnemonics depends on ICU culture and clinician preferences, and should not replace exhaustive screening for all common causes of delirium (such as urinary retention, hypoglycemia, slow bowel movement)
.

Light therapy, family involvement care, and psychological counseling are three independent interventions evaluated by the ICU
.

Three studies evaluated the effect of bright light therapy, but did not find a reduction in delirium time or ICU stay
.

Therefore, the PADIS guidelines propose conditions against its use
.

The PADIS guidelines recommend the use of multiple interventions such as redirection, cognitive stimulation, use of the clock, sleep enhancement, increased arousal, early activity, and the use of hearing aids and glasses when needed
.

Multiple combinations have been shown to improve outcomes in critically ill adult patients, including reductions in delirium, ICU stays, and hospital mortality
.

An example of a combination strategy is the A2F combination (A, assessment, prevention and control of pain; B, spontaneous arousal and spontaneous breathing test; C, choice of analgesia and sedation; D, assessment, prevention and management of delirium; E, early activity And exercise; F, family participation)
.

This easy-to-remember combination has 6 steps and aims to make it easier to perform clinically
.

In a single-center study, a multi-hospital/single-regional system study, and a large national collaborative study, the combination has been shown to improve a range of patient outcomes
.

However, it is worth noting that all the trials discussed below are non-randomized and no controlled trials were conducted at the same time
.

Although it is widely regarded as effective, there is currently no randomized controlled trial to prove the benefits of the A2F combination.
Randomized controlled trials are the gold standard for proving therapeutic effects
.

A prospective cohort quality improvement study of ventilated and non-ventilated patients was conducted in 6,064 patients in 7 community hospitals
.

For every 10% increase in compliance with the entire A2F combination, the hospital survival rate increased by 7% (OR1.
07; 95% CI, 1.
04–1.
11; p <0.
001)
.

For every 10% increase in compliance with some measures of the A2F combination, the hospital survival rate will increase by 15% (odds ratio, 1.
15; 95% CI, 1.
09–1.
22; p <0.
001)
.

Compliance with the entire combination (relative incidence index, 1.
02; 95% CI, 1.
01–1.
04; p = 0.
004) and partial combinations (relative incidence index, 1.
15; 95% CI, 1.
09–1.
22; p <0.
001 ), the patient will survive longer, and there will be more days without delirium and coma
.

In a 20-month experimental period, in a prospective, multi-center, quality improvement collaborative study from 68 colleges, communities, and federal ICUs, the effect of a complete A2F strategy and death within 7 days (HR 0.
32; CI, 0.
17 – 0.
62) , The next day received mechanical ventilation (OR 0.
28; CI, 0.
22–0.
36), coma (OR 0.
35; CI, 0.
22–0.
56), delirium (OR 0.
60; CI, 0.
49–0.
72), physical restraint (OR 0.
37); CI, 0.
30–0.
46), re-entry to the ICU (OR 0.
54; CI, 0.
37–0.
79), and discharge to institutions other than home (OR 0.
64; CI.
0.
510.
80) were less relevant
.

There is a dose-response relationship between compliance with the A2F combination and the improvement of each clinical outcome (p <0.
002)
.

As compliance increased, pain became more common (p = 0.
0001), probably because more patients were awake
.

The two papers released by the research team members implemented the A2F combination
.

Finally, a prospective cohort study was conducted on 1855 mechanically ventilated patients to evaluate the effect of the phased implementation of the A2F combination
.

After adjusting the patient level covariates, the implementation of all combination strategies and some combination strategies can shorten the duration of mechanical ventilation (- 22.
3%; 95% CI,-22.
5% to-22.
0%; p <0.
001), ICU hospital stay (- 10.
3) %; 95% CI,-15.
6% to − 4.
7%; p = 0.
028) and length of stay (− 7.
8%; 95% CI, − 8.
7% to − 6.
9%; p = 0.
006)
.

ICU costs and hospitalization costs were also reduced by 24.
2% (95% CI, -41.
4% to -2.
0%; p = 0.
03) and 30.
2% (95% CI, -46.
1% to -9.
5%; p = 0.
007)
.

However, Bannon et al.
's recent meta-analysis of randomized controlled trials showed the exact opposite
.

The authors identified 15 trials (2812 participants) that focused on analyzing the effectiveness of non-pharmacological interventions and standard care in reducing the incidence and duration of ICU delirium.
The results indicate that the current evidence is too weak to support the use of non-pharmacological interventions (Mainly a single intervention) Reduce the incidence and duration of delirium in critically ill patients
.

However, in order to support the importance of the F (family) element in the A2F combination, trials using home sound relocation have shown beneficial effects [n = 30, MD (day)-1.
30, 99% CI-2.
41 to-0.
19, p = 0.
003]
.

The recently determined goals to be achieved in future delirium research and care in the ICU should include all the above-mentioned non-pharmacological interventions and practices, including the A2F combination
.

It should be noted that the "A" element of the A2F combination stands for assessment, prevention and treatment of pain
.

Untreated pain can make patients prone to delirium
.

However, the use of opioids can also cause delirium
.

This highlights the importance of using evidence-based medicine tools (such as digital rating scales, intensive care pain observation tools, or behavioral pain scales) to diagnose pain in critically ill patients
.

In addition, it should be noted that the "C" element of the A2F combination represents the choice of sedation, and we must always be vigilant to ensure that patients use the lowest effective dose of sedatives
.

The PADIS guidelines recommend propofol or dexmedetomidine to replace benzodiazepines for sedation in severely ventilated adults
.

These recommendations are based on observational studies of increased risk of delirium when receiving benzodiazepines, and comparative studies of propofol or dexmedetomidine with benzodiazepines, each of which shows benzodiazepines The drug-like group had worse results
.

In three randomized trials involving a total of 850 patients, comparing dexmedetomidine and propofol, no significant differences were found in extubation time or other important secondary outcomes
.

SPICE III is an open-label, randomized controlled trial conducted after the publication of the PADIS guidelines, comparing dexmedetomidine as the main sedative with conventional treatment (propofol, midazolam or other sedatives) for mechanical Patients who took medication within 12 hours of ventilation and are expected to continue mechanical ventilation for at least another day
.

The target RASS is − 2 to + 1
.

The total number of participants in the trial was 1956.
At 90 days, there were 569 deaths (29.
1%) in the routine group and 566 (29.
1%) deaths in the dexmedetomidine group (adjusted risk difference, 0.
0 percentage point; 95% CI-2.
9 to 2.
8)
.

In the first 2 days after randomization, 64% of patients in the dexmedetomidine group received propofol, 3% received midazolam, and 7% received both treatments
.

It is worth noting that 60% of patients in the dexmedetomidine group received propofol, 12% received midazolam, and 20% received both
.

In view of the use of multiple sedatives in both groups, the conclusions of this study are difficult to adopt
.

In the dexmedetomidine group, 5.
1% and 2.
7% of patients had bradycardia and hypotension, respectively
.

Compared with the conventional treatment group, the median time without coma or delirium in the dexmedetomidine group increased by 1 day [24 (11-26) vs.
23 (10-26) ], and the adjusted risk difference was 1 (95% CI 0.
5 –1.
5)
.

Maximizing the sedative effect of patients with sepsis and acute respiratory failure, reducing neurological dysfunction and mortality (MENDS 2) is a multi-center, double-blind, randomized controlled trial, with 432 patients randomly receiving dexmedetomidine or Propofol, observe for 14 days or until extubation
.

The number of days of survival without delirium or coma (OR 0.
96; 95% CI, 0.
74–1.
26), days without mechanical ventilation (OR, 0.
98; 95% CI, 0.
63 –1.
51), or 90-day mortality rate (HR, 1.
06; 95% CI, 0.
74–1.
52) there was no difference
.

Finally, the entire A2F portfolio is dedicated to reducing the use of sedatives
.

In this way, non-pharmacological preventive measures may completely avoid sedation interventions in non-essential situations
.

A randomized controlled trial of 137 patients admitted to the ICU after peritonitis and septic shock.
The sedation was stopped immediately after the operation.
Compared with the moderate sedation (RASS -3) lasting one and a half days after the operation, the incidence of delirium in the former ( 72% vs.
43%;-29 (- 50 to-14)%, p <0.
001) and the duration of delirium was significantly reduced [2 (0–4) days vs.
0 (0–2) days; − 0.
5 (− 1.
0–0.
0) days, p = 0.
003]
.

In view of the new coronavirus pneumonia pandemic, the best sedation strategy and ICU delirium prevention for patients with severe respiratory failure and adult ARDS mechanically ventilated have become particularly important
.

The recently published COVID-D study included 2,088 COVID-19-positive ICU patients in 69 regions and 14 countries/regions, and reported that 81% of patients were unconscious for a median time of 10 days [IQR 6-15], 55% The median time of delirium in patients is 3 days [IQR 2-6]
.

Deep sedation and prolonged sedative infusion during mechanical ventilation are common.
64% of people received benzodiazepines for 7 days and 71% received propofol for 7 days.
The median RASS was − 4 [− 5 to − 3]
.

Benzodiazepines are associated with an increased risk of delirium, and a decrease in the number of days of survival without delirium or coma
.

In addition, having family or friends visits (face-to-face or virtual) is associated with a reduced risk of delirium
.

These data support the management goals behind the A2F combination in each clinical and epidemiological situation of the ICU: use fewer sedatives, avoid the use of benzodiazepines, and involve family, friends, and caregivers in providing targeted humanistic care , Even for ARDS patients, including COVID-19 patients
.

Recently, an expert group recommends A2F clustering strategy for these patients, and proposes an update to add an R (A2F-R combination) for controlling respiratory drive
.

From the A2F perspective, in order to reduce the risk of sedatives and cognitive dysfunction, non-pharmacological interventions are preferred.
For mechanically ventilated patients, priority is given to optimizing ventilator settings and prefers comfortable ventilation modes, allowing the use of opioids and sedatives to be reduced , As well as the screening and management of factors related to the patient’s high respiratory demand (metabolic acidosis, fever, stress conditions such as pain, anxiety, dyspnea)
.

This strategy will benefit the prognosis of patients and reduce the use of analgesics, sedatives, and neuromuscular blockers, which are critical during epidemics and periods of high ICU resource demand
.

Figure 3 is a way to guide clinicians to assess the sudden changes in the patient's mental state
.

Future development direction Knowledge gap and research agenda in the next 10 years 1.
Validate and develop objective tools for diagnosing delirium, such as EEG or computer-based applications
.

2.
Grasp the pathophysiology of delirium and its relationship with long-term cognitive impairment
.

3.
Develop a new phenotypic model of delirium
.

4.
In addition to inference, it is also necessary to understand the connection between delirium and outcome
.

5.
Learn more about delirium biomarkers and their practical applications in predictive models
.

6.
Carry out large-scale randomized clinical trials in critically ill patients to evaluate the effects of sleep optimization, cognitive/physical training, alternative safety practices and family participation/non-pharmacological interventions on delirium and long-term outcomes
.

Future directions include the evaluation of diagnostic tools (electroencephalogram, cerebrospinal fluid, and imaging studies (MRI)), and the application of predictive models in different groups
.

In addition, it is necessary to evaluate the effect of antipsychotics on hallucinations and delusional symptoms in ICU patients with delirium
.

Finally, a larger-scale randomized study is needed to evaluate the effects and impact of non-pharmacological prevention and treatment of delirium, including clinically significant long-term outcomes
.

Conclusion Delirium is an acute organ dysfunction that can independently predict mortality and various morbidities, including increased length of stay in ICU and total length of stay, cognitive dysfunction, and medical expenses
.

A variety of tools have been shown to be useful for the diagnosis of delirium in the ICU
.

CAM-ICU and ICDSC are the two tools recommended by the PADIS guidelines
.

Antipsychotics, dexmedetomidine, statins, and ketamine are not recommended to prevent delirium
.

Antipsychotics are also not recommended for the treatment of delirium
.

However, antipsychotics can be used to control severe agitation or stress symptoms (anxiety, hallucinations, delusions, fear) in the short term
.

Non-pharmacological measures including A2F combination are the main means of preventing or treating delirium, including the suggestion to increase "R" to emphasize the effect of better management of respiratory drive and ventilator settings on ARDS and all mechanically ventilated patients
.

Diagnostic tools, the impact of antipsychotic drugs on hallucinations and delusions, non-drug prevention and treatment of delirium, and the association with long-term outcomes are the primary research issues to be tackled in the field of delirium in the ICU
.

-END-Please long press the picture below to identify the QR code and pay attention to dopamine.
Read more wonderful articles "The patient I miss the most has passed away" "After three rescues, I regret the original efforts!" "The teacher's grave has grown grass 》I used a stethoscope to measure the lives of those who met in peace one after another, and the lives that passed away in my hands explained the meaning of life to me with the tears piled up in the corners of my eyes.

.

I am the last dopamine, recording sounds from the real world
.

Some pictures are from the Internet.
If there is any infringement, please contact the back office in time
.

Picture: source network copyright, cooperation WeChat: dba0604 Contribution email: last-dopamine@foxmail.
com