|Year : 2017 | Volume
| Issue : 20 | Page : 2498-2502
Delirium in Intensive Care Unit Patients: Ten Important Points of Understanding
Xiao-Ting Wang1, Lin Lyu2, Bo Tang1, Cui Wang3, Da-Wei Liu1
1 Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
2 Department of Neurology, Baotou Central Hospital, Baotou, Inner Mongolia 014040, China
3 Department of Critical Care Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550001, China
|Date of Submission||09-May-2017|
|Date of Web Publication||10-Oct-2017|
Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730
Source of Support: None, Conflict of Interest: None
Keywords: Analgesia; Assessment; Delirium; Intensive Care Unit Management; Sedation
|How to cite this article:|
Wang XT, Lyu L, Tang B, Wang C, Liu DW. Delirium in Intensive Care Unit Patients: Ten Important Points of Understanding. Chin Med J 2017;130:2498-502
|How to cite this URL:|
Wang XT, Lyu L, Tang B, Wang C, Liu DW. Delirium in Intensive Care Unit Patients: Ten Important Points of Understanding. Chin Med J [serial online] 2017 [cited 2018 Jun 22];130:2498-502. Available from: http://www.cmj.org/text.asp?2017/130/20/2498/216405
Xiao-Ting Wang and Lin Lyu contributed equally to this study.
| Introduction|| |
Delirium is a significant independent indicator of poor prognoses for critically ill patients (including in-hospital mortality, prolonged hospitalization, increased medical costs, and long-term cognitive impairment). Intensive care medicine experts have been paying attention to and carried out research on delirium for better prediction, prevention, management, and treatment, and even better prognosis of patients in critical condition. Based on the latest findings of theoretical research and in combination with clinical experience, literature on delirium has been reviewed and ten points of basic understanding of delirium in critically ill patients have been identified.
| Delirium Is at the Core of Pain, Agitation, and Delirium Triangle|| |
Clinically, critical patients often experience severe pain, agitation, and delirium (PAD). Agitation is what the three symptoms share in common, with delirium as the most common cause of agitation.,,,,,,, Untreated pain and inadequate analgesia are strong risk factors of delirium in Intensive Care Unit (ICU) patients. Most of the aggressive behaviors are caused by extreme agitation in patients with acute brain dysfunction. Patients with more discomfort due to pain and anxiety might get more medical intervention and evaluation, which increases sleep disturbance or stress response, and may induce delirium. Delirium, in turn, can lead to more acute feelings of pain and agitation.
| Delirium Is Essentially a Disorder of Consciousness|| |
The level of consciousness depends on the level of sanity. People's mental activity, which senses environment, determines the content of consciousness. Delirium is essentially a disorder of consciousness. To be specific, it is a disorder of perception (content of consciousness) of internal and external environments as a result of change in the clarity (level) of consciousness. It is a syndrome characterized by acute brain dysfunction. The level of consciousness in delirium varies and the content of consciousness is disorganized. The main features of delirium include changes in consciousness with decreased ability to concentrate, maintain or divert attention; fluctuation in many cases; frequent cognitive impairment that cannot be explained in terms of dementia; and physical illness, substance intoxication, and withdrawal or side effects of medication were clearly indicated as the causes of delirium by some case histories, physical examinations, and laboratory data. Delirium is often characterized by impaired attention.
| Delirium Is a Pathological State in Addition to an Abnormal Mental State|| |
The pathophysiological mechanism of delirium includes impaired acetylcholine synthesis, impaired cholinergic synapses, elevated level of dopamine, and decreased levels of norepinephrine, 5-hydroxytryptamine, and γ-aminobutyric acid.,,, “There is a research has confirmed that surgical trauma, infection and other external factors will make vascular endothelial cell activation, destruction of blood-brain barrier, so that inflammatory factors easily through the blood-brain barrier, stimulate astrocytes and microglia cells to activate, Further release of proinflammatory factors, resulting in neurotoxicity and delirium. And another study confirms that vascular endothelial cell activation increases blood-brain barrier permeability and reduces cerebral blood flow can lead to brain perfusion abnormalities and brain dysfunction leading to delirium. In addition to the changes in neurotransmitters, Koponen et al. have found via imaging that brain structure of delirium patients underwent pathological changes such as ventricular enlargement and brain parenchymal atrophy. Furthermore, Suchyta et al. reported that 64% of critically ill patients underwent head CT examination due to abnormal changes in cognitive function and consciousness, persistent delirium, and other reasons was presented with abnormal imaging performance including brain atrophy, ventricular enlargement, white matter lesions, and cortical or subcortical lesions. Such changes are likely to be the pathological causes of long-term cognitive impairment in critically ill patients who survived, especially those experienced delirium in ICU. In addition, a new study shows that the right hemisphere subcortical white matter and hippocampus injury is a risk factor of delirium symptoms. Basically, the causes of delirium are disruption of the central nervous system's polysynaptic pathways and changes in the balance between excitatory and inhibitory amino acids. Therefore, delirium is indeed a “disease” with clearly defined pathophysiological mechanism. ICU delirium should not be regarded as a psychological need to meet, but should be treated as a disease.
| Reviewing Delirium from the Perspective of the Complex Relationship between Delirium and Different Drugs|| |
According to recent meta-analyses and studies, the relationship between delirium and sedative drugs is not clear; the occurrence of delirium during the period of sepsis is associated with the inflammatory mediators of infection and is not clearly related to the use of benzodiazepines., To understand delirium, we must understand the following concepts clearly.
It refers to the state of restlessness or excitement that happens during the recovery period after anesthesia. This kind of delirium, which does not last long and is seen in different age groups, especially young people and children, can be treated by means of sedation, analgesia, and other measures. The type of anesthetic during the operation, be in general or regional, does not seem to affect the risk of delirium., However, the incidence rate of postoperative delirium after light sedation is about 50% lower than that of deep sedation (19% vs. 40%). The rate of postoperative delirium is high in patients with deep sedation whose electroencephalogram indicated intraoperative burst suppression or those who experienced intraoperative blood pressure fluctuation/arrhythmia.
It refers to the discomfort and agitated state patients experience within 2 h after the withdrawal of continuous sedation. With the metabolism of drugs, such symptoms can be gradually relieved; otherwise, sedative treatment has to be restarted.,,,
Drug withdrawal-induced delirium
It refers to a series of withdrawal symptoms known as withdrawal syndrome caused by sudden withdrawal of illicit or prescription drugs, sedative drugs and opioids used in conventional treatment in ICU, or alcohol in patients who have developed tolerance to and physical and psychological dependence on the drugs or alcohol over long-term use. Delirium occurred in ICU patients due to drug or alcohol withdrawal usually falls into the category of hyperactive delirium.,
Critical-associated delirium or persistent delirium
It refers to delirium that lasts for more than a week, and that is often closely related to sepsis, acute respiratory distress syndrome, or complex operations such as cardiac surgery, hip fracture repair, or aortic surgery.,,,,, If delirium persists, special attention should be paid to the possible risks of deterioration such as latent infection.,, Most critical-associated delirium is reversible, so immediate identification and treatment is very important.,,,,,, Dexmedetomidine (DEX) produced a sedative state in patients similar to normal sleep from which they could be “waken up” through the activation of the locus coeruleus alpha-2 adrenergic receptors and spinal alpha-2 adrenergic receptors. It can accelerates resolution of delirium. Drug-induced delirium is an adverse drug effect caused by administration of various drugs that affect neural cell metabolism in different ways without distinguishing the internal mechanisms of different states of consciousness of patients with severe systemic inflammatory response and cerebral cortex peripheral circulation reperfusion injury.
Assessment of Delirium Requires Confusion Assessment Method for the Intensive Care Unit Combined With Intensive Care Delirium Screening Checklist, the Richmond Agitation-Sedation Scale Score Is the Basis, and Disturbance in Attention Is a Common Prerequisite
Confusion Assessment Method for the ICU (CAM-ICU), a measurement scale of delirium, and Intensive Care Delirium Screening Checklist (ICDSC), are fast, simple, and effective instruments for bedside assessment of delirium. Both CAM-ICU and ICDSC can identify new or persistent delirium, but cannot quantify the severity of delirium. When the result of CAM-ICU is negative, delirium assessment requires CAM-ICU combined with ICDSC. If patients score one to three points according to ICDSC, they are diagnosed with subclinical delirium.,, If the score is four points or more, the patients are diagnosed with delirium.
Prerequisites for the diagnosis of delirium include changes in the score of Richmond Agitation-Sedation Scale (RASS) and impairment of attention. In other words, RASS score is the basis of delirium assessment.
| The Best Treatment of Delirium Is Prevention, Early Mobilization Is the Most Important Measure|| |
Early mobilization has been proved beneficial for critically ill patients according to a lot of research findings in the recent years.,, In addition to the daily interruption of sedation treatment, early mobilization in combination with professional treatment that begins within 72 h since the start of mechanical ventilation can improve the prognosis of the disease., Early mobilization is the only nondrug intervention recommended for the prevention of delirium in terms of PAD.
Early mobilization includes daily exercise programs tailored for individual patients, beginning with passive range of motion for unconscious patients, followed by active range of motion, bed activities, sitting up and moving on bed, and eventually walking.,, Although ICU patients can significantly benefit from the early mobilization, the actual daily practice of diagnosis and treatment varies greatly at different medical centers and under different clinical circumstances, and a lot of obstacles hinder the development of such training.,
| Attention Should Be Paid to the Relationship between Severe Sleep Deprivation and Delirium in Critically Ill Patients, as Sedation Does not Mean Sleep|| |
In the process of awakening and sleep, consciousness is transformed into perception, orientation, attention, memory, and emotion.,, Patients in ICU are prone to sleep deprivation. Sleep deprivation can cause cognitive impairment, depression, or agitation, thereby causing delirium.,, Functional neuroimaging examination showed that, after sleep deprivation, brain activity decreases at the frontoparietal attention network (in the prefrontal cortex and the intraparietal sulcus) and at the prominence network (in the insular and medial frontal cortex). Hence, nondrug measures that can be taken to improve sleep quality and avoid stimulation to the sleep cycle of patients include lighting and noise control; avoidance of routine nursing activities and advocacy of gentle movements of nursing activities during patients' sleep; and use of eye shades and earplugs, all of which improve sleep environment and can effectively prevent delirium.
Although sedative drugs can put patients into sedative state and play the role of hypnosis, almost all the sedative drugs shorten the period of rapid eye movement, and the vast majority of sedatives and opioids shorten the period of N3., Therefore, sedation does not mean sleep. The key to sleep in a sedative state is to create a favorable sleep environment, put patients into a process that is close to the physiological process of sleep, which then leads to high-quality sleep and prevention of delirium.
| Dexmedetomidine Is Used to Shorten the Duration of Delirium, and Antipsychotic Drugs Should Be Used With Caution|| |
Application of dexmedetomidine can improve the prognosis of delirium patients with mechanical ventilation. It can shorten the duration of delirium in patients with agitated delirium when used in combination with analgesics., Use of antipsychotic drugs in patients with no mental disorders is not recommended. All antipsychotic drugs will lead to prolonged QT interval, and therefore they should be used with caution in patients who already have prolonged QT intervals., The use of haloperidol and atypical antipsychotics should be prohibited in patients with high risks of Torsades de pointes ventricular tachycardia.,,, Benzodiazepines play a limited role in the treatment of delirium and are mainly indicated for cases associated with withdrawal of sedative drugs and alcohol and those contraindicated for the use of antipsychotic medications.
| Ipad Is the Management of Pain, Agitation, and Delirium, Pain Management Is the Basis of Pain, Agitation, and Delirium Management, and Delirium Management Is at the Core of Pain, Agitation, and Delirium Management|| |
Pain management is the foundation of PAD management. Severe pain itself can aggravate stress response, cause sleep deprivation, disorientation, agitation, and even delirium and posttraumatic brain dysfunction. Research shows that full and effective analgesia can reduce the need and dosage of sedative drugs, and analgesia combined with sedation is more conducive to the hemodynamic stability of patients so as to reduce the occurrence of delirium.
ICU PAD management is one of the basic measures that can definitely improve the prognosis of patients. The primary goals of PAD management for ICU patients include constant attention to patients' safety and comfort and prevention of short- and long-term complications caused by excessive or inadequate treatment. The combination of routine assessment of pain and sedation, pain management, and sedation minimization, and monitoring and prevention of delirium is probably the best solution in ICU to avoid excessive sedation. Such PAD standard practice can also facilitate the communication between ICU health-care providers to develop the most appropriate sedation and analgesia plan for patients. Early identification of delirium contributes to the identification of reversible factors, which prompts medical professionals to give effective treatment of delirium.
| The Comprehensive Management Strategy “abcdef” Is the Trend in Prevention and Treatment of Delirium|| |
The ABCDEF bundle refers to A for Assess, Prevent, and Manage Pain: prevention of agitation and delirium by adjusting the type and dose of analgesic drugs based on the assessment of patients' pain levels; B for Both Spontaneous Awakening Trials and Spontaneous Breathing Trials: daily interruption of sedative and analgesic infusions until the patient is awake and can follow instructions, or until the patient feels uncomfortable or agitated, and it is believed that the sedation therapy should be restarted; C for Choice of Analgesia and Sedation: light sedation does not mean inadequate sedation, deep sedation does not mean excessive sedation, sedation assessment means assessment of agitation and sedation, goal-directed sedation and analgesia based on sedation can reduce the severity and duration of delirium, and prevent delirium; D for Delirium: Assess, Prevent, and Manage: daily delirium assessment and constant monitoring of delirium when RASS scores fluctuate is an important measure for the management of delirium; E for Early Mobility and Exercise; and F for Family Engagement and Empowerment: both E and F can promote the recovery of patients and prevent delirium and shorten its duration.
The ABCDEF bundle for delirium management originated from PAD, but is better than PAD. It has been recommended by the US Society of Critical Care Medicine for extensive research and application. Recently, eCASH program was initiated in Europe, which is similar to the ABCDEF bundle, to prevent delirium and related side effects as an important part of the management of critically ill patients.
Combined with the European and American bundles and the actual situation in China, we put forward the “ESCAPE” bundle [Figure 1], more emphasis on early mobility, sleep management and psychosis evaluation(cognitive function assessment) on the importance of delirium management.
|Figure 1: The ESCAPE bundle: Early implementation to manage and prevent delirium|
Click here to view
In conclusion, for delirium in critically ill patients, we should recognize the importance of delirium, have a correct understanding and evaluation of delirium, comply with the iPAD and ABCDEF management strategies, strengthen teamwork spirit of the intensive care team to prevent the occurrence of delirium, treat delirium effectively, improve medical care, and better the prognosis of patients.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Barr J, Fraser GL, Puntillo K, Ely EW, Gélinas C, Dasta JF, et al.
Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the Intensive Care Unit. Crit Care Med 2013;41:263-306. doi: 10.1097/CCM.0b013e3182783b72.
Trzepacz PT. Is there a final common neural pathway in delirium? Focus on acetylcholine and dopamine. Semin Clin Neuropsychiatry 2000;5:132-48. doi: 10.153/SCNP00500132.
Trzepacz PT. The neuropathogenesis of delirium. A need to focus our research. Psychosomatics 1994;35:374-91. doi: 10.1016/S0033-3182(94)71759-X.
Young GB, DeRubeis DA. Metabolic encephalopathies. In: Young GB, Ropper AH, Bolton CF, editors. Coma and Impaired Consciousness. New York: McGraw-Hill; 1998. p. 307.
Pandharipande PP, Morandi A, Adams JR, Girard TD, Thompson JL, Shintani AK, et al.
Plasma tryptophan and tyrosine levels are independent risk factors for delirium in critically ill patients. Intensive Care Med 2009;35:1886-92. doi: 10.1007/s00134-009-1573-6.
Tsuruta R, Oda Y. A clinical perspective of sepsis-associated delirium. J Intensive Care 2016;4:18. doi: 10.1186/s40560-016-0145-4.
Hughes CG, Pandharipande PP, Thompson JL, Chandrasekhar R, Ware LB, Ely EW, et al.
Endothelial activation and blood-brain barrier injury as risk factors for delirium in critically ill patients. Crit Care Med 2016;44:e809-17. doi: 10.1097/CCM.0000000000001739.
Suchyta MR, Jephson A, Hopkins RO. Neurologic changes during critical illness: brain imaging findings and neurobehavioral outcomes. Brain Imaging Behav. 2010;4:22-34. doi: 10.1007/s11682-009-9082-3.
Naidech AM, Polnaszek KL, Berman MD, Voss JL. Hematoma locations predicting delirium symptoms after intracerebral hemorrhage. Neurocrit Care 2016;24:397-403. doi: 10.1007/s12028-015-0210-1.
Cerejeira J, Firmino H, Vaz-Serra A, Mukaetova-Ladinska EB. The neuroinflammatory hypothesis of delirium. Acta Neuropathol 2010;119:737-54. doi: 10.1007/s00401-010-0674-1.
Sharshar T, Carlier R, Bernard F, Guidoux C, Brouland JP, Nardi O, et al.
Brain lesions in septic shock: A magnetic resonance imaging study. Intensive Care Med 2007;33:798-806. doi: 10.1007/s00134-007-0598-y.
Barr J, Egan TD, Sandoval NF, Zomorodi K, Cohane C, Gambus PL,et al
. Propofol dosing regimens for ICU sedation based upon an integrated pharmacokinetic-pharmacodynamic model. Anesthesiology 2001;95:324-33. doi: 10.1097/00000542-200108000-00011.
Brummel NE, Ely EW. Sedation level and the prevalence of delirium. Intensive Care Med 2014;40:135. doi: 10.1007/s00134-013-3083-9.
Golinger RC, Peet T, Tune LE. Association of elevated plasma anticholinergic activity with delirium in surgical patients. Am J Psychiatry 1987;144:1218-20. doi: 10.1176/ajp.144.9.1218.
Chang YL, Tsai YF, Lin PJ, Chen MC, Liu CY. Prevalence and risk factors for postoperative delirium in a cardiovascular Intensive Care Unit. Am J Crit Care 2008;17:567-75.
Patel SB, Poston JT, Pohlman A, Hall JB, Kress JP. Rapidly reversible, sedation-related delirium versus persistent delirium in the Intensive Care Unit. Am J Respir Crit Care Med 2014;189:658-65. doi: 10.1164/rccm.201310-1815OC.
Kress JP, Pohlman AS, O'Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N
Engl J Med 2000;342:1471-7. doi: 10.1056/NEJM200005183422002.
Girard TD, Kress JP, Fuchs BD, Thomason JW, Schweickert WD, Pun BT, et al.
Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in Intensive Care (Awakening and breathing controlled trial): A randomised controlled trial. Lancet 2008;371:126-34. doi: 10.1016/S0140-6736(08)60105-1.
Haenggi M, Blum S, Brechbuehl R, Brunello A, Jakob SM, Takala J, et al.
Effect of sedation level on the prevalence of delirium when assessed with CAM-ICU and ICDSC. Intensive Care Med 2013;39:2171-9. doi: 10.1007/s00134-013-3034-5.
Sessler CN, Gosnell MS, Grap MJ, Brophy GM, O'Neal PV, Keane KA, et al.
The Richmond agitation-sedation scale: Validity and reliability in adult Intensive Care Unit patients. Am J Respir Crit Care Med 2002;166:1338-44. doi: 10.1164/rccm.2107138.
Pandharipande PP, Pun BT, Herr DL, Maze M, Girard TD, Miller RR, et al.
Effect of sedation with dexmedetomidine vs. lorazepam on acute brain dysfunction in mechanically ventilated patients: The MENDS randomized controlled trial. JAMA 2007;298:2644-53. doi: 10.1001/jama.298.22.2644.
van den Boogaard M, Pickkers P, Slooter AJ, Kuiper MA, Spronk PE, van der Voort PH, et al.
Development and validation of PRE-DELIRIC (Prediction of Delirium in ICU patients) delirium prediction model for Intensive Care patients: Observational multicentre study. BMJ 2012;344:e420. doi: 10.1136/bmj.e420.
McNicoll L, Pisani MA, Zhang Y, Ely EW, Siegel MD, Inouye SK, et al.
Delirium in the Intensive Care Unit: Occurrence and clinical course in older patients. J Am Geriatr Soc 2003;51:591-8. doi: 10.1034/j.1600-0579.
Pisani MA, Murphy TE, Van Ness PH, Araujo KL, Inouye SK. Characteristics associated with delirium in older patients in a medical Intensive Care Unit. Arch Intern Med 2007;167:1629-34. doi: 10.1001/archinte.167.15.1629.
Earnest MP, Parker WD. Metabolic encephalopathies and coma from medical causes. In: Grotta J, editor. Management of the Acutely Ill Neurological Patient. New York: Churchill Livingstone; 1993. p. 1.
Hsieh SJ, Soto GJ, Hope AA, Ponea A, Gong MN. The association between acute respiratory distress syndrome, delirium, and in-hospital mortality in Intensive Care Unit patients. Am J Respir Crit Care Med 2015;191:71-8. doi: 10.1164/rccm.201409-1690OC.
Plaschke K, von Haken R, Scholz M, Engelhardt R, Brobeil A, Martin E, et al.
Comparison of the confusion assessment method for the Intensive Care Unit (CAM-ICU) with the Intensive Care Delirium Screening Checklist (ICDSC) for delirium in critical care patients gives high agreement rate(s). Intensive Care Med 2008;34:431-6. doi: 10.1007/s00134-007-0920-8.
Ely EW, Inouye SK, Bernard GR, Gordon S, Francis J, May L, et al.
Delirium in mechanically ventilated patients: Validity and reliability of the confusion assessment method for the Intensive Care Unit (CAM-ICU). JAMA 2001;286:2703-10. doi: 10.1001/jama.286.21.2703.
Wong CL, Holroyd-Leduc J, Simel DL, Straus SE. Does this patient have delirium? Value of bedside instruments. JAMA 2010;304:779-86. doi: 10.1001/jama.2010.1182.
Pisani MA, Murphy TE, Araujo KL, Slattum P, Van Ness PH, Inouye SK, et al.
Benzodiazepine and opioid use and the duration of Intensive Care Unit delirium in an older population. Crit Care Med 2009;37:177-83. doi: 10.1097/CCM.0b013e318192fcf9.
Francis J. Drug-induced delirium: Diagnosis and treatment. CNS Drugs 1996;5:103.
Chew ML, Mulsant BH, Pollock BG, Lehman ME, Greenspan A, Mahmoud RA, et al.
Anticholinergic activity of 107 medications commonly used by older adults. J Am Geriatr Soc 2008;56:1333-41. doi: 10.1111/j.1532-5415.2008.01737.x.
Inouye SK, Schlesinger MJ, Lydon TJ. Delirium: A symptom of how hospital care is failing older persons and a window to improve quality of hospital care. Am J Med 1999;106:565-73. doi: 10.1016/S0002-9343(99)00070-4.
Reade MC, Eastwood GM, Bellomo R, Bailey M, Bersten A, Cheung B, et al.
Effect of dexmedetomidine added to standard care on ventilator-free time in patients with agitated delirium: A Randomized clinical trial. JAMA 2016;315:1460-8. doi: 10.1001/jama.2016.2707.
Flinn DR, Diehl KM, Seyfried LS, Malani PN. Prevention, diagnosis, and management of postoperative delirium in older adults. J Am Coll Surg 2009;209:261-8. doi: 10.1016/j.jamcollsurg.2009.03.008.
Hermans G, Van den Berghe G. Clinical review: Intensive Care Unit acquired weakness. Crit Care 2015;19:274. doi: 10.1186/s13054-015-0993-7.
Strijbos MJ, Steunenberg B, van der Mast RC, Inouye SK, Schuurmans MJ. Design and methods of the hospital elder life program (HELP), a multicomponent targeted intervention to prevent delirium in hospitalized older patients: Efficacy and cost-effectiveness in Dutch health care. BMC Geriatr 2013;13:78. doi: 10.1186/1471-2318-13-78.
Schweickert WD, Pohlman MC, Pohlman AS, Nigos C, Pawlik AJ, Esbrook CL, et al.
Early physical and occupational therapy in mechanically ventilated, critically ill patients: A randomised controlled trial. Lancet 2009;373:1874-82. doi: 10.1016/S0140-6736(09)60658-9.
Burtin C, Clerckx B, Robbeets C, Ferdinande P, Langer D, Troosters T, et al.
Early exercise in critically ill patients enhances short-term functional recovery. Crit Care Med 2009;37:2499-505. doi: 10.1097/CCM.0b013e3181a38937.
Hodgin KE, Nordon-Craft A, McFann KK, Mealer ML, Moss M. Physical therapy utilization in Intensive Care Units: Results from a national survey. Crit Care Med 2009;37:561-6. doi: 10.1097/CCM.0b013e3181957449.
Nordon-Craft A, Schenkman M, Ridgeway K, Benson A, Moss M. Physical therapy management and patient outcomes following ICU-acquired weakness: A case series. J Neurol Phys Ther 2011;35:133-40. doi: 10.1097/NPT.0b013e3182275905.
Lee CM, Fan E. ICU-acquired weakness: What is preventing its rehabilitation in critically ill patients? BMC Med 2012;10:115. doi: 10.1186/1741-7015-10-115.
Pulak LM, Jensen L. Sleep in the Intensive Care Unit: A Review. J Intensive Care Med 2016;31:14-23. doi: 10.1177/0885066614538749.
Hirshkowitz M, Rose W, Sharafkhaneh A. Neurotransmitters, Neurochemistry, and the Clinical Pharmacology of Sleep. In: Chokroverty S. (eds) Sleep Disorders Medicine. Springer, New York, NY2009 :67-79. doi: 10.1007/978-1-4939-6578-6_7.
Ma N, Dinges DF, Basner M, Rao H. How acute total sleep loss affects the attending brain: A meta-analysis of neuroimaging studies. Sleep 2015;38:233-40. doi: 10.5665/sleep.4404.
Litton E, Carnegie V, Elliott R, Webb SA. The efficacy of earplugs as a sleep hygiene strategy for reducing delirium in the ICU: A Systematic review and meta-analysis. Crit Care Med 2016;44:992-9. doi: 10.1097/CCM.0000000000001557.
Fanfulla F, Ceriana P, D'Artavilla Lupo N, Trentin R, Frigerio F, Nava S,et al
. Sleep disturbances in patients admitted to a step-down unit after ICU discharge: The role of mechanical ventilation. Sleep 2011;34:355-62.
Schweitzer PK. Drugs that disturb sleep and wakefulness. In: Kryger MH, Roth T, Dement WC, editors. Principles and Practices of Sleep Medicine. 5th
ed. St. Louis, MO: Elsevier Saunders; 2011. p. 542.
Skrobik YK, Bergeron N, Dumont M, Gottfried SB. Olanzapine vs. haloperidol: Treating delirium in a critical care setting. Intensive Care Med 2004;30:444-9. doi: 10.1007/s00134-003-2117-0.
Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: Meta-analysis of randomized placebo-controlled trials. JAMA 2005;294:1934-43. doi: 10.1001/jama.294.15.1934.
Reade MC, Eastwood GM, Bellomo R, Bailey M, Bersten A, Cheung B, et al
. Effect of dexmedetomidine added to standard care on ventilator-free time in patients with agitated delirium: A randomized clinical trial. JAMA 2016;315:1460-8. doi: 10.1001/jama.2016.2707.
Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, et al.
Dexmedetomidine vs. midazolam for sedation of critically ill patients: A randomized trial. JAMA 2009;301:489-99. doi: 10.1001/jama.2009.56.
Pandharipande PP, Pun BT, Herr DL, Maze M, Girard TD, Miller RR, et al.
Effect of sedation with dexmedetomidine vs. lorazepam on acute brain dysfunction in mechanically ventilated patients: The MENDS randomized controlled trial. JAMA 2007;298:2644-53. doi: 10.1001/jama.298.22.2644.
Murray MJ, DeBlock H, Erstad B, Gray A, Jacobi J, Jordan C, et al.
Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient. Crit Care Med 2016;44:2079-103. doi: 10.1097/CCM.0000000000002027.