Clinical risk factors associated with postoperative delirium and evaluation of delirium management and assessment team in lung and esophageal cancer patients
© Murakawa et al.; licensee BioMed Central. 2015
Received: 26 June 2014
Accepted: 3 September 2014
Published: 28 January 2015
Delirium is an acute change in cognition and concentration that complicates the postoperative course. Patients who suffer delirium after surgery have an increased risk of persistent cognitive impairment, functional decline, and death. Postoperative delirium is also associated with an increased length of hospital stay and higher costs. With the goal of preventing delirium in postoperative patients, we organized a medical team from the Delirium Management and Assessment Center (D-mac) at Okayama University Hospital in January 2012. The team members consisted of physicians, pharmacists, nurses, and clinical psychologists.
We retrospectively reviewed the medical records of patients with delirium to examine risk factors related to the patients’ background.
Fifty-nine postoperative patients with lung or esophageal cancer were investigated; 25% exhibited delirium during hospitalization. Multiple logistic regression analysis showed significant associations between the presence of delirium and a past history of delirium (odds ratio, 4.22; 95% CI, 1.10-16.2; p = 0.09) and use of benzodiazepine receptor agonists (odds ratio, 3.97; 95% CI, 1.09-14.5; p = 0.03). Intervention by the D-mac significantly reduced the rate of delirium episodes in lung cancer patients (p =0.01). Notably, prior to intervention, the incidence of delirium was 100% when three high-risk factors for delirium were present. In contrast, the incidence of delirium in patients with three high-risk factors decreased following implementation of the D-mac intervention.
These findings suggest that active participation by various staff in the medical team managing delirium had a marked therapeutic impact.
KeywordsDelirium Postoperative patients Medical team Risk factors
Delirium is a disturbance of consciousness characterized by changes in cognition, perceptual disturbances, and a reduced ability to focus, sustain, or shift attention . These symptoms typically manifest in disorientation, memory impairment, and alteration of mental processes, which can present as a hyperactive form, a hypoactive form, or a combination of the two [2,3]. Delirium has been associated with an increase in the length of hospital stay and complication rates, as well as functional decline [3,4]. Several studies have investigated risk factors such as advanced age, preoperative cognitive impairment, cephalopathy and delirium events, and alcoholism [3,5,6].
Surgery itself may play a role in delirium . Postoperative delirium, a common and serious complication following surgery, has been associated independently with prolonged hospital stays, increased costs, and higher mortality .
In general, delirium-inducing factors are categorized as predisposing factors, promoting factors, or direct factors . Pharmaceuticals are considered a direct factor in the development of a delirium episode . As a prophylactic intervention against delirium, the pharmacists in charge of the D-mac mainly evaluated any medicines taken by the patients as well as postoperative medications.
In the present study, we identified the predictive factors (age (over 70), past history of cephalopathy, past history of delirium, cognitive decline, and alcoholism) for delirium by examining the relationship between baseline patient characteristics and delirium in patients with postoperative-induced delirium, particularly those with lung and esophageal cancer. Furthermore, we configured the clinical end point for the intervention of the D-mac to be the incidence of delirium in this study. To investigate the impact of intervention by the D-mac, we examined the frequency of delirium episodes before and after participation by the D-mac.
Data were collected retrospectively on 119 patients with delirium in our hospital during the period from 1 January, 2011, to 31 December, 2011. We researched age, sex, the presence or absence of surgical intervention, and the duration of delirium. Delirium was diagnosed postoperatively by the attending physician based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders IV edition, Text Revision (DSM-IV-TR), which are regarded as the most inclusive criteria for delirium. The study was conducted in accordance with the ethics committee of the Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University.
Effects of delirium-inducing risk factors in postoperative patients with lung or esophageal cancer
Data on 59 preoperative patients with lung or esophageal cancer at our hospital during the period from 30 June, 2011, to 1 January, 2012, were collected retrospectively. We researched age, sex, disease (lung or esophageal cancer), 5 high-risk factors for delirium (age >70 years, past history of cephalopathy with cerebrovascular disorder, past history of delirium, cognitive decline, and alcoholism), and sleep disorder as the primary symptom of delirium . Furthermore, we examined the utilization of 8 classifications of high-risk drugs, as follows: (1) benzodiazepines, (2) H2 blockers, (3) antihistamine drugs, (4) steroids. (5) anti-cholinergic drugs with tricyclic and tetracyclic anti-depressants, (6) anti-epileptic drugs, (7) anti-parkinson drugs, and (8) opioids.
Effects of D-mac interventions in postoperative lung cancer patients
The present D-mac-implemented program was initially adopted by our hospital on 1 January, 2012. Data were collected retrospectively on 88 preoperative patients with lung cancer for the period from 1 January, 2011, to 31 December, 2011, prior to implementation of the D-mac interventions; 99 preoperative patients with lung cancer who were treated from 1 January, 2012, to 31 December, 2012, provided data for the period following implementation of the D-mac intervention. We researched age, sex, disease, the presence or absence of the five high-risk factors for delirium (age > 70 years, past history of cephalopathy with cerebrovascular disorders, past history of delirium, cognitive decline, and alcoholism).
Categorical variables were compared using the χ2 test. The association between risk factors and the occurrence of delirium was assessed using multivariate logistic regression and expressed in terms of the odds ratio (OR) and 95% confidence interval (CI). Sex, age, past history of cephalopathy with cerebrovascular disorders, past history of delirium, cognitive decline, alcoholism, sleep disorders, and medications served as covariates. Statistical significance was defined as p <0.05.
Background of postoperative delirium patients
Number of patients
Sex (male female)
Number of postoperative delirium patients
Durations of delirium events (days)
Background of period of postoperative induced delirium
After operation (<3 days)
After operation (> days)
Number of patients
Effects of delirium-inducing factors in postoperative lung and esophageal cancer patients
Background of postoperative delirium of lung and esophageal cancer patients
Number of patients
Sex (male female)
Lung cancer: esophageal cancer
Delirium inducing high-risk factors
Past history of cephabpathy
Past history of delirium
Postoperative delirium events
Number of postoperative delirium
Sex (male: female)
Delirium-inducing high-risk drugs
Taking medication (%)
Anticholinergic drugs (tricyclic and tetracyclic antidepressant)
Relationships between patient background and postoperative delirium events
Past history of cephalopathy
Past history of delirium
Relationship between high-risk drugs and postoperative delirium events
Anticholinergic drugs (tricyclic and tetracyclic antidepressant)
Relationship between benzodiazepines and postoperative delirium events
Effect of D-mac management on delirium in postoperative patients with lung cancer
Background of postoperative delirium in lung patients
Before intervention (2011)
After intervention (2012)
Past history of cephalopathy
Past history of delirium
Discussion and conclusions
The present study demonstrated that team medical care-implemented pharmaceutical management for the patients contributed to a prevention in surgical patients with lung and esophageal cancer. Furthermore, the active participation of pharmacists in the cases of surgical patients with lung and esophageal cancer contributed to a decrease in the incidence of delirium through pharmaceutical care.
In general, delirium is characterized by symptoms of disturbance in consciousness, such as disorientation, hallucinations, and delusion . Delayed improvement in illness due to the aggravation of delirium has been reported . Early discovery of delirium and intervention are desirable as one-third of delirium cases can be prevented through the identification of high-risk patients and appropriate intervention .
Causes of delirium are broadly categorized as predisposing, promoting, and direct factors. In this study, many patients with delirium developed this condition after surgery. As such, postoperative delirium has been reported in about 40% of surgical patients [13,14]. ‘Surgery’ is considered a predisposing factor for delirium  and influences physical causes, such as pain, mental causes, such as postoperative anxiety and depression, and promoting factors, such as environmental changes in an intensive care unit. The onset of postoperative delirium occurred relatively early following surgery, as previously reported, and this tendency for early onset was stronger in more elderly patients [15,16]. This suggests that elderly surgical patients may bear a higher risk for delirium and may therefore require early intervention before surgery. In our study, the incidence of delirium was higher in older patients for several days immediately following surgery.
The D-mac at our hospital identified several high-risk factors for delirium. Of these, ‘past medical history of delirium’ was shown to be a significant risk factor for postoperative delirium. The presence of a past medical history of delirium was the only significant independent high-risk factor. However, the incidence of delirium rose when multiple high-risk factors were present, suggesting the importance of confirming the presence of multiple high-risk factors in patients before surgery. In fact, the incidence of delirium rose to 100% in patients who had three high-risk factors before D-mac intervention in surgical patients in this study.
‘Drugs’ are considered to be a ‘direct factor’ causing delirium , and represent causative factors for delirium in many elderly patients [17,18]. The prevalence of insomnia has recently increased and is particularly high in the elderly . Accordingly, commensurate with the aging of the population in Japan, the prescription rate for benzodiazepine receptor agonists has increased . Benzodiazepine receptor agonists are well known for inducing delirium [21-23]; these drugs were most frequently brought in by patients on admission in this study. The incidence of postoperative delirium was significantly higher in patients who were medicated with these drugs. Many benzodiazepine receptor agonists are mainly metabolized in the liver . Liver and kidney functions are generally reduced in the elderly, particularly after surgery [13,25]. Moreover, absorption of benzodiazepine receptor agonists is influenced by intestinal peristalsis, but this function is reduced after surgery in many cases. Therefore, the ability to metabolize benzodiazepine receptor agonists may be markedly reduced postoperatively in elderly patients. The reduced metabolism and changes in absorption may promote drug accumulation and sensitivity and induce cognitive dysfunction, a known effect specific to benzodiazepine receptor agonists. Given these mechanisms, benzodiazepine receptor agonists are likely to cause postoperative delirium in elderly patients. Attention should be given to patients who are treated with these drugs prior to surgery. Brotizolam, zolpidem, and etizolam accounted for a large proportion of the benzodiazepine receptor agonists brought to the hospital by patients on admission. In particular, etizolam was significantly associated with the development of postoperative delirium. This finding suggests that etizolam should be administered to postoperative elderly patients with extreme caution. Moreover, of the three drugs, etizolam is the most lipid-soluble (distribution coefficient: 354, pH 7, octanol/water) and exhibits high potency. Benzodiazepine receptor agonists were most frequently brought in by patients on admission. However, it was not obvious whether delirium occurred under conditions in which benzodiazepine receptor agonists were taken or not taken in this retrospective study. Further study is underway to clarify this point. For patients complaining of insomnia and at risk for postoperative delirium, the D-mac currently recommends prescribing trazodone hydrochloride, which, among the triazolopyridine derivatives, exerts a strong hypnotic effect but does not act on the benzodiazepine receptor. However, the usefulness of trazodone hydrochloride in preventing postoperative delirium should be further investigated.
The incidence of postoperative delirium was significantly reduced by the D-mac intervention team comprised of psychiatrists, pharmacists, nurses, and clinical psychologists. This demonstrates that early identification of high-risk factors and drugs potentially inducing delirium along with appropriate interventions are beneficial in preventing postoperative delirium. Since delirium may develop when multiple risk factors are concomitantly present [17,26,27], a comprehensive approach involving the collaboration of an interdisciplinary team may be effective.
On the other hand, the role of the ward pharmacists is to evaluate the patient’s background characteristics and medications brought from home and to formulate appropriate recommendations based on these assessments. When reviewing a patient’s medications on admission, it is essential that ward pharmacists identify drugs associated wuth a high risk of delirium and advise the attending physicians to withdraw these drugs and prescribe alternative medications. Expanding and developing the pharmacist’s role in this regard may assist in improving the quality of medical care aimed at preventing delirium. In turn, these measures may benefit the patient, and thereby achieve an important goal of ward drug management.
- Rigolin GM, Martinelli S, Formigaro L, Cibien F, Lista E, Cavallari M, Ambrosio M, Pizzolato M, Daghia G, Sofritti O, Cuneo A: Delirium in acute promyelocytic leukemia patients: two case reports. BMC Res Notes 2013, 6:469.PubMed CentralPubMedView ArticleGoogle Scholar
- Meagher D: Motor subtypes of delirium: past, present and future. Int Rev Psychiatry 2009, 21:59–73.PubMedView ArticleGoogle Scholar
- Lipowski ZJ: Delirium : acute confusional states. New York: Oxford University Press; 1990.Google Scholar
- Marcantonio ER, Goldman L, Mangione CM, Ludwig LE, Muraca B, Haslauer CM, Donaldson MC, Whittemore AD, Sugarbaker DJ, Poss R, Haas S, Cook EF, Orav J, Lee TH: A clinical prediction rule for delirium after elective noncardiac surgery. JAMA 1994, 271:134–139.PubMedView ArticleGoogle Scholar
- Flinn DR, Diehl KM, Seyfried LS, Malani PN: Prevention, diagnosis, and management of postoperative delirium in older adults. J Am Coll Surg 2009, 209:261–268. quiz 294.PubMedView ArticleGoogle Scholar
- Michaud L, Bula C, Berney A, Camus V, Voellinger R, Stiefel F, Burnand B: Delirium: guidelines for general hospitals. J Psychosom Res 2007, 62:371–383.PubMedView ArticleGoogle Scholar
- Marcantonio ER, Goldman L, Orav EJ, Cook EF, Lee TH: The association of intraoperative factors with the development of postoperative delirium. AmJ Med 1998, 105:380–384.View ArticleGoogle Scholar
- Lipowski ZJ: Update on delirium. Psychiatr Clin North Am 1992, 15:335–346.PubMedGoogle Scholar
- Liptzin B, Levkoff SE: An empirical study of delirium subtypes. Br J Psychiatry 1992, 161:843–845.PubMedView ArticleGoogle Scholar
- Cavaliere F, D’Ambrosio F, Volpe C, Masieri S: Postoperative delirium. Curr Drug Targets 2005, 6:807–814.PubMedView ArticleGoogle Scholar
- Inouye SK, Charpentier PA: Precipitating factors for delirium in hospitalized elderly persons. Predictive model and interrelationship with baseline vulnerability. JAMA 1996, 275:852–857.PubMedView ArticleGoogle Scholar
- Potter J, George J: The prevention, diagnosis and management of delirium in older people: concise guidelines. Clin Med 2006, 6:303–308.PubMedView ArticleGoogle Scholar
- Dyer CB, Ashton CM, Teasdale TA: Postoperative delirium. A review of 80 primary data-collection studies. Arch Intern Med 1995, 155:461–465.PubMedView ArticleGoogle Scholar
- Leung JM, Sands LP, Vaurio LE, Wang Y: Nitrous oxide does not change the incidence of postoperative delirium or cognitive decline in elderly surgical patients. Br J Anaesth 2006, 96:754–760.PubMedView ArticleGoogle Scholar
- Tsutsui S, Kitamura M, Higashi H, Matsuura H, Hirashima S: Development of postoperative delirium in relation to a room change in the general surgical unit. Surg Today 1996, 26:292–294.PubMedView ArticleGoogle Scholar
- Golinger RC: Delirium in Surgical Patients Seen at Psychiatric-Consultation. Surg Gynecol Obstet 1986, 163:104–106.PubMedGoogle Scholar
- Tuma R, DeAngelis LM: Altered mental status in patients with cancer. Arch Neurol 2000, 57:1727–1731.PubMedView ArticleGoogle Scholar
- Bruera E, Miller L, McCallion J, Macmillan K, Krefting L, Hanson J: Cognitive failure in patients with terminal cancer: a prospective study. J Pain Symptom Manag 1992, 7:192–195.View ArticleGoogle Scholar
- Doi Y, Minowa M, Okawa M, Uchiyama M: Prevalence of sleep disturbance and hypnotic medication use in relation to sociodemographic factors in the general Japanese adult population. J Epidemiol 2000, 10:79–86.PubMedView ArticleGoogle Scholar
- Nakao M, Sato M, Nomura K, Yano E: Benzodiazepine prescription and length of hospital stay at a Japanese university hospital. Bio Psycho Social Med 2009, 3:10.Google Scholar
- Clarke C, Friedman SM, Shi K, Arenovich T, Monzon J, Culligan C: Emergency department discharge instructions comprehension and compliance study. CJEM 2005, 7:5–11.PubMedGoogle Scholar
- Clegg A, Young JB: Which medications to avoid in people at risk of delirium: a systematic review. Age Ageing 2011, 40:23–29.PubMedView ArticleGoogle Scholar
- Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, Whitten P, Margolis BD, Byrne DW, Ely EW, Rocha MG: Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA 2009, 301:489–499.PubMedView ArticleGoogle Scholar
- Kamijo Y, Hayashi I, Nishikawa T, Yoshimura K, Soma K: Pharmacokinetics of the active metabolites of ethyl loflazepate in elderly patients who died of asphyxia associated with benzodiazepine-related toxicity. J Anal Toxicol 2005, 29:140–144.PubMedView ArticleGoogle Scholar
- Bowen JD, Larson EB: Drug-induced cognitive impairment. Defining the problem and finding solutions. Drugs Aging 1993, 3:349–357.PubMedView ArticleGoogle Scholar
- Morita T, Tei Y, Tsunoda J, Inoue S, Chihara S: Underlying pathologies and their associations with clinical features in terminal delirium of cancer patients. J Pain Symptom Manag 2001, 22:997–1006.View ArticleGoogle Scholar
- Inouye SK, Bogardus ST Jr, Charpentier PA, Leo-Summers L, Acampora D, Holford TR, Cooney LM Jr: A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med 1999, 340:669–676.PubMedView ArticleGoogle Scholar
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