Hypoalbuminemia in Delirium

Hypoalbuminemia in Delirium LESLEY

R.

DICKSON, M.D.

The charts of 100 delirious patients seen by a psychiatric consultation service were reviewed. The most common chronic medical problems included diabetes and cardiovascular disease. while infections and trauma were the most common acute problems. The mostfrequent laboratory abnormality was hypoalbuminemia, appearing in 66% ofthose tested. Hypoalbuminemic patients were more likely to have a combination ofmedical problems, long hospital stays, and increased mortality, while patients with normal albumin were more likely to have drug toxicities and short hospital stays. While hypoalbuminemia develops because ofmany physiological processes. the data suggest that more attention should be paid to nutrition and serum transport capability in medical patients.

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elirium, as defined in DSM-III-R, J is a common problem of the medical or surgical patient, appearing most frequently in the elderly. 2 The appearance of a delirious state may serve as a sign of change in the physical condition of the patient. It may increase mortality or morbidity and may lengthen hospital stay.2-4 For these reasons, it is important to identify predisposing factors and early signs of a developing delirium in order to intervene before serious complications or death ensue. Additionally, it is important to understand the mechanism whereby a medical condition occurring in a remote part of the body can so profoundly affect the function of the central nervous system. There have been many case reports, summarized in several review articles, that document a relationship between a medical condition or introduction of a drug and the development of delirium. 2.s Thus, it becomes difficult to propose a unifying mechanism for the production of the delirious state. To solve this problem, it may be useful to look for similarities in a large group of delirious patients with a wide age range and with multiple putative etiologies of the syndrome. A recent report by Levkoff et aI. 6 looked at patients age 60 years or older and identified several facVOLUME 32· NUMBER 3· SUMMER 1991

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tors associated with delirium, including urinary tract infections, low serum albumin, elevated white blood count, and proteinuria. Perhaps younger patients would show a similar pattern, suggesting that age might be only partly responsible for the development of delirium. Alternatively, younger patients may require a much more significant insult to the brain to develop delirium, and thus the reported factors may not be as useful in predicting a predisposition to the development of a confusional state in the nonelderly population. This study looks at a group of delirious patients seen by a psychiatric consult service over a period of 9 years. The study group included a wide age range of patients with diverse medical problems. All data obtained on each patient were collected and analyzed in an attempt to identify some factors that are relatively frequent and may Received June 13. 1990; revised October 2. 1990; accepted October II. 1990. From the Department of Psychiatry. University of Kentucky Medical Center. Lexington. Address reprint requests to Dr. Dickson. Department of Psychiatry. Annex II. University of Kentucky Medical Center. Lexington. Kentucky 40536-0080. Copyright © 1991 The Academy of Psychosomatic Medicine.

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Hypoalbuminemia in Delirium

serve both predictive and treatment functions in addition to suggesting a common pathogenic mechanism. METHODS The charts of 100 patients who were seen by the psychiatric consultation service in a university hospital and who were given the diagnosis of delirium were reviewed. The patients were seen over the period from 1980 to 1988 and represented 5% of the consults seen. The charts reviewed were obtained from a list of 127 patients listed in the consultation logbook and given a diagnosis of delirium or organic brain syndrome. Fourteen patients could not be identified sufficiently to obtain medical records for the chart review. The review also consisted of confirmation that the patients' symptoms met the criteria for a DSM-III-R diagnosis of delirium within 48 hours preceding the visit of the consulting psychiatrist. This time period was necessary since the fluctuating symptoms and rapid intervention by the treatment team frequently resulted in significant improvement by the time the psychiatrist arrived. The review therefore excluded 13 patients who received diagnoses of organic mental syndromes other than delirium, leaving 100 patients with delirium. Data obtained from the record included demographic information, discharge diagnoses, procedures, reason for admission, previous psychiatric history, substance abuse history, and social history. If medications or other data obtained from the medical record strongly suggested diagnoses not listed in the official discharge diagnoses, they were also recorded. Also collected were medications at time of admission and at the time of the consult, laboratory values over the period ofhospitalization, and results ofspecial tests such as EEG and CT scans. The changes in mental status leading to the diagnosis of delirium were noted, as was the consultant's recommendation, the course following consultation, and the ultimate outcome of hospitalization. After all 100 charts were reviewed, the data were considered, and the author determined the most likely explanation for the development of delirium in each 318

patient. The data on all patients then were collated. The significant findings are reported here. Discharge diagnoses were counted only if they represented true medical syndromes rather than descriptions such as hypokalemia and hypoxia. Chronic medical problems represented ongoing syndromes such as cancer, chronic obstructive pulmonary disease (COPD), and cardiac arrhythmias. Acute problems consisted of entities that could be conceptualized as reversible, including infection, metabolic abnormalities, intoxications, and acute trauma. Abnormal laboratory values were counted if they occurred any time during hospitalization. Statistical analyses of differences were done by chi-square analysis in order to compare values between groups and by Student's ( test to compare continuous data (specifically the length of hospital stay and the age of the patients). Pearson's correlation coefficient was used to look at the relationship of albumin with age and chronic illness. Descriptive data are given by standard deviation of the mean. RESULTS Of the 100 patients, 50 were male and 50 were female. The mean age was 56.5±16.3 years with a range of 18 to 90 years. The mean age of the female patients was 59.3±13.4, and the mean age of the male patients was 53.6±18.2, a nonsignificant difference. Thirty-nine were age 65 or older, and 10 subjects died during the admission. The average length of stay was 24.2±29 days, with a range of I to 221 days. This is significantly greater than the hospital's average length of stay of 5.06 days «(=6.6, p
Dickson

19 patients had no chronic problems reported. Of the 39 patients 65 years or older. 62% had more than one chronic problem. while only 8% had no chronic problems reported. Nine patients had a preexisting dementia; eight had a seizure disorder; four had a history ofcerebrovascular disease; two had Parkinson's disease; two were mentally retarded; and one was diagnosed with Korsakoff's psychosis. The acute problems were numerous and dominated by infections. although only four were central nervous system infections (one with encephalitis and three with meningitis) (Table I). The causes of death for the 10 patients were varied and included three cases of cancer, two cases of renal failure. and one case each of end-stage COPD. rheumatic heart disease. Guillain-Barre syndrome. pneumonia with a GI bleed. and pulmonary embolus. Many patients also had psychiatric histories. including 29 with a history of alcohol abuse. 15 with major depression. 8 with bipolar illness. 5 with other substance abuse. TABLE 1. Medical disorders Disorder

No. or Patients

Chronic-Most Common Diabetes mellitus Hypenension Coronary anery disease Malignancies Congestive hean failure Chronic obstructive pulmonary disease Chronic renal failure Dementia/organic brain syndrome Seizure disorder Arrhythmias Peripheral vascular disease Acute-Most Frequent Urinary tract infection Trauma Other infections Pneumonia Endocrine/electrolyte imbalance Cardiac dysfunction Hypoxia/adult respiratory distress syndrome Other pulmonary Blood dyscrasias Hypovolemia/hypotension Vascular Sepsis Tricyclic overdose Cerebrovascular

22 19 15 15 13 13 10 9 8 7 6 15 13 13 II II 10 9 9 8 7 7 6 6 6

Note: Some patients had more than one diagnosis.

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and 4 with schizophrenia. When the course of the delirium was considered. it was found that 63 patients had a delirium on admission. Of those patients older than 65, 64% were delirious on admission. Of the 37 patients who developed a delirium during hospitalization. the range of hospital stay was I to 85 days with a mean of 11.4±14.9 days after date of admission. Since most patients had been exposed to multiple biological and social stressors. it became very difficult to establish the etiology of the delirium. However, it was possible to divide the patients into two large groups: in 42 cases. medications were felt to be of primary etiologic significance. and in 58 cases. medical problems, either singly or in combination. were of etiologic significance. The most frequently implicated medications were tricyclic antidepressants, narcotics. lithium. steroids. and benzodiazepines. When abnormal laboratory values were collated (Table 2). low serum albumin «3.5 g/dl) was found to be the most frequent. occurring in 55 of the 83 patients (66%) who had the value measured. Hypoproteinemia was also frequent. with 49% of those tested having a low value at some point during hospitalization. Other abnormal values are listed in decreasing frequency. with most being easily explained by the patient's chronic or acute medical problems. The hypoalbuminemia was not explained by some of the common causes of low-serum albumin: only one patient had cirrhosis; five were diagnosed with TABLE 2. Number or patients who had medical disorders with abnormal laboratory values Disorder

No. or Patients

Hypoalbuminemia Hypoproleinemia Anemia Hyperglycemia Elevated white blood cell count Increased blood urea nitrogen/creatinine Hypoxia Hyponatremia Elevated creatinine phosphokinase Elevated liver function tests Elevated bilirubin DocumeOled drug toxicity (Lithium. dilantin. digoxin. theophylline)

55 40 29 25 25 25 23 17 15 II 9 7

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malnutrition; and those with renal failure were distributed into the normal and abnormal albumin pool at the same frequency as the total group. Age also did not explain the abnormality since the mean age forthose with normal albumin was 59.9 and for those with abnormal albumin 56.0 (Table 3). The number of chronic problems did not differentiate the groups; 59% of patients in both the hypoalbuminemia and the normal albumin groups had more than one chronic medical problem. Pearson's correlation coefficient failed to demonstrate a relationship between albumin and age (r=O.06) or between albumin and the number of chronic problems (r=O.OO9). When comparing the two groups, two differences can be noted. Patients with low albumin were much more likely to have medical problems reported as the presumed etiology of the delirium. and those with normal albumin were more likely to have medications or drugs of abuse reported as the etiology (Table 3). Additionally, the mean length of hospital stay was considerably different. with the hypoalbuminemic patients having mean stays of 33.7 days and the normal patients having mean stays of 11.5 days. Of the 10 patients who died, 8 had low serum albumin with a mean value of 2.5I±O.89 gld!. It was very difficult to correlate the delirious state temporally with hypoalbuminemia since 24 of the 55 hypoalbuminemic subjects had albumin levels measured once, usually on admission. Of those who had multiple determinations. the usual

pattern was a sequential drop in the value. with an occasional increase in the patient who had aggressive nutritional support. Those patients who were delirious on admission had an albumin of 3.08±O.62 when admitting values (or only value available) were collated and a value of 2.56±O.57 when the lowest values (or only value available) were collated. This low value occurred anywhere from I to 45 days after admission. Patients who developed a delirium after admission had an albumin level of 2.4±O.66 when the values closest to the day of development (or only value available) were collated. Other data collected on these patients are not reported since such data were either obtained too infrequently on individual patients or failed to suggest a significant explanation ofdelirium. Additionally, medications are not reported since there was an enormous range and multiple combinations that were difficult to sort out. Finally. although 10 patients died. most patients improved rapidly after appropriate interventions were instituted. supporting the transient nature of this syndrome.

DISCUSSION This study shows. as many have in the past. that delirium is a syndrome that results from many clinical conditions and that is associated with lengthened hospital stay and increased mortality.2-4 However. it also demonstrates that a large

TABLE 3. Correlation of albumin with age. length of hospital stay. and presumed cause of delirium Factor Age. years· Length of hospital stay. days· Presumed cause of delirium Medication problemsb(%) Medical problems«%)

Total(%)

Normat Albumin

Low Albumin

59.9±14.8 11.5±7.6

56.0±16.4 33.7±34.8·

20(69)

16 (29)" 39(55)" 55(66)

8(31) 28 (34)

·Values are means±SD. "Medication problems included cases of overdose. drug withdrawal, documented toxicity. or cases in which there was strong evidence thaI drugs known to cause delirium were etiologic due to a temporal relationship.
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Dickson

number of delirious patients seen by a psychiatric consult service are not elderly and do not have a history of organic brain disease. Dickson and Ranseen7 recently pointed out that organic mental syndromes are increasing in frequency, particularly in the young, due to behaviors such as drug abuse, sexual promiscuity, and impulsivity, which put them at risk. Indeed, many of the healthier patients were delirious due to drug reactions and injuries that were, at least in part, due to risk-taking behaviors. Therefore, it is important to search for early signs and symptoms in all patients and to determine risk factors for the development of delirium. The percentage of patients with delirium and other organic mental syndromes (OMSs) referred to our consultation service was low in our survey compared to others in the literature. Trzepacz et al. 8 found a frequency of 17.3% in their survey, while only 5%-6% of our patients had various OMSs. We do not know the explanation for this. Perhaps we were called more frequently for the unexpected delirious patient who was healthy prior to injury, illness, or intoxication and were not called as often for the sicker patient on neurological and medical services where there was some understanding of the patient's psychopathology. This is at least partially supported by the higher frequency of referrals from surgery to our service, 27%, compared to the findings by Trzepacz et al. 8 of 15% from surgery. By contrast, neurology referrals represented only 8% of our subjects, while Trzepacz et al. saw 23% from neurology. Therefore, it might be useful to study consultation practices by looking at which symptoms and types of patients are most likely to generate a call for help. Alternatively, we also need to look at which symptoms of delirium are overlooked while medical problems are being addressed. A retrospective study of this kind has some serious limitations. The chart review covered a period of 9 years, and thus changes in medical practice may have altered either the type of data obtained or the treatment approaches used. There was considerable variability in laboratory values obtained, and record-keeping practices of physicians frequently limited the amount of informa-

tion available. Automated blood chemistry studies were introduced and increased the information available on the patients admitted later in the time period evaluated, but studies such as the EEG and drug screens were always infrequently done and therefore could not really be used in any quantitative way. During the time period studied, the diagnostic-related groups system was initiated, and financial reimbursement became tied to diagnoses. Thus, length of stay became an important issue 4 and may have resulted in more aggressive treatment of medical problems to reduce hospital stays and to limit costs. Although potentially advantageous to the patient, this approach may have eliminated careful searching for causative factors of delirium, and it may have resulted in early discharges, thereby preventing careful assessment of the patient's underlying functioning once the delirium had resolved. Another limitation was the more frequent presentation of delirium at admission rather than during hospitalization. The inability to carefully document potential causative factors in these patients makes it difficult to chart the temporal sequence of events and the etiological possibilities. For these reasons, it is important to identify groups of patients who are at risk for developing a delirium and to follow them prospectively while obtaining a standardized battery of tests and sequential monitoring of mental functions, such as has been done with patients undergoing cardiac surgery and with transplant candidates.9-11 Although there were many acute and chronic problems representing many organ systems, the albumin abnormality stood out as being a common factor in many of these cases. Malnutrition has frequently been mentioned in the psychiatric literature as a cause of, or predisposing factor in, delirium, but either it has been poorly defined l2 or the focus has been on vitamin deficiencies such as thiamine, folate, or B./ Levkoff et al. 6 did find hypoalbuminemia in many of their delirious elderly patients, and Trzepacz et al.I 1.13 have remarked on a similar finding in candidates awaiting liver transplantation. In these two populations, hypoalbuminemia could potentially be explained by malnutrition in the elderly or by 321

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liver failure in the transplant candidates. Neither factor can totally explain the finding in this study. Nevertheless, nutritional status should be regularly assessed by the consult service, as well as by other members of the health care team, as suggested recently by Trzepacz and Francis. 14 Protein-calorie malnutrition in the hospitalized patient has been extensively studied and reported in the surgical and medical literature. 15.16 Hypoalbuminemia is best conceptualized as the end result of many processes, including malnutrition preceding hospitalization, underfeeding combined with aggressive hydration in the hospital, hypercatabolic states, losses to extravascular spaces, and decreased synthesis. '7.'K It is known to increase infections, increase hospital stays, and delay wound-healing.'~-21 Obviously, all of these factors can contribute to the development of a delirium. However. hypoalbuminemia could also have a more direct effect on the brain or serve as a prognostic indicator of stresses that the central nervous system may be receiving directly. Albumin is the primary transport protein in the plasma, and it is this transport function that may put the brain at risk of developing a delirium. Albumin transports many drugs and toxic substances, and it is usually the combination of the bound and unbound amount appearing at any transport system that determines the amount of uptake. 22 A low albumin may favor a high amount of unbound drug at the blood-brain barrier, thus promoting uptake and toxicity. Alternatively, a high percentage of unbound drugs may favor more rapid elimination by hepatic and renal mechanisms and therefore lead to subtherapeutic levels of important drugs. Many hospitalized patients are on multiple medications, and the sum total may exceed the ability of albumin to transport them, particularly if the albumin is also transporting endogenous toxins such as bilirubin.22.2~ Additionally, drug binding to albumin can potentially be altered by glucosylation or by the presence of free fatty acids in diabetic serum. 24 Hypoalbuminemia was not found in all pa-

tients, and it did not always correlate directly with the appearance ofthe delirious state. Frequently, albumin dropped rapidly after hospitalization, probably due to underfeeding, hydration, movement into extravascular spaces, and synthesis of acute-phase serum proteins. Thus, sequential determinations of albumin and other proteins are necessary to evaluate the relationship further. Additionally, it is possible that patients who had a normal albumin on admission and who had only one value measured developed low values at some point during the admission, perhaps correlating with development of delirium. This study suggests that closer attention needs to be paid to the nutritional status of patients early in their admission. Much is known about its importance, but it seems to be one of the last issues to be addressed in the care of a patient. As consulting psychiatrists, we neglect nutrition as often as our medical colleagues, except in our suggestion to obtain levels of folate and 8 12 , Clearly, this is not enough. In addition to proposing an adequate assessment, we can also take more responsibility for interventions that increase appetite and cooperation with feeding regimens. Furthermore, since hypoalbuminemia is the result of many disorders other than malnutrition, we also need to consider its effects on drugbinding and serum transport capability. We need to become more aggressive in monitoring drug levels, dosages, and endogenous toxins in the patient who appears to be compromised by lowserum albumin. Although the study of delirium is in its infancy,2 perhaps it is one illness for which all medical specialties can collaborate more effectively for the improvement of patient care and outcome.

This study was presented as a poster at the Annual Meeting of the Academy of Psychosomatic Medicine. Las Vegas. Nevada. October 1989. The author thanks MarkC. Hyatt.M.D.,for his editorial assistance and Sue Ellen Stephens. M.D .. Leslie Greenwell. and Melinda Wells for technical assistance in reviewing medical records.

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References I. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. 3rd Edition. Revised. Washington. DC. American Psychiatric Association. 1987 2. Lipowski ZJ: Transient cognitive disorders (delirium. acute confusional states) in the elderly. Am J Psychiatry 140:1426-1436.1983 3. Rabins PV. Folstein MF: Delirium and dementia: diagnostic criteria and fatality rates. Br J Psychiatry 140:149-153.1982 4. Thomas RI. Cameron DJ. Fahs MC: A prospective study of delirium and prolonged hospital stay. Arch Gen Psychiatry 45:937-940. 1988 5. Beresin EV: Delirium in the elderly. J Geriatr Psychiatry Neurol 1:127-143. 1988 6. Levkoff SE. Safron C. Cleary PD. et al: Identification of factors associated with the diagnosis of delirium in elderly hospitalized patients. J Am Geriatr Soc 36:10991104.1988 7. Dickson LR. Ranseen JD: An update on selected organic mental syndromes. Hasp Community Psychiatry 41:290-300.1990 8. Trzepacz PT. Teague GB. Lipowski ZJ: Delirium and other organic mental disorders in a general hospital. Gen Hasp Psychiatry 7:101-106.1985 9. Calabrese JR. Skwerer RG. Gulledge AD. et al: Incidence of postoperative delirium following myocardial revascularization. Cleve Clin J Med 54:29-32. 1987 10. Wragg RE. Dimsdale JE. Moser KM. et al: Operative predictors of delirium after pulmonary thromboendanerectomy. J Thorac Cardiovasc Surg 96:524-529. 1988 II. Trzepacz PT. Maue FR. Coffman G: Neuropsychiatric assessment of liver transplantation candidates: delirium and other psychiatric disorders. Int J Psychiatry Med 16:101-111.1986-1987

12. Simon A. Cahan RB: The acute brain syndrome in geriatric patients. Psychiatry Research Reports 16:8-21. 1963 13. Trzepacz PT. Breener RP. Coffman G. et al: Delirium in liver transplantation candidates: discriminant analysis of multiple test variables. Bioi Psychiatry 24:3-14. 1988 14. Trzepacz PT. Francis J: Low serum albumin and risk of delirium [letter). Am J Psychiatry 147:675. 1990 IS. Bistrion BR. Blackburn GL. Vitale J. et al: Prevalence of malnutrition in general medical patients. JAMA 235:1567-1570.1976 16. Mullen JL. Genner MH. Buzby GP. et al: Implications of malnutrition in the surgical patient. Arch Surg 114:121-125.1979 17. Steffer WP: Malnutrition in hospitalized patients. JAMA 244:2630-2635. 1980 18. Shakespeare PG. Ball AJ. Spurr ED: Serum protein changes afler abdominal surgery. Ann Clin Bim'hem 26:49-57.1989 19. Mullen JL: Consequences of malnutrition in the surgical patient. SlIrg Clin Narth Am 61 :465-487. 1981 20. Anderson CF. Wochos DN: The utility of serum albumin values in the nutritional assessment of hospitalized patients. Mayo Clin Pmc 57: 181-184.1982 21. Wasnold I. Lundholm K: Clinical significance of preoperative nutritional status in 215 noncancer patients. Ann Surg 199:299-305. 1984 22. Koch-Weser J. Sell us EM: Drug therapy: binding of drugs to serum albumin (pans I and II). N Engl J Med 294:311-316.526-531.1976 23. Vallner JJ: Binding of drugs by albumin and plasma protein. J Pharm Sci 66:447-465. 1977 24. Ruiz-Cabello F. Erill S: Abnormal serum protein binding of acidic drugs in diabetes mell itus. C Ii n Pharmacal Ther 36:691-695. 1984

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