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 RESEARCH ARTICLE

Risk factors for delirium in patients undergoing hematopoietic stem cell transplantation

Michelle T. Weckmann, MS, MD

Department of Family Medicine, Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA

Roger Gingrich, MD

Department of Internal Medicine, Division of Hematology, Oncology and Blood and Marrow Transplantation, University of Iowa Carver College of Medicine, Iowa City, IA, USA

James A. Mills, MS

Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA

Larry Hook, MD

Department of Psychiatry, Medical College of Wisconsin, Milwaukee, WI, USA

Leigh J. Beglinger, PhD

Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA

BACKGROUND: Delirium is common after hematopoietic stem cell transplantation (HSCT) and is associated with increased morbidity and mortality. Early recognition and treatment have been shown to improve long-term outcomes. We sought to investigate the relationship between potential risk factors and the development of delirium following HSCT.

METHODS: Fifty-four inpatients admitted for HSCT were assessed prospectively for delirium every 2 to 3 days during their inpatient stay using standardized delirium and neuropsychological measures. Self reports of medical history, medical records, and neurocognitive and psychiatric assessments were used to identify risk factors. Both pre- and post-HSCT risk factors were examined.

RESULTS: Delirium incidence was 35% and occurred with highest frequency in the 2 weeks following transplant. The only pre-transplantation risk factor was lower oxygen saturation (P = .003). Post-transplantation risk factors for delirium included higher creatinine (P < .0001), higher blood urea nitrogen levels (P = .005), lower creatinine clearance (P = .0006), lower oxygen saturation (P = .001), lower hemoglobin (P = .04), and lower albumin (P = .03). There was no observed association with level of cognitive performance, transplant type, disease severity, medical comorbidity index, age, or conditioning regimen.

CONCLUSIONS: Routine laboratory values can assist in the identification of high-risk patients before delirium onset to improve early detection and treatment of delirium after HSCT.

KEYWORDS: delirium, risk factors, cancer, hematopoietic stem cell transplantation

  INTRODUCTION

Delirium is the most common neuropsychiatric disorder in cancer patients, with an incidence ranging from 18% to 85%.1,2 The incidence is particularly high in patients with hematologic (up to 73%) or terminal (up to 85%) cancer.3 The acute and long-term negative outcomes from delirium are numerous and include significant patient distress, a greater mortality risk, longer hospital stay, increased hospital charges, decreased ability for self care resulting in nursing home placement, increased caregiver burden, long-term cognitive decline, and worsened Alzheimer’s disease.4-12 More than one-half of cases of recognized delirium can be reversed through the identification and management of underlying causes and the provision of concurrent symptomatic treatment. Unfortunately, delirium typically is not recognized in cancer patients, with >50% of the cases not diagnosed.5 With early recognition and treatment, some of the burden of delirium can be decreased.13 Identification of risk factors can aid in the recognition of delirium in cancer patients.14

Most studies examining delirium risk factors have focused on older hospitalized or medically ill inpatients. Recent studies focusing on risk factors for delirium in hospitalized patients with advanced cancer have reported inconsistent results, which may reflect the multi-factorial cause of delirium. In cancer patients, delirium has been linked to hypoxia, dehydration (increased creatinine, blood urea nitrogen [BUN], or sodium), anemia, decreased magnesium, decreased glucose, and decreased albumin as well as exposure to opioids, corticosteroids, and benzodiazepines.14-16 To our knowledge there have been 3 published studies6,17,18 looking specifically at the risk factor for delirium in hematopoietic stem cell transplantation (HSCT) patients with 2 of them6,17 looking at pre-transplant risk factors. Fann et al17 studied at 90 HSCT patients and reported that pre-transplant risk factors for delirium onset and severity included lower cognitive function, higher BUN, higher alkaline phosphatase, lower physical functioning, and higher magnesium.17 Re-analysis of the same 90-patient HSCT sample in 2011 focused on post-transplant risk factors and concluded that pre-transplant risk factors were higher mean alkaline phosphatase and BUN levels, and the only post-transplant risk factor for delirium onset was higher doses of opioid medications.18 Beglinger et al reported that pre-transplant risk factors for delirium in HSCT patients included decreased white blood cell count (WBC), hemoglobin, and platelet count.

Each year, approximately 50,000 patients worldwide undergo HSCT. Even if only one-third of these patients were to experience delirium, the potential burden and cost to the patient and society would be large. Although there have been studies detailing the phenomenon of delirium in HSCT patients and of risk factors for delirium in cancer patients, data on specific risk factors for delirium in HSCT patients are limited. Identifying delirium risk factors in the HSCT population may lead to increased detection and prevention of delirium as well as earlier treatment. These improvements could have a cascading effect to decrease morbidity, mortality, and cost. Our purpose was to replicate and extend previous work characterizing delirium. This was accomplished by prospectively identifying delirium following HSCT while looking for pre-and post-transplant risk factors for developing delirium.

  METHODS

Patients

Patients presenting to the University of Iowa Blood and Marrow Transplantation Program for an allogeneic or autologous bone marrow or peripheral blood HSCT between 2004 and 2008 were recruited for 2 delirium-related studies before or upon their admission. All patients scheduled for a transplant during the study enrollment period were evaluated for study eligibility, and were approached for enrollment if they met inclusion criteria. Participants who enrolled in 1 of 2 studies during this time where prospectively examined for delirium as well as for cognitive, psychiatric, and metabolic sequelae of HSCT. After completion of both studies, potential risk factors for delirium (ie, laboratory values and vital signs) were retrospectively extracted from the electronic medical record.

Procedures

The protocol and all study procedures were approved by the University of Iowa institutional review board. All patients provided written informed consent and were financially compensated for their participation in the study. Patients were assessed during a pre-transplantation visit ideally before any conditioning treatments occurred (eg, total body irradiation) with a 90-minute screening battery assessing cognitive and psychiatric functioning, delirium, demographics, and medical information. Patients who had delirium at the pre-transplantation screening were excluded from the study. During their inpatient stay after HSCT, patients completed a brief battery to monitor for delirium at scheduled 2- or 3-day intervals; a full description of the neuropsychological testing procedures completed during those visits are presented elsewhere.6,19,20 In addition, if hospital staff noticed delirium symptoms during a non-assessment day, the research team was notified and a visit was scheduled as soon as possible. A trained research assistant or neuropsychologist conducted all cognitive and psychiatric functioning and delirium assessments. If a psychiatric consultation was requested during the course of the study the patient received usual treatment with no effect on participation in the study.

Transplantation assessment/measurements

Medical history and status. General and medical backgrounds of each patient was assessed using a semi-structured clinical interview at enrollment. Specifics can be found in previously published papers.6 Medical comorbidity information was extracted by chart review after the hospital admission and was documented using the hematopoietic cell transplantation comorbidity index (HCT-CI), which is validated in HSCT patients and correlates with survival in this patient population.21-23 Performance status (ie, functional level) was measured with the Karnofsky Performance Status (KPS), which was collected from the pre-transplantation medical assessment. The KPS correlates well with the Eastern Cooperative Oncology Group performance status scale and is predictive of treatment failure in geriatric cancer patients.23,24 Types of conditioning regimens, including total body irradiation, were documented.

A retrospective chart review was conducted to compile vital signs and laboratory test data in the 24-hour period before the pre-transplantation visit and the 24- and 48-hour intervals before post-transplantation delirium assessments. The shortest time between delirium assessments was 48 hours. We did not look at earlier data collection to prevent overlap between collection times and delirium assessments. The 24-hour mark was selected because it was available for most patients and the literature does not clearly define how long a risk factor needs to be present before delirium occurs. Data collected for the study included laboratory values for hemoglobin, hematocrit, WBC count, platelet count, BUN, creatinine, estimated creatinine clearance (calculated using the Cockcroft-Gault formula), magnesium, alkaline phosphatase, albumin, aspartate aminotransferase, alanine transaminase, total bilirubin, sodium, and glucose. In addition, highest temperatures, highest nursing-reported scaled pain levels, and lowest oxygen saturation levels (obtained by bedside oximetry) were collected. Values not present in the chart were treated as a missing data point in the statistical analysis.

Delirium assessment. The delirium assessment interval varied because each of the 2 studies analyzed had a different assessment schedule. All attempts were made to adhere to the scheduled delirium assessment intervals, but some assessments were not completed because of logistics or patient-centered reasons. On average, each patient was assessed 2 to 3 times per week after transplant using validated screening instruments. There are no screening tools validated in HSCT patients; however, the most common research tools to diagnose delirium are the Delirium Rating Scale (DRS) and DRS-Revised (DRS-R).25,26 These scales of delirium severity are based on all available information from patient interviews, family and nurses’ reports, cognitive tests, and medical reports measured over the previous 24 hours (DRS cutoff >12; DRS-R cutoff is 15 for severity or 18 total score). We also used the Memorial Delirium Assessment Scale (MDAS),27 which measures delirium presence and severity, can be administered multiple times a day (cutoff ≥8), and is validated in patients with advanced cancer.28 The following tests also were included in the delirium assessment during the inpatient stay to measure neuropsychological status and assist with delirium assessment: Trail Making Test, Modified Mini-Mental State (3MS), and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)—List Learning, Coding, Semantic Fluency, and Digit Span. For more details about the neuropsychological battery, please refer to Beglinger et al.20

Statistical analysis

Patients with DRS or MDAS scores higher than the cutoff value at any point after transplantation were coded as having delirium. Time to delirium was defined as the time between transplant and a positive delirium assessment. Patients were censored if they had not experienced delirium by the end of the hospital stay. Baseline cognitive, psychiatric, and medical laboratory variables were analyzed univariately with the Cox proportional hazards regression model to determine their relationship with time to delirium.29 Post-transplantation medical laboratory variables were treated as time-dependent in univariate Cox proportional hazards regression models to examine their association with delirium. Multivariate Cox proportional hazards regression models were created using the most highly significant variables from the univariate analysis. All Cox models used Efron’s method for handling ties.30 A P value of <.05 was considered significant. All statistical tests were corrected for multiple comparisons using a false discovery rate of ≤.05.31

  RESULTS

Patient characteristics

Fifty-four patients consented to participate in the 2 studies. One patient was excluded because of delirium at the pre-transplant assessment. Two patients in the delirium group did not experience a delirium episode during their hospitalization after HSCT, but did at a later date, and have been excluded from the analysis. The remaining patients completed 2 to 4 acute-phase assessments after transplantation (mean = 3.3; standard deviation [SD] = 1.0). The majority of the patients were male (71%), had lymphomas or leukemia (59%), and received myeloablative therapy (94%). Mean age was 53.3 (SD = 10.7). More patients received an autologous transplant (57%) than an allogeneic transplant (43%). Patients who underwent autologous HSCT received high-dose, multi-agent chemotherapy for myeloablative therapy. Allogeneic HSCT patients mostly received total body irradiation and high-dose chemotherapy or busulfan-based high-dose chemotherapy. The majority of the transplants were done using peripheral blood hematopoietic stem cells (75%). Patient characteristics are shown in TABLE 1.


TABLE 1

Description and univariate analysis of pre-transplant characteristics of patients undergoing HSCT (N = 51)

Characteristics Number of sample (%) (N = 51) No delirium (n = 35) Delirium (n = 16) Hazard ratio (95% CI) P value uncorrected P value corrected
Age, yrs (range, 21 to 69) 51 (100%) 35 16 1.02 (0.97 to 1.08) .38 .64
  Mean (SD)   52.4 (10.3) 55.3 (11.8)      
Education, yrs (range, 11 to 21) 51 (100%) 35 16 1.03 (0.87 to 1.23) .69 .85
  Mean (SD)   14.2 (2.5) 14.5 (3.6)      
Sex 51 (100%) 35 16 1.13 (0.39 to 3.25) .83 .90
  Male (reference) 36 (71%) 25 11      
  Female 15 (29%) 10 5      
Diagnosis 51 (100%) 35 16   .07 .36
  Leukemia 11 (22%) 10 1 0.57 (0.18 to 1.80) .34  
  Lymphoma 19 (37%) 11 8 0.09 (0.01 to 0.79) .03  
  Myeloma 13 (25%) 11 2 0.20 (0.04 to 1.02) .05  
  Other (reference) 8 (16%) 3 5  
Donor type 51 (100%) 35 16 0.71 (0.26 to 1.96) .51 .76
  Autologous (reference) 29 (57%) 19 10      
  Allogeneic 22 (43%) 16 6      
Stem cell type 51 (100%) 35 16 0.70 (0.24 to 2.03) .51 .76
  Bone marrow (reference) 13 (25%) 8 5      
  Peripheral 38 (75%) 27 11      
Functional status (KPS) 43 (84%) 29 14 1.03 (0.96 to 1.10) .40 .66
  ≤70 2 (5%) 2 0      
  80 11 (26%) 8 3      
  90 23 (53%) 14 9      
  100 7 (16%) 5 2      
HCT-CI Score 50 (98%) 34 16 1.17 (0.33 to 4.18) .81 .89
  0 to 1 29 (58%) 16 13      
  2 to 3 14 (28%) 14 0      
  >3 7 (14%) 4 3      
Conditioning agents 51 (100%) 35 16      
  Number of agents (continuous) 51 (100%) 35 16 1.33 (0.86 to 2.05) .20 .46
  Total body irradiation       0.94 (0.21 to 4.14) .93 .95
  No (reference) 45 (88%) 31 14      
  Yes 6 (12%) 4 2      
  Agent that crosses blood brain barrier       1.62 (0.52 to 5.04) .41 .66
  No (reference) 18 (35%) 14 4      
  Yes 33 (65%) 21 12      
Neuropsychological
  3MS total 51 (100%) 35 16 1.04 (0.93 to 1.16) .48 .74
  RBANS total 27 (53%) 19 8 1.01 (0.97 to 1.04) .77 .89
  Trails A Z-score 27 (53%) 19 8 1.22 (0.71 to 2.10) .47 .74
  Trails B Z-score 27 (53%) 19 8 0.98 (0.73 to 1.31) .90 .92
Psychiatric
  Depression 51 (100%) 35 16 1.78 (0.87 to 3.62) .11 .36
3MS: Modified Mini-Mental State; CI: confidence interval; HCT-CI: hematopoietic cell transplantation specific comorbidity index; HSCT: hematopoietic stem cell transplantation; KPS: Karnofsky Performance Status; RBANS: Repeatable Battery for the Assessment of Neuropsychological Status; SD: standard deviation; Trails A: Trail Making Test Part A; Trails B: Trail Making Test Part B.

The following case illustrates delirium risk factors that may occur in a patient after HSCT. Mrs. R was a 52-year-old married female who had been diagnosed with lymphoma 2 years before transplant. She received 2 chemotherapeutic regimens before transplant. At hospital admission she had an excellent functional status (KPS = 80) and her medical comorbidities included fibromyalgia, hypothyroidism, and arthritis. Mrs. R’s baseline testing showed good cognitive functioning and no evidence of delirium or depression. Her conditioning regimen was myeloablative and included carmustine, cytarabine, etoposide, and cyclophosphamide, which she tolerated well. She received standard medications after transplant, which included prophylactic antibiotics per guidelines (including trimethoprim/sulfamethoxazole, voriconazole, levofloxacin, piperacillin/tazobactam, and acyclovir). She received IV morphine for mouth and throat pain. Transplant complications were all expected and included pancytopenia, requiring transfusion support, as well as GI toxicity with oral mucositis and diarrhea requiring total parenteral nutrition. Five days after transplant the treatment team remarked that she had a difficult night with a post-transfusion fever (38.5°C) and chest discomfort. That morning her delirium screen was positive (MDAS = 9, DRS = 8), with deficits in her performance on the 3MS, Trail Making Test Part A (Trails A), and RBANS—Coding and List Recall subtests. No behavioral disturbances are described in the chart. Abnormal labs in the 24 hours before her delirium showed creatinine (1.6 mg/dL), BUN (40 mg/dL), WBC count (200/μL), hemoglobin (9.1 g/dL), and platelets (8 ×103/μL). Her electrolytes, vital signs, pulse oximetry, and pain scores were normal. Her fever and elevated creatinine resolved over the next day. Her delirium screen remained slightly elevated, but not to the diagnostic cut-off, indicating a potential subsyndromal delirium and she showed continued deficits in cognitive functioning (deficits in Trails A as well as List Recall and Coding), which persisted at discharge 2 weeks later.

Descriptive delirium results

The number of patients who exceeded the cutoff for delirium on either scale at any point during hospitalization after HSCT was 18/51 (35%). The highest prevalence for delirium was in the first 2 weeks after transplant (15/18; 84%) and most of the delirium was only picked up during 1 screening visit (12/18; 67%), with a mean duration of 2.4 days. The timing is defined in more detail in a previous paper.20 Because 2 studies were combined for the purpose of exploring predictors of delirium, only 2-week data following HSCT (the length of the shorter study) were looked at. In addition 2 patients with delirium were excluded from the analysis of risk factors because delirium occurred >2 weeks after transplant, making the total number of patients with delirium 16 (31%) for the analysis.

Delirium risk factors

Pre-transplantation. Descriptions and univariate comparisons of pre-transplantation characteristics among patients with and without delirium are shown in TABLE 1. Using univariate Cox proportional hazards regression model, we examined demographic and disease-related variables at baseline, including age, diagnosis, medical comorbidity using the HCT-CI, functional status using the KPS, and chemotherapeutic agents. None of these were statistically significant predictors of delirium in our sample. Cox proportional hazards regression model was used to analyze the conditioning agents based on the number of agents received; whether the agent used crosses the blood-brain barrier or has known neurological effects (carmustine, etoposide, cytarabine, busulfan); and the use of total body irradiation. In addition, there was no association with pre-transplant depression score or cognitive level measured by RBANS, 3MS, and Trails Parts A and B. Univariate comparisons of pre-transplant laboratory values and vital signs did not show an association with delirium, with the exception of a lower oxygen saturation (hazard ratio = 0.66; 95% confidence interval 0.50 to 0.87; P = .003). Of the 16 patients who experienced delirium, 10 had a recorded pre-transplant oxygen saturation. Pre-transplant oxygen saturation predicted delirium at the first visit post-transplant (P = .03) but not at subsequent visits (2, 3, or 4), and it appeared that oxygen saturation levels ≤92% were of concern.

Post-transplantation. Descriptions and univariate comparisons of post-transplantation risk factors among patients with and without delirium are shown in TABLE 2. Because this was a small exploratory study, we are reporting the uncorrected P values (analysis does not correct for multiple variables) to ensure inclusion of any variables that might be related to delirium are highlighted, recognizing that we may have false positives. The corrected P values (corrected for multiple variables) also are reported in TABLE 1, TABLE 2, and TABLE 3. In univariate tests, higher 24- and 48-hour creatinine (P = .0003, P < .0001), higher 24- and 48-hour BUN (P = .002, P = .005), lower 24- and 48-hour creatinine clearance (P = .0009, P = .0006), lower 24- and 48-hour oxygen saturation (P = .010, P = .001), lower 48-hour hemoglobin (P = .04), and lower 24-hour albumin (P = .03) were significant. With the exception of albumin, no values showed significance at only the 24-hour collection time. Therefore, for simplicity, only 48-hour values are shown in TABLE 2. Multivariate analysis of 48-hour blood urea nitrogen, 48-hour creatinine, and 48-hour oxygen showed that 48-hour BUN and 48-hour creatinine are redundant in the model. For the other 2 models (1 with 48-hour blood urea nitrogen and 48-hour oxygen and the other with 48-hour creatinine and 48-hour oxygen), both predictors remained significant (TABLE 3).


TABLE 2

Descriptive and univariate analysis of clinical risk factors for delirium following HSCT (N = 51)

Laboratory and vitals (ref range) Mean (range; SD) Hazard ratio (95% CI) P value uncorrected P value corrected
Electrolytes
Sodium (135 to 145 mEq/L)   0.98 (0.87 to 1.12) 0.80 0.89
  Delirium (n = 16) 136 (126 to 141; 3.9)      
  No delirium (n = 34) 136 (125 to 142; 3.9)      
Magnesium (1.5 to 2.9 mEq/L)   2.57 (0.85 to 7.80) 0.09 0.36
  delirium (n = 16) 2.1 (1.3 to 2.8; 0.3)      
  No delirium (n = 33) 1.9 (1.5 to 2.8; 0.3)      
Glucose (65 to 99 mg/dL)   1.00 (0.99 to 1.00) .48 .74
  delirium (n = 13) 151 (75 to 262; 52)      
  No delirium (n = 28) 209 (72 to 868; 166)      
Metabolic
Blood urea nitrogen (10 to 20 mg/dL)   1.05 (1.01 to 1.09) 0.005 .05
  delirium (n = 16) 27 (8 to 73; 17)      
  No delirium (n = 34) 18 (7 to 61; 11)      
Creatinine (0.7 to 1.4 mg/dL)   31.8 (5.60 to 180.79) <.0001 .007
  delirium (n = 16) 1.1 (0.6 to 1.7; 0.3)      
  No delirium (n = 34) 0.8 (0.5 to 1.9; 0.3)      
Creatinine clearance (80 to 120 mL/min/1.73 m2)   0.97 (0.95 to 0.99) .0006 .01
  delirium (n = 16) 96 (40 to 197; 38)      
  No delirium (n=34) 142 (13 to 334; 57)      
Alkaline phosphatase (40 to 129 U/L)   0.98 (0.96 to 1.01) .27 .54
  delirium (n = 11) 67 (44 to 125; 26)      
  No delirium (n = 17) 83 (47 to 146; 33)      
Aspartate aminotransferase (0 to 37 U/L)   0.99 (0.96 to 1.02) .60 .80
  delirium (n = 13) 23 (8 to 62; 17)      
  No delirium (n = 21) 24 (8 to 110; 22)      
Bilirubin, total (0.2 to 1.0 mg/dL)   0.97 (0.78 to 1.20) .77 .89
  delirium (n = 15) 1.4 (0.3 to 9.6; 2.3)      
  No delirium (n = 26) 1.7 (0.2 to 21.1; 4.1)      
Albumin (3.4 to 4.8 g/dL)   0.43 (0.10 to 1.75) .24 .51
  delirium (n = 6) 3.0 (1.7 to 3.5; 0.6)      
  No delirium (n = 18) 3.2 (2.8 to 4.2; 0.3)      
Hematologic
White blood cells (3,700 to 10,500/μL)   0.69 (0.32 to 1.50) .35 .63
  delirium (n = 16) 0.4 (0.1 to 2.5; 0.6)      
  No delirium (n = 34) 1.4 (0.1 to 9.0; 2.1)      
Platelets (150 to 400 ×103/μL)   0.96 (0.92 to 1.01) .14 .36
  delirium (n = 16) 14 (3 to 45; 12)      
  No delirium (n = 34) 22 (5 to 71; 16)      
Hemoglobin (11.9 to 17.7 g/dL)   0.61 (0.39 to 0.97) .04 .25
  delirium (n = 16) 8.4 (6.7 to 10.6; 1.0)      
  No delirium (n = 34) 9.2 (7.0 to 11.6; 1.0)      
Vital signs
Weight (kg)   0.99 (0.96 to 1.01) .28 .54
  delirium (n = 16) 83 (57 to 125; 16)      
  No delirium (n = 34) 91 (61 to 143; 21)      
Oximetry (0 to 100%)   0.82 (0.72 to 0.92) .001 .02
  delirium (n = 15) 92 (79 to 97; 4.5)      
  No delirium (n = 32) 94 (89 to 98; 1.9)      
Pain score (0 to 10)   1.17 (0.95 to 1.45) .14 .36
  delirium (n = 15) 3.5 (0 to 8; 2.9)      
  No delirium (n = 30) 1.7 (0 to 7; 2.1)      
Temperature (36.1 to 37.2°C)   1.40 (0.91 to 2.17) .13 .36
  delirium (n = 16) 38.5 (37.6 to 39.8; 0.7)      
  No delirium (n = 33) 37.8 (36.5 to 40.3; 0.9)      
CI: confidence interval; HSCT: hematopoietic stem cell transplantation; SD: standard deviation.

TABLE 3

Multivariate analysis of 48-hour blood urea nitrogen, creatinine, and oxygen levela

Parameter Hazard ratio 95% hazard ratio confidence limits P value
Creatinine 25.32 4.45 to 144.07 .0003
Oxygen 0.81 0.71 to 0.92 .002
       
Creatinineb 35.13 3.12 to 396.09 .004
Blood urea nitrogenb 1.00 0.95 to 1.05 .90
       
Blood urea nitrogen 1.05 1.00 to 1.09 .04
Oxygen 0.84 0.74 to 0.94 .004
apatients undergoing hematopoietic stem cell transplantation (N = 51).
bredundant.

  DISCUSSION

In our sample of adults undergoing HSCT, the incidence of delirium was 35% and occurred most frequently during the first and second week after transplantation. The frequency of delirium found in this study was lower than that reported by Fann,32 higher than that reported by Prieto et al,33 but similar to the frequency reported by Beglinger et al.6 The similarity with Beglinger et al is to be expected because of sample overlap, and the low incidence reported by Prieto et al is likely because of once-weekly screening. The median duration of delirium was significantly shorter than reported by Fann et al (8 days)17 in HSCT patients but similar to that reported in advanced cancer patients.15 It is possible that in the decade since the Fann sample was collected, improved supportive care measures mitigate toxicities of conditioning regimens. Results among studies are remarkably consistent with regard to timing, with the highest delirium prevalence the first 2 weeks post-transplantation. The results of these studies underscore the importance of monitoring for delirium immediately after transplantation because most patients are likely to develop at least mild symptoms. These symptoms have the potential to complicate care, leading to increased costs and length of stay. Emerging evidence on the reliability of delirium timing also may inform preventative treatment strategies similar to those in geriatric patients before they undergo a surgical procedure.34,35

Diagnosis of delirium requires an underlying medical abnormality for delirium to be diagnosed. A person’s predisposition to developing delirium is based on baseline and precipitating factors, and risk increases with the number of risk factors.36 Baseline risk factors include age, sex, education, and cognitive functioning and often cannot be mitigated. Precipitating factors in cancer patients include medications, infections, hypoxia, hematological vs solid tumors, presence of bony metastases, dehydration, withdrawal, and CNS involvement.8,37 Although many factors have been suggested to increase delirium risk in cancer patients, there is substantial variance and little is known about specific risk factors in the various cancer populations. Causes of delirium are numerous; often delirium is multi-factorial (>40%), making it difficult to treat.38 This study succeeded in identifying additional precipitating factors for developing delirium after HSCT.

In this study we found the lower blood oxygen saturation and renal dysfunction correlated with delirium in our HSCT patients. Blood oxygen saturation level is notable because it was the only positive factor both pre- and post-transplant. Reduced oxygen saturation may be a surrogate marker for other underlying conditions such as sepsis or cardiorespiratory insufficiency making it difficult to determine if delirium is a result of low blood oxygen saturation or an underlying process. We feel sepsis is less likely in this population because of rigourous screening and monitoring for acute infection as well as the lack of significant association between delirium and an altered WBC count (most patients demonstrated laboratory evidence of bone marrow suppression). Renal dysfunction—as evidenced by increased BUN and creatinine levels and lower creatinine clearance in patients with delirium—was strongly correlated with delirium in the 48 hours before developing delirium. The tendency for patients with renal dysfunction to develop delirium may be caused by direct biochemical changes associated with increased lab values, reduced clearance of drugs, or underlying medical condition. Altered renal blood flow and resulting renal dysfunction often is a surrogate measure of severity of various underlying medical diseases. In addition, a number of factors that can serve as overall markers of disease severity and functional status (hemoglobin, hematocrit, and albumin) were not as strongly significant. These findings likely are related the fact that delirium often is multifactorial.

Although our findings partially support the finding of Fann et al17 that an elevated BUN level pre-transplant is associated with an increased rate of delirium, our pre-transplant markers of renal function were not associated with delirium. This may be related to the small sample size and missing data. We also found additional post-transplant factors, which were not identified by Fann et al.18 Although both studies assessed patients after HSCT, there is a significant difference in the sample characteristics. The sample by Fann et al had a preponderance of allogenic (81%) and bone marrow transplants (74%) receiving total body irradiation (59%) while our sample characteristics were the opposite (43% allogenic, 13% bone marrow, 12% total body irradiation). It is possible that the types of transplant, stem cell used, and conditioning may affect delirium risk. Larger studies are needed to separate out these differences.

Although we identified an association between delirium and several precipitating factors in our sample, we were struck by the number of variables that did not show an association with delirium risk. Although age has been found to be a risk factor for delirium in cancer patients,14,39 it has not been a significant predictor of delirium in studies of HSCT patients; this may reflect the fact that older patients are less likely to receive HSCT. In a frequency distribution of age in our sample we found 50% of the delirium occurred in patients age <55 and 14% in patients age <40. It is difficult to find studies that examine delirium in patients age <65 with which to compare. Our findings may reflect a unique aspect of delirium in HSCT patients (such as high-dose chemotherapy), or it may be an indicator of severity of physiological stressors associated with HSCT and how acutely medically ill these patients are after transplant. Medical comorbidity has been shown to be a risk factor for delirium in older medical patients40 but had not been well studied in cancer patients. Comorbidity was not a significant predictor of delirium in our sample even when using a morbidity index specific to HSCT patients. This confirms previous studies in patients after HSCT that did not find disease severity or functional status to be a predictor of delirium.41 These results may reflect a built-in selection bias for otherwise healthier patients who are candidates for transplantation. It is unclear as to whether transplant type influences delirium risk but our work supports published work indicating no correlation.32,33 Chemotherapy is a massive inflammatory insult to the brain and body; therefore, we had expected a relationship between conditioning agents and delirium, specifically those that cross the blood-brain barrier. The lack of correlation we found may be related to our sample size and the frequency each agent is used in conditioning patients for transplantation. A larger study may show that toxicity related to specific chemotherapeutic agents is a risk factor for delirium. Pain is related to delirium in medical patients42,43; however, we did not see a statistical difference although patients with delirium had a nurse-reported pain score 3-times higher than the patients without delirium. Although it is possible that patients undergoing HSCT do not experience much pain, we believe the lack of relationship between delirium and pain may be related to the difficulties in objectively translating patient pain levels to a reliable numeric scale.

This study adds to the growing body of literature on risk factors and prevalence of delirium in patients receiving HSCT. It is notable that even in our small sample, oxygen levels and creatinine were more predictive of delirium than age, disease severity, or medical comorbidities. Although the prospective structure of this study in identifying delirium is a clear advantage, there are limitations, most notably being the sample size in comparison with multiple variables examined. The study was powered to identify only robust associations and equally important but weaker associations may have been overlooked. The study size was not robust enough to define laboratory values above or below which a prediction for developing delirium can be made. Rather, we have generated mean values for a group of patients that vary between the patients with and without delirium and those values become surrogate markers for derangements in pathology that are statistically correlated with delirium onset. The initial study focus was prospective identification of delirium and its neuropsychiatric sequelae, and the treatment team was allowed to follow usual clinical care without interference. The retrospective capture of laboratory correlates led to missing values, which would have been avoided if the study had been designed to draw a select panel of laboratory tests before each delirium evaluation. The delirium evaluations were not performed daily, leaving some uncertainty regarding the exact time of delirium onset and the possibility of missing a delirium episode. However, given the duration of delirium in this study as well as our daily chart review and regular contact with the treatment team we believe the chance of missing a delirium episode is low.

This study identified common metabolic markers that indicate a risk for developing delirium after HSCT. The high rate of delirium in the first 2 weeks after transplant supports the need for close monitoring of this patient population. Early detection is particularly critical because there is evidence that successful interventions can improve outcomes for patients with delirium.34,44 Our findings continue to highlight the differences between the HSCT patient population and other cancer patients. Further research is needed before our findings can be generalized to other patient populations. We hope that our findings will lead to prospective studies on treatment and delirium prevention. By identifying high-risk patients, clinicians can focus their efforts on modifiable delirium risk factors, such as preventative supplemental oxygen for mild hypoxia, attention to nutritional status with early supplementation based on albumin levels, and monitoring renal function and fluid status. These efforts could reduce the rate of delirium in this high-risk population. In addition, clinicians need to develop a lower threshold for recognition and early treatment of delirium, which may result in decreased morbidity and mortality in this critically ill population.

DISCLOSURES: Dr. Weckmann receives grant or research support from the American Cancer Society. Drs. Gingrich, Hook, and Beglinger, and Mr. Mills report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

ACKNOWLEDGEMENTS: The authors wish to acknowledge the patients and families who volunteered their time to participate in this study, the nurses and physicians of our participants, and Stacie M. Vik, Sara Van Der Heiden, and William H. Adams for their assistance.

Support for this research was provided by the University of Iowa Cancer and Aging Program in the Holden Comprehensive Cancer Center to L.J. Beglinger (NCI/NIA P20 CA 103672, PI: Wallace).

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CORRESPONDENCE: Michelle T. Weckmann, MS, MD, Department of Family Medicine, 01102 PFP, University of Iowa Carver College of Medicine, Iowa City, IA 52242-1000 USA E-MAIL: michelle-weckmann@uiowa.edu