Studies on delirium and associated cognitive and functional decline in older surgical patients
Beishuizen, Sara
DOI:
10.33612/diss.135861414
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Publication date: 2020
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Beishuizen, S. (2020). Studies on delirium and associated cognitive and functional decline in older surgical patients: The time is now to improve perioperative care and outcomes. University of Groningen.
https://doi.org/10.33612/diss.135861414
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Chapter 5
The effect of blood transfusion on delirium incidence
Vera van der Zanden Sara J. Beishuizen Rikie M. Scholtens Annemarieke de Jonghe Sophia E. de Rooij Barbara C. van Munster
ABSTRACT
Objectives: Both anemia and blood transfusion could be precipitating factors for delirium, hence in postoperative patients with anemia at high risk for delirium, it is controversial whether transfusion is the best option. The aim of this study is to investigate the association of anemia and delirium and the role of blood transfusion within the multicomponent prevention strategy of delirium.
Design, Setting, Participants, Measurements: We conducted a sub study of a multi-center randomized controlled trial. Four hundred and fifteen patients aged 65-102 years old, admitted for hip fracture surgery, were enrolled. Delirium was assessed daily using criteria of the
Diagnostic and Statistical Manual of Mental Disorders, fourth edition. Data on hemoglobin
values and transfusion were collected from the electronical medical records.
Results: One hundred and fifteen (32.5%) patients experienced delirium during hospitalization, 238(57.5%) had a hemoglobin level ≤6.0 mmol/l(9.7 g/dl) at any time during hospitalization, and 140(33.7%) received a blood transfusion. Anemia (a hemoglobin level ≤6.0 mmol/l(9.7 g/dl)) was associated with delirium (OR 1.81, 95%CI 1.15-2.86). Blood transfusion was a protective factor for delirium in patients with lowest measured hemoglobin level ≤6.0 mmol/l (9.7 g/dl) (OR 0.26, 95%CI 0.10-0.70).
Conclusion: Low hemoglobin level is associated with delirium and receiving a blood transfusion is associated with a lower delirium incidence. It would be interesting to investigate the effect of blood transfusion as part of the multicomponent treatment of delirium in patients with anemia.
INTRODUCTION
Delirium has an incidence of 37-46% in a general surgery population, and is associated with a higher risk of hospital-acquired complications.1,2 By reducing the incidence of delirium, negative
sequels for the patient can be prevented and health care related costs can be reduced.2
Delirium is by definition caused by the direct physiological consequences of a general medical condition, mostly a combination of different factors.3 Taking away these underlying factors in a
multicomponent approach is the cornerstone of the prevention and treatment strategy of delirium.2 Since anemia is potentially one of the precipitating factors for post-operative delirium,
prevention or treatment of perioperative anemia should be part of this multicomponent approach.4-6 The quickest way to treat anemia is through a blood transfusion, but transfusion in
itself is identified as risk factor for delirium as well.7 Blood transfusion can lead to a systemic
inflammatory response, which can result in neuro inflammation in patients with a reduced functional reserve of the brain.8-12
There have been a number of Randomized Controlled Trials (RCTs)13-16 that demonstrate a lower
transfusion threshold is as safe as a conservative transfusion strategy. They all showed either no benefit or increased harm from lower transfusion thresholds, but they did not specifically included delirium as outcome. Consequently, in postoperative patients with anemia at high risk for delirium or with prevalent delirium, it is still controversial whether transfusion is the best option for delirium management. Therefore, the aims of this study were: 1. To investigate the association of anemia with delirium incidence and 2. To explore the effects of blood transfusion on delirium incidence.
METHODS
Study design and setting
Data of a multicenter randomized controlled trial (RCT), of which the protocol17 and the results18
have been published previously, were used. This trial investigated whether prophylactic in hospital use of melatonin could prevent delirium after hip fracture, which could not be demonstrated. The study was conducted between November 2008 and May 2012 in the surgical,
orthopedic and trauma surgery wards of the Academic Medical Center and Tergooi Hospitals in the Netherlands. The study was undertaken in compliance with the Helsinki Declaration and Good Clinical Practice Guidelines and approved by the Medical Ethics Committee of the Academic Medical Centre. From all patients, or a legal representative in case of cognitive impairment, written informed consent was obtained. The trial was registered with the Dutch Clinical Trial Registry (NTR1576).
Participants
Patients aged 65 years or older who were admitted for any kind of surgical treatment of hip fracture were enrolled in the original trial.18 Patients were excluded in the trial if they had been
transferred from another hospital, if postoperative admission to the ICU or coronary care unit was anticipated, if they were already taking melatonin, or if they were unable to speak or understand Dutch. For the present study, we also excluded patients without available hemoglobin and transfusion data.
Procedures
Within 24 hours of admission all patients aged 65 years or older with emergent hip fracture were screened for eligibility and asked to participate by a member of the research team, which consisted of geriatricians and trained research nurses with experience in geriatrics. Surgery usually took place on the first or second day of hospitalization, in accordance with national guidelines.
In case of postoperative delirium all patients were treated according to standard procedures and assessed for delirium severity and duration. The multicomponent treatment consisted of non-pharmacological interventions and treatment of any underlying disease according to the hospital guidelines, combined with anti-psychotics (most frequently haloperidol) in case of a clinical diagnosis of hyperactive or mixed delirium. Daily adjustment of medication took place depending on the clinical judgment of the consulting geriatric team and/or the attending physician. Antipsychotic medication was standardized as much as possible, with escape medication in case of acute aggravation. No antipsychotics were given for preventive purposes. Patients on psychiatric medication, apart from their delirium medication, could continue their prescriptions throughout the study period.17
Data assessment
At baseline, demographic data, medical history, medication use and surgery related characteristics were recorded. Functional status was assessed with the 15-item modified Katz Index of Activities of Daily Living 19, based on the two weeks prior to admission. This
instrument was completed by the patient or, in case of cognitive impairment, by his or her closest relative. Functional impairment was calculated as the sum of activities of daily living with impairment.19 Primary caregivers were asked to complete the Informant Questionnaire on
Cognitive Decline short form (IQCODE-sf) by recalling the two weeks before the hip fracture and comparing this period with 10 years earlier.20,21 Cognitive impairment was defined as a score
of 3.4 or higher on this questionnaire or a record of dementia in the medical history.22 The
number and severity of comorbidities was scored with the Charlson Comorbidity Index.23
Patients were asked whether they had ever experienced an episode of delirium.
Fracture characteristics, type of anesthesia, type of surgery, length of stay, in hospital deaths, hemoglobin levels, and number and date of transfusions were obtained from the electronic medical records. Data on 30-day mortality were obtained at a follow-up contact with the patient or caregiver. We used two different variables to assess anemic state: lowest hemoglobin level measured during hospitalization, and hemoglobin level ≤6.0 mmol/l (9.7 g/dl) during hospitalization (yes/no). The latter cut-off point was chosen because transfusion is considered below this level in The Netherlands.24
Delirium was assessed by a member of the research team using criteria from the Diagnostic and
Statistical Manual of Mental Disorders, fourth edition.25 Each patient was assessed daily during
the first eight study days or until discharge. For patients who had delirium on day 8, daily clinical assessments were continued to determine the duration of delirium, until discharge. This assessment incorporated all patient information from medical and nursing records for the previous 24 hours. In addition, the Delirium Observation Screening Scale26 was completed for
each patient during each nursing shift.
Statistical analysis
All statistical analysis were performed using the Statistical Package for the Social Sciences (SPSS), version 22.0. Baseline differences between patients with and patients without delirium
and with and without blood transfusion for the different study groups (prevention/treatment) were compared using a Chi square test or Mann Whitney U test, as appropriate.
To determine if anemia is associated with delirium, all eligible patients were included. Given the close temporal relationship between the first occurrence of hemoglobin level ≤6.0 mmol/l (9.7 g/dl) and the onset of delirium, that is, mostly occurring on the day of surgery or the day after, we decided to assess the association between hemoglobin level ≤6.0 mmol/l (9.7 g/dl) and delirium at any time during hospitalization, instead of focusing only on patients in whom delirium first occurred the day after a hemoglobin level ≤6.0 mmol/l (9.7 g/dl) was measured. We performed a logistic regression with hemoglobin level ≤6.0 mmol/l (9.7 g/dl) during hospitalization (yes/no) as outcome measure. Age and Charlson Comorbidity Index >1 (because the median score was 1) were added as covariates. In a backward selection, variables with a p-value>0.05 were discarded from the model.
To study an effect of transfusion on delirium incidence, we included only patients with a lowest measured hemoglobin level ≤6.0 mmol/l (9.7 g/dl) at any time during hospital stay. Patients in the group that received a transfusion were only included when the transfusion took place before the onset of delirium. Because transfusion and delirium timing were both only known per day, patients that got their transfusion on the same day as delirium onset were excluded. Also, patients that received transfusions in more than one separated period (for example on day 1 and 4) were excluded. For the control group there were no other exclusion criteria. A logistic regression was performed with delirium incidence as the outcome variable and lowest measured hemoglobin level, age, Charlson Comorbidity Index >1 and Katz-ADL as covariates. In a backward selection, variables with a p-value >0.05 were discarded from the model.
RESULTS
Participants and baseline data
From the 452 eligible patients, we included 415 patients in our sub analysis (Figure 1). Table 1 shows the baseline characteristics of all included patients. One hundred thirty-five (32.5%) patients experienced delirium during hospitalization. They were significantly older and had higher scores on the Charlson Comorbidity Index. Additionally, they had lower hemoglobin
levels, more often received a blood transfusion, had a longer length of hospital stay, and a higher rate of 30-day mortality. Delirium was most frequently diagnosed on the day of surgery (N=43 (32.1%)), and on that same day the highest frequency of blood transfusions occurred (N=59 (42.1%)). A hemoglobin level ≤6.0 mmol/l (9.7 g/dl) was most often measured for the first time on the day of surgery (N=77 (32.2%)) or the day after surgery (N=78 (32.6%)).
Association between anemia and delirium incidence
In multivariate analysis, adjusted for age and score of the Charlson Comorbidity Index, having a hemoglobin level ≤6.0 mmol/l (9.7 g/dl) in at least one measurement during hospitalization (OR 1.81, 95%CI 1.15-2.86) was associated with a higher delirium incidence.
Association between transfusion and delirium incidence
To analyze the effect of blood transfusion on delirium incidence, 160 patients were included. Reasons for exclusion were: hemoglobin level above 6.0 mmol/l (9.7 g/dl) (N=177), more transfusion periods (N=30), delirium present before transfusion (N=40), and delirium and transfusion on the same day (N=8). Patients with and without transfusion differed only in terms of preadmission Katz score (median 7.0 versus 5.0, p=0.018) and lowest hemoglobin level measured during hospitalization (median 4.9 mmol/l (7.9g/dl) versus 5.4 mmol/l (8.7g/dl),
p<0.001). There were no significant differences between the groups in age, sex, living at home,
Charlson Comorbidity Index, cognitive impairment, prior delirium, medication use at home, type of fracture, type of surgery, type of anesthesia, length of hospital stay, in hospital deaths, and 30-day mortality. In a multivariate analysis, corrected for age, preadmission Katz-ADL score, and score of the Charlson Comorbidity Index, receiving a blood transfusion decreased the odds to develop delirium (OR 0.26, 95%CI 0.10-0.70)(table 2).
Figure 1. Flowchart of inclusion
Eligible patients in original database (n = 452)
Included for anemia analysis (n = 415)
Academic Medical Center n = 135 Tergooi Hospitals n = 280
Excluded (n = 37)
No Hb/transfusion data known n = 4 Incomplete data: did not finish trial n = 33
(Withdrew informed consent, transferred to other department, no surgery, died before day 9, lost study medication, or participated before)
Included for transfusion analysis (n = 160)
Transfusion
(n = 65) No transfusion (n = 95)
Excluded for analysis (n = 255)
Hb level above 6.0 mmol/l n = 177 More than one transfusion period n = 30 Delirium present before transfusion n = 40 Transfusion and delirium onset on n = 8 the same day
Table 1. Characteristics of all Included Patients
Study group; no. (%) of patients, unless indicated otherwise
Factor Delirium (n = 135)
No delirium (n = 280)
p-value
Median age in years (IQR) 87.9 (81.6-91.3) 83.5 (77.9-88.1) <0.01 Sex, male 42 (31.1) 74 (26.4) 0.32 Living at home 58 (43.0) 193 (68.9) <0.01 missing data 1 (0.7) 0 (0.0)
Median Preadm. Katz-ADL score*
(IQR)
8.0 (5.0-12.0) 4.0 (1.0-9.0) <0.01 missing data 6 (4.4) 5 (1.8)
Cognitive impairment 109 (80.7) 138 (49.3) <0.01 Median Charlson Comorbidity
Index† (IQR)
2.0 (1.0-2.0) 1.0 (0.0-2.0) <0.01 Prior delirium 50 (37.0) 44 (15.7) <0.01 Medications at home
Median number (IQR) 5.0 (3.0-7.0) 4.0 (2.0-7.0) 0.14 Benzodiazepines 21 (15.6) 38 (13.6) 0.59 Antipsychotics 13 (9.6) 13 (4.6) 0.05 Anticoagulants/antiplatelet therapy 62 (45.9) 117 (41.8) 0.43 Type of fracture 0.12 Femoral neck 52 (38.5) 145 (51.8) Intertrochanteric 59 (43.7) 97 (34.6) Other 24 (17.7) 38 (13.7) Spinal anesthesia 33 (24.4) 90 (32.1) 0.27 Unknown 3 (2.2) 5 (1.8) Type of surgery 0.66
Dynamic hip screw 73 (54.1) 153 (54.6) Proximal femur nail 9 (6.7) 16 (5.7) Hip replacement 53 (39.3) 108 (38.6) Other 0 (0.0) 3 (1.1)
Median hospital stay in days (IQR) 10.0 (6.0-14.0) 8.0 (5.0-13.0) 0.03 missing data 8 (5.9) 7 (2.5)
Study group; no. (%) of patients, unless indicated otherwise Factor Delirium (n = 135) No delirium (n = 280) p-value 30-day mortality 20 (14.8) 13 (4.6) <0.01 Lowest measured hemoglobin level
during hospitalization (g/dl), median (IQR)
8.9 (7.9-10.2) 9.7 (8.4-11.4) <0.01
Anemia‡ at any time during hospitalization
95 (70.4) 143 (51.1) <0.01 Blood transfusion 66 (48.9) 74 (26.4) <0.01 If transfusion: total number of
packed cells during hospitalization, median (IQR)
2.0 (2.0-3.0) 2.0 (2.0-4.0) 0.68
Preadm. Katz-ADL = Preadmission Katz Index of Activities of Daily Living, IQR = inter quartile range.*
The Katz-ADL score ranges from 0 to 15, with higher scores indicating more severe functional dependence. † The Charlson Comorbidity Index ranges from 1 to 31, with higher scores indicating more comorbidities. ‡ Hemoglobin level ≤6.0 mmol/l (9.7 g/dl)
Table 2. Results from Univariate and Multivariate Analysis, Effects of Blood Transfusion on
Delirium Incidence (n=160)
Factor p-value Odds ratio (95% confidence interval)
p-value Odds ratio (95% confidence interval)
Univariate analysis Multivariate analysis*
Blood transfusion 0.04 0.39 (0.17-0.94) <0.01 0.26 (0.10-0.70) Lowest measured hemoglobin
level during hospitalization
0.25 1.32 (0.82-2.11)
Age 0.01 1.09 (1.02-1.16) 0.06 1.07 (1.00-1.56) Preadmission Katz-ADL score† <0.01 1.14 (1.05-1.25) 0.01 1.14 (1.03-1.27) Charlson Comorbidity Index >1‡ <0.01 3.38 (1.46-7.85) 0.06 2.36 (0.96-5.80)
* Odds ratios adjusted for age, preadmission Katz-ADL score, and Charlson Comorbidity Index >1. † The
Katz-ADL score ranges from 0 to 15, with higher scores indicating more severe functional dependence. ‡ The Charlson Comorbidity Index ranges from 1 to 31, with higher scores indicating more comorbidities.
DISCUSSION
In this study of 415 older hip fracture patients, a hemoglobin level ≤6.0 mmol/l (9.7 g/dl) was found to be associated with developing postoperative delirium. Blood transfusion was found to be a protective factor for the development of delirium.
We have found a low hemoglobin level to be associated with incident delirium. This is in line with the current literature that shows a consistent association between lower hemoglobin levels and higher delirium risk.4-7
Maldonado et. al.27 suggested that, in critically ill patients with an imbalanced oxygen supply and
demand, anemia might evoke delirium because it might lead to decreased cerebral oxygenation. This might evoke or contribute to ‘spreading depressions’ (low velocity spreading of depression of electroencephalography activity across the cortical surface28), abnormal neurotransmitter
synthesis, metabolism, and release, and failure to eliminate neurotoxic byproducts effectively, which all can lead to delirium.27
We found that transfusion decreased delirium incidence. This is in line with our hypothesis that treatment of anemia as one of the precipitating factors for delirium probably is effective to prevent delirium. Most studies performed previously found that perioperative blood transfusion might be associated with perioperative delirium.29-45 Fan46 and Gruber-Baldini47 investigated a
liberal versus a restrictive transfusion strategy, both reported that the transfusion strategy was not associated with postoperative delirium. Nonetheless, in all of these studies it was unclear if transfusion was administered before the onset of delirium and/or there was no adjustment for relevant confounders. Therefore, it is difficult to draw these conclusions from former results. Behrends and colleagues8 attempted to rule out the onset of delirium before transfusion and
corrected for relevant confounders in their analysis. They reported intraoperative blood transfusion of ≥1000 ml as a risk factor for subsequent delirium (OR 3.68, 95%CI 1.32-10.94). However, the relatively short follow-up in this study prevents us from drawing strong conclusions. We found that blood transfusion might serve as a protective factor for incident delirium and addressed this question in a relevant population, that is, hip fracture surgery patients at high risk to develop the need for a blood transfusion and at risk for delirium. Therefore, it is more likely that in the former studies, factors that were the reason for blood transfusion, like anemia, were the risk factor for delirium, instead of blood transfusion in itself. The unpublished
study of Blandfort et. al.48 found that a liberal blood transfusion strategy was protective for the
development of postoperative delirium ten days after hip fracture surgery in nursing home residents. This is in line with our findings. However, they only screened for delirium on postoperative day ten, while we found that delirium developed mostly on the day of surgery, so it is probable that this study underestimates delirium incidence.
Strengths and limitations
A Randomized Controlled Trial (RCT) would have been better to answer our research questions. However, because it was still unsure if blood transfusion could cause delirium, we first wanted to know the outcome of this cohort study to better ground the ethics for a possible RCT. Therefore we tried to imitate a RCT design within this cohort study by including the right population (only patients with hemoglobin level ≤6.0 mmol/l (9.7 g/dl) and transfusion before delirium onset). Despite this there could have been indication bias, because the decision to start transfusion was not random. This decision is partly based on guidelines but might also be on clinical experiences and preferences of a physician, especially if hemoglobin level is between 5.0 and 6.0 mmol/l (8.1 and 9.7 g/dl). Probably, vulnerable patients are more likely to get transfused. Another limitation was that data collection of hemoglobin data was retrospective (from the electronical medical status), and consequently we did not have daily hemoglobin levels, or postoperative hemoglobin for all patients. By choosing ‘lowest measured hemoglobin value during hospitalization’ as variable for hemoglobin, we hope to have included the most extreme values of hemoglobin. Furthermore, it is impossible within one day to state if transfusion, or delirium happened first. Delirium is a diagnosis over 24 hours with a fluctuating character and transfusion is given over a period of four to six hours. Therefore we could not include patients with occurrence of delirium and transfusion on the same day in the analysis (n=8). Also, we were not able to adjust for blood loss and severity of illness in our analysis, because this was not noted in the medical records of the patients. These could have been confounders.
A strength of our study is that this is the first study that investigated relation between delirium and timing of the blood transfusion. We incorporated the time course in our analysis by including only patients that developed delirium after transfusion to determine the effect of transfusion on delirium incidence. Another strength was that delirium assessment was on a daily base by a
specialized team, using a clear definition of delirium based on the gold standard (DSM-IV) definition2,25, which makes it unlikely that we missed cases of delirium.
CONCLUSION
Physicians can be advised to give blood transfusions to their vulnerable patients with anemia (hemoglobin level ≤6.0 mmol/l or 9.7 g/dl) to decrease the risk for delirium, taking all other indications and contraindications into account. It would be interesting to investigate the effect of blood transfusion in the treatment of delirium in patients with anemia in a randomized controlled trial, especially because we have found positive associations between receiving blood transfusion and delirium incidence.
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