Early Diagnosis Of Postoperative Delirium In Patients Who Underwent General Surgery

Objective: Postoperative delirium (POD) is a common postoperative complication. This study aimed to diagnose POD early primarily in patients who underwent General Surgery. This study also aimed to shorten the duration of hospital stays, prevent re-hospitalization after discharge and decrease the rates of morbidity/mortality through investigating the relationship with the characteristics of the patients/surgery/anesthesia in patients diagnosed with postoperative delirium in an early period. Material and Methods: Data of 303 patients at the age of 18 and above who were operated by General Surgery Clinic between March 2018 and May 2018, who were followed up by the Department of Anesthesiology and Reanimation for preoperative, intraoperative and postoperative periods and who received general anesthesia were included in the study. Patients’ demographic data, occupation, educational status, income level, additional diseases, ASA (American Society of Anesthesia) score, previous surgeries, history of a psychiatric or neurological disease, history of alcohol, cigarette, or drug use, and memory problems were recorded. Mini Mental State Examination (MMSE) was used to identify preoperative mental levels of the patients. Diagnosis of the patient, name, duration and features of the surgery to be performed, whether the surgery was urgent or elective, drugs used, type of catheterization (artery, central, foley or nasogastric), Hb value, intraoperative vital ndings, and duration of postoperative discharge were recorded. The diagnosis of POD in patients was evaluated with Confusion Assessment Method (CAM). Results: POD developed in 2-6% (8 patients) of the patients. A signicant relationship was recorded between the diagnosis of POD and age and additional diseases (ASA score). Results showed that the risk of delirium decreased as the education levels of the patients increased. A signicant relationship was recorded between delirium and only midazolam among anesthetic agents used. A signicant relationship was recorded among hypercarbia that developed during the surgery, invasive procedures, prolonged duration of surgery and hospitalizations in Intensive Care Units and Post-Anesthesia Care Units. Conclusion: The rate of POD (2.6%) and risk factors determined for POD within the rst three days in our study were in compliance with literature. Diagnosing POD with CAM in an early postoperative period was advantageous. The treatment planning of the patients for POD could be done in the early period. By doing this, increase in mortality, morbidity and cost as a result of missing the diagnosis of POD was prevented.


Introduction
Delirium is a clinical syndrome that rapidly and suddenly starts, that develops due to disruption of cerebral homeostasis for a temporary period, and that is also accompanied by changes in consciousness, perception, thought, and sleep/wake cycle (1). It is a common and crucial medical condition that is accompanied by acute changes in consciousness, attention de cit and impaired cognitive functions mostly in patients with ongoing hospitalization (2). It has three clinical types as "Hypoactive", "Hyperactive" and "Mixed". Hypoactive form is the one diagnosis of which is mostly missed as patients are somnolent and quiet. It is easier to diagnose hyperactive form as patients are agitated, active and in a condition that they can damage themselves and others. "Postoperative Delirium" in patients who undergo a surgery is characterized by acute impairments in consciousness and cognitive thoughts. There is a signi cant disorientation. It has a sudden onset and the symptoms differ. Moreover, the symptoms become more severe at nights. That is why it is also called "Sundown Syndrome". If the patient is examined at his or her normal times, course of the delirium and accordingly its diagnosis may easily be missed out. POD is a syndrome that prolongs the recovery period and that increases morbidity and mortality as well as the duration of hospital stay (3).
It is important to evaluate preoperative mental status of the patients in order to diagnose POD. Therefore, standardized Mini Mental State Examination (MMSE) is the most commonly used test for this purpose.
Delirium is clinically diagnosed with DSM-IV diagnostic criteria and laboratory tests such as EEG detecting the changes in cerebral metabolism and Single Photon Emission Computerized Tomography (SPECT) detecting cerebral hypoperfusion in addition to mental status evaluation tests (4).
CAM used in the diagnosis of POD is a test compliant with DSM-IV criteria. It is a delirium evaluation test most commonly used by people who are not psychiatrist. It can easily be applied. Its utility has been revealed in important clinical studies (5,6).
While the prevalence of POD is 1-2% in general population it rises to 14% especially in patients at the age of 85 and above (7). Although its incidence and effects are more signi cant in old patient group it can be seen in all age groups. As the delirium which is preoperatively present and delirium which postoperatively develops can be distinguished, factors inducing this clinical condition can be detected and required interventions to prevent this can be done (8).
In the studies, predisposing factors apart from age were as follows: male gender, cognitive impairment or dementia, weak functional capacity, drug and alcohol addiction, primary neurological diseases, shock, hypoxia, electrolyte imbalances, chronic disease (infectious, metabolic, cardiologic, pulmonary, endocrine and neoplastic diseases) or comorbidity, chronic renal failure, dehydration, malnutrition and visual/auditory impairment. Both hypoxia and hypercarbia may be the responsible factors for the development of delirium (9). POD is seen 2-5 times more in patients with dementia than in patients without dementia.
Intraoperative factors that increase the risk of POD can be listed as follows: long duration of surgery, intraoperative hypotension, hypoxia, Hb value of < 10 g/dL as a result of excessive bleeding, metabolic acidosis, dementia, low cardiac output, postoperative hypoxia and anticholinergic drug use.
POD is a complicated disease that impairs the functional and cognitive capacity. Its diagnosis and treatment are very di cult. Delirium in hospitalized patients is associated with increase in morbidity and mortality, extension in the duration of hospital stay, loss of physical function, delay in rehabilitation, increase in the costs at hospital, and increase in the need to be placed into nursing homes (10).
If the patient cannot be treated after being diagnosed with POD, the mortality and morbidity of the patient increase (11,12). The rst step in the treatment is treating the factor that initiates delirium. Providing su cient hydration, xing electrolyte imbalance and preventing probable hypoxia are the most common interventions (13). Then, antipsychotics, benzodiazepines, cholinergic drugs, vitamins depending on the etiology or electroconvulsive treatment can be considered (11,12). In patients with severe POD, drug therapy should be considered if symptoms prevent the required interventions (such as intubation and intravenous treatment) to the patient and if the patient and people around the patient are in danger.
According to the American Psychiatric Association (APA) guideline, the standard drug in the treatment of delirium is haloperidol (D2 dopamine receptor antagonist). Haloperidol is still the major drug used in POD today.

Material And Methods
Approved by the ethical committee of Akdeniz University Faculty of Medicine (21.02.2018/136), our study included the data of 303 patients who were operated by General Surgery Clinic between March 2018 and May 2018, who were preoperatively, intraoperatively and postoperatively followed up by the Department of Anesthesiology and Reanimation, who were at the age of 18 and above, and who received general anesthesia.
Surgeries of the patients included in the study were planned by the Department of General Surgery at Akdeniz University Faculty of Medicine and these patients were followed up by the Department of Anesthesiology and Reanimation at Akdeniz University Faculty of Medicine at Akdeniz University Faculty of Medicine Hospital, Outpatient Clinic of Anesthesiology and Reanimation, Operating Room, Anesthesia Intensive Care Units, Post-Anesthesia Care Unit and General Surgery Clinic. These patients were preoperatively informed and accepted in the study after their informed consents with signature were obtained.
Patients who were under the age of 18, patients who did not speak Turkish, patients who had visual or hearing impairment, patients who had mental retardation, patients who underwent a surgery under regional anesthesia, and patients who did not accept to participate in the study were excluded from the study.
Data of the patients who matched the inclusion criteria for the study were obtained by using the Information Management System (MiaMed ver.1.0.1.2812) of Akdeniz University Faculty of Medicine Hopsital and by face-to-face or telephone interviews with patients. Patients' demographic data (name, surname and le name, age, weight, height and body mass index), occupation, educational status, income level, additional diseases, ASA (American Society of Anesthesia) score, previous surgeries, history of a psychiatric or neurological disease, history of alcohol, cigarette and drug use, and memory problems were recorded.
Preoperative cognitive status of the patients who accepted to participate in the study were evaluated with MMSE (Mini Mental State Examination) test. The test was performed by the same person. Patients were divided into three groups according to their MMSE scores (≤ 17: Severe Cognitive Impairment, 18-24: Moderate Cognitive Impairment, and ≥ 25: Normal Cognitive Value).
Diagnosis of the patients, the surgery to be performed and its duration, whether the surgery was emergent or elective, the drugs used, the types of catheterization (arterial, central, Foley or nasogastric catheter), and patients with intraoperative Hb value of < 8 mg/dL were collected from anesthesia records and recorded. In addition, intraoperative vital ndings (blood pressure, mean arterial pressure, peripheral oxygen saturation and end-tidal CO2) of the patients were obtained from anesthesia records at 30 minute intervals and recorded. A decrease in mean arterial pressure more than 20% from baseline value was evaluated as hypotension.
The criteria of CAM that was performed by the same person in 24th, 48th and 72nd hours in the rst 3 postoperative days and the effects of anesthesia and surgery on the level of consciousness were evaluated and it was aimed to diagnose POD early. Data were analysed with IBM SPSS Statistics 18© Copyright SPSS Inc. 2009 software. Whether continuous variables followed normal distribution was evaluated. Variables that followed parametric distribution were evaluated with Student's T-test and nonparametric continuous variables with Mann Whitney U test. Nonparametric/discrete variables were analysed with Chi-Square test. Statistically signi cance level was accepted as 0.05 in the study.

Results
Mean age of the patients was 52.5 ± 14.3 years. The youngest age was 18 and the oldest was 86 (Table 1). When evaluated in terms of the level of education, POD was seen in 2 (11.1%) out of 18 patients who were literate, in 5 (5.9%) out of 85 patients who were primary school graduate, and in 1 (1.1%) out of 86 patients who were secondary school graduate while POD was not seen in any of the patients who were high school and university graduate. The difference is statistically signi cant (p: 0.015).  Table 2). POD did not develop in any of the patients with arrhythmia, valvular heart disease, hyperthyroid, hypothyroid, chronic renal failure, cerebrovascular disease, and Alzheimer. While POD developed in 2 out of 138 patients in the category of ASA 1, it developed in 2 (1.8%) out of 112 patients in the category of ASA 2, and in 4 (7.5%) out of 53 patients in the category of ASA 3. The difference is statistically signi cant (p: 0.049). There were no patients in the groups of ASA 4-5-6.   (Table 3). While POD was seen in 4 (5.9%) out of 68 patients who underwent gastrointestinal surgery it was seen in 3 (3.7%) out of 82 patients who underwent hepatobiliary surgery and 1 (1.9%) out of 52 patients who underwent Endocrine surgery. POD was not seen in any of 101 patients who underwent breast surgery, proctology or other operational types. While POD was seen in 1 (14.3%) out of 7 patients with intraoperative hemoglobin results of Hb < 8 mg/dL it was seen in 7 (2.4%) out of 296 patients with Hb ≥ 8 mg/dL (p: 0.052). While POD developed in 7 (2.3%) out of 300 patients with End-tidalCO2 < 45 mmHg, it developed in 1 (33.3%) out of 3 patients with End-tidalCO2 ≥ 45 mmHg (p: 0.001)( Table 4). While POD was not seen in any of 199 patients who were awakened in the operation room after the surgery it was seen in 1 (1.6%) out of 61 patients who were awakened in PACU (Post-Anesthesia Care Unit) and 7 (16.3%) out of 43 patients who were awakened in intensive care units (ICU). The difference is statistically signi cant (p:0.000).
While POD was seen in 8 (6.8%) out of 118 patients who underwent invasive arterial cannulation it was not seen in any of 185 patients who did not undergo arterial cannulation (p:0.000).
While POD was seen in 4 (19.0%) out of 21 patients in whom central venous catheter was used it was seen in 4 (1.4%) out of 282 patients in whom central venous catheter was not used (p:0.000). While POD was seen in 8 (7.8%) out of 103 patients in whom Foley catheter was used it was not seen in any of 200 patients in whom Foley catheter was not used (p:0.000).
While POD was seen in 7 (6.4%) out of 109 patients in whom nasogastric (NG) tube was used it was seen in 1 (0.5%) out of 194 patients in whom NG tube was not used (p:0.002).
While the mean duration of surgery was 175.0 minutes in patients with POD it was 100.1 minutes in patients without POD. The difference between them is statistically signi cant (p:0.0001). While mean postoperative discharge time was 12.37 days in patients with POD it was 2.34 days in patients without POD. The difference is statistically signi cant (p:0.000). While the shortest discharge time was 1 day the longest discharge time was 31 days.

Discussion
With the improvement in the surgical techniques and increase in pharmacological and mechanical opportunities of general anesthesia, it is possible to perform surgical intervention under general anesthesia for higher number of patient groups. Moreover, the improvement in living conditions has led to the extension of human lifespan and indispensably more patients in need of surgery under general anesthesia in old ages. Therefore, higher number of patients receive general anesthesia these days and the risk for the development of POD increases more compared to previous times.
This study aimed to investigate the early diagnosis of POD in patients for whom a surgery was planned by General Surgery clinic, characteristics of the patients in whom POD developed and who were diagnosed early, features of the surgery and anesthesia, risk factors and conditions affecting morbidity/mortality. POD developed in 8 (2.6%) out of 303 patients who were included in the study.
In our study, mean age of the patients in whom POD developed was 70.2 years and mean age of the patients in whom POD did not develop was 52 years. There was a POD rate that increased to 13.2% in patients at the age of 65 and above (p:0.000). This increase may be associated with low level of cognitive reserve and high number of concurrent diseases in old patients. The relationship between age and POD rate in patients whom we diagnosed early is in compliance with literature (7).
It was reported in the study of Kyzirids et al. that the incidence of POD was higher in men and that male gender was a risk factor for POD. In our study, the rate of POD was 2.4% in women and 2.9% in men. No statistically signi cant difference was found between two genders in terms of POD development. The reason why there was no difference between men and women can be explained with the fact that the risk factors and variables in our study were not in parallel with those in the study of Kyzirids et al (14).
Sprung et al. reported in their study that the incidence of POD decreased by the increase in educational level (15). In our study, none of the patients who were high school and university graduate had POD. The incidence of POD decreases as the literacy rate increases, which is consistent with the study of Sprung et al.
In the study of Raats et al., an increase was observed in the frequency of POD development with additional diseases and increase in ASA score (16). In our study, we recorded a signi cant relationship between the increase in ASA score and POD development. In addition, a signi cant relationship between POD development and HT, DM and CAD in patients who were transferred to ICU after a major surgery was recorded in the study of Abelha et al (17). ASA score and the rate of presence of additional disease were higher in patients who were diagnosed with POD at an early period in our study, which is consistent with literature.
No other agent but midazolam, one of intravenous or volatile anesthetic drugs that were preoperatively used, was reported to be responsible for the development of POD (18). POD did not develop in any of 46 patients in whom only propofol was used during induction. In the meta-analysis performed by Wang Peng et al., midazolam used for sedation was compared with other drugs (dexmedetomidine and propofol) and the rates of POD were higher in midazolam groups (19). In our study, the riskiest drug in terms of POD was midazolam and POD was not seen in any of the patients for whom propofol was used, which is clinically very signi cant. In addition, the use of midazolam and other drugs together could not be evaluated in our study. This is because we did not create separate groups for drug combinations in our study which was designed as an observational study. It is necessary to perform randomized controlled studies in order to obtain statistically precise and strong results. Evaluating midazolam as the riskiest drug in patients diagnosed with POD at an early period was consistent with literature and our knowledge. Therefore, patient selection should be considered in terms of the development of POD during the use of midazolam.
A signi cant relationship between invasive catheterization used for patients and the development of POD was reported in literature (20). In our study, a signi cant increase in the incidence rate of POD was recorded among patients in whom arterial cannulation, central venous catheterization, Foley catheter and nasogastric tube were used. Higher incidence of POD may be because arterial and CVP catheterizations are generally used in patient groups with high risk for POD development and in long-duration surgeries.
In the study of Nazemi et al., hypercarbia was effective in the development of POD (21). In our study, while POD developed in patients with End-tidal CO2 < 45 mmHg at a rate of 2.3% it developed in patients with End-tidal CO2 ≥ 45 mmHg at a rate of 33.3%. The incidence rate of POD was signi cantly higher in patients with End-tidal CO2 ≥ 45 mmHg than in patients with End-tidal CO2 < 45 mmHg, which is consistent with literature.
Hypotension and hypoperfusion alone are among the risk factors for POD. In our study, a decrease in mean arterial pressure more than 20% from baseline value was evaluated as hypotension. According to this de nition, while POD was seen in 3.6% of the patients in whom hypotension developed it was seen in 2.3% of the patients in whom hypotension did not develop. No statistically signi cant difference was recorded (p:0.531). In our study which was designed as an observational study, it is not correct to comment on the rates of POD because the patients are intervened in the direction of routine protocols of our clinic and hypotension therapy is initiated in case hypotension develops. However, a higher rate of POD was recorded for patients with hypotension (6).
In the study of Raats et al., a signi cant relationship between preoperative anemia (Hb < 7.6 mmol/L for women and < 8.2 mmol/L for men) and POD was recorded (16). In our study, although the threshold value for Hb was different the incidence of POD in patients with Hb < 8 mg/dL in intraoperative blood gases or hemogram results was higher, which is consistent with the study of Raats et al.
Regarding the places where the patients were awakened, POD developed in patients admitted to ICU at a rate of 16.3% and in patients admitted to PACU at a rate of 1.6%. These rates were statistically signi cant. However, POD was not seen in any of the patients who were awakened in the operating room. A long-lasting immobilization that changes the sleep/wake cycle, high number of catheterizations, and ICU hospitalization in addition to admission to ICU after a risky and major surgery are separately risk factors for POD (18). The results in our study are consistent with literature. Apart from induction, midazolam is frequently used for sedation in patients who will be transferred to ICU or PACU after the surgery. Patients who has a history of ICU and PACU are already at risk due to both their additional diseases and the risky and major surgeries they underwent. All these can increase the incidence rate of POD.
Like in literature, longer "durations of hospital stays" in patients in whom POD developed were found in our study (22). It is obvious that the development of POD extends the "duration of hospital stay". However, it is also possible to conclude that "duration of hospital stay" in patients with a risk factor for POD may be extended as well and accordingly the risk of POD increases.
Major surgeries with long duration are reported as a risk factor for the development of POD. In our study, the durations of the surgeries in patients in whom POD developed were longer. In addition, the development of POD is more and the duration of hospital stay extends in patients who undergo a more major surgery with longer duration (6).
In literature, POD was diagnosed within the rst seven days or in a longer period (23,24). In our study, there were 8 patients (2.6%) who were diagnosed early (the rst 3 postoperative days). This rate is consistent with the reported rates of patients who were diagnosed with POD in literature (25). Moreover, the data obtained from the risk factors we investigated and the risk factors due to patients, surgery or anesthesia were consistent with literature. Diagnosing POD with CAM in the rst 3 postoperative days in patients who underwent general surgery was highly bene cial. Thanks to this, it was possible to perform the treatment planning of the patients and start the treatment at an early period.

Conclusion
It is important to detect a disorder in patients in risk groups, especially in old patients, with cognitive tests while preoperatively evaluating the patients in detail. It is highly important to preoperatively receive geriatric or psychiatric help and provide necessary information and training about the surgery and postoperative period for old patients. The anesthetist and surgeon should share the risky situation with family for patients in high-risk group. In case of the necessity of the surgery, it is recommended to minimalize the duration of surgery and anesthesia and avoid benzodiazepines or other drugs that may cause the development of POD.
With the developments in medical science and improvements in living conditions worldwide, an increase in the surgical need of older patient group is predicted. Therefore, it is believed that POD is an important health problem that should be focused on more in the future as it may result in increase in mortality, morbidity and costs and it is highly possible to often miss its diagnosis.