Incidence and Risk Factors of Postoperative Delirium in Patients Undergoing Radical Cystectomy, an Observational Prospective Cohort Study

Delirium is the second most common psychiatric diagnosis among hospitalized cancer patients. There are no previous studies on postoperative delirium after radical cystectomy. The relation between postoperative delirium and mortality has not been studied in cancer patients. We designed this observational prospective cohort study in order to determine the incidence and risk factors for postoperative delirium in this particular patient group with bladder cancer undergoing radical cystectomy, and to investigate the relation of postoperative delirium to mortality in these patients. This study was carried out at South Egypt Cancer Institute, Assiut University, Assiut, Egypt in the period from January 2012 to June 2013. Patients undergoing radical cystectomy for management of bladder cancer in this period were included. Peri-operative data were recorded, and development of postoperative delirium was diagnosed with the aid of CAM-ICU (Confusion Assessment Method for Intensive Care Unit). Twenty-nine patients (30.8%) developed delirium out of the ninety-four who were included during the study period. Delirium was significantly related to age, presence of COPD, blood loss. Postoperative delirium was significantly related to length of hospital stay, and to mortality. A lot of peri-operative factors are associated with increased risk of developing postoperative delirium following radical cystectomy, which is associated with higher mortality, an information that requires more attention while dealing with these patients. INTRODUCTION Urinary bladder cancer is the main cancer in Egypt, with an incidence of 32.67 % that is related to chronic infection with Schistosoma haematobium and to tobacco smoking, thus it is peculiar in affecting both young and old people (1) (Zheng et al., 2012). JOURNAL OF INTERNATIONAL ACADEMIC RESEARCH FOR MULTIDISCIPLINARY Impact Factor 1.393, ISSN: 2320-5083, Volume 2, Issue 5, June 2014 797 Postoperative delirium (POD) is a common complication after major surgery and is characterized by acute confusion with fluctuating consciousness. It is associated with poor functional recovery, delayed independence, longer hospital stays, increased homecare and rehabilitation facility requirements, and increased morbidity and mortality (Parikh and Chung, 1995). A number of studies have been published on POD following major cancer surgeries, but, to our knowledge; this is the first Egyptian study to investigate POD following radical cystectomy. The primary aim of this study was to estimate the incidence of POD in patients undergoing radical cystectomy for management of bladder cancer. Secondary aims were to investigate the possible peri-operative factors associated with POD and its relation to mortality rate during the hospital stay. Patients and methods: After approval of the local ethics committee, this study was carried out at South Egypt Cancer Institute, Assiut University, Assiut, Egypt in the period from January 2012 to June 2013. Patients with ASA class I-III, undergoing radical cystectomy for management of bladder cancer in this period were included. Excluded from this study were patients with pre-existing neuro-cognitive dysfunction, documented signs of dementia after psychiatric evaluations, language barriers or deafness, psychosis stroke, meningitis, or brain tumors. Pre-operative data included: age, sex, smoking, tumor stage, and history of medical disease. Intra-operative data included: duration of operation, blood loss, blood and fluid transfusion. Post-operative data included: length of hospital stay, and condition on discharge (living/dead). Management of patients was standardized, where radical cystectomy and lymph node dissection under combined general and epidural anesthesia. With very limited exceptions, patients were transmitted, after completion of surgery, to the urology department. Where they received 3500cc of intravenous fluids per day for three days, then oral feeding was gradually started and they were ambulated on the morning of the second postoperative day, analgesia was maintained in the first three postoperative days by patient-controlled epidural analgesia, then by oral analgesics. JOURNAL OF INTERNATIONAL ACADEMIC RESEARCH FOR MULTIDISCIPLINARY Impact Factor 1.393, ISSN: 2320-5083, Volume 2, Issue 5, June 2014 798 Development of postoperative delirium was diagnosed with the aid of CAM-ICU (Confusion Assessment Method for Intensive Care Unit). CAM-ICU is based on the DSM-IV criteria and diagnosis of delirium is made by a yes or no answer to a four-point algorithm (3) (Inouye, 2008). It is considered the "gold standard" for the diagnosis of delirium with a sensitivity of 94-100% and specificity of 90-95% (Riekerka et al., 2009). CAM-ICU was performed once daily during period of hospitalization by a trained researcher. Statistical analysis: Analysis was performed using the SPSS soft ware version 17 (ChicagoUSA). Data were expressed as mean ± SD, number and percentage. MannWhitny test used to compare non parametric data between two groups. The Chi-square test was used to analyze frequency and percentage. A P-value <0.05 was considered statistically significant. Results: Twenty-nine patients (30.8%) developed delirium out of the ninety-four who were included during the study period. There was a significant relation between delirium and age (P=0.000), where 55.9% of patients aged 70 years and older developed delirium during the study, while 22.2% of the patients aged 60-70 years and only 12.1% of patients aged < 60 years developed delirium. There was no significant relation between delirium and gender, smoking, tumor stage, or ASA classification. Looking to the medical history of participating patients, there was only a significant relation between presence of COPD and development of delirium where 37.9% of patients with delirium had COPD (P=0.043). Among the intra-operative variables studied, delirium was significantly related only to blood loss (P=0.000), no significant relation between delirium and operative time, blood transfusion, fluid transfusion, was found. In the postoperative period, delirium was significantly associated with longer hospital stay ≥ 7 days (P=0.012), where all patients who developed delirium during JOURNAL OF INTERNATIONAL ACADEMIC RESEARCH FOR MULTIDISCIPLINARY Impact Factor 1.393, ISSN: 2320-5083, Volume 2, Issue 5, June 2014 799 the study had a length of hospital stay of 7 days or more. POD was also significantly related to mortality during hospitalization where 17.2% of patients developed POD died during period of hospitalization (P=0.047). Discussion Recent evidence highlights the poor clinical outcomes, higher morbidity, higher mortality, and longer stay in the hospital or in the intensive care unit. Deterioration in the cognitive processes and higher cost of treatment linked to the delirium development (Jackson, 2006). In this study, we investigated the incidence and risk factors of postoperative delirium in one of the main types of cancer in Egypt, bladder cancer, following radical cystectomy. We found that delirium was remarkably prevalent as approximately one third (30.8%) of the patients in the study developed delirium. In comparison to our figures, Large et al. 2013 reported a similar, CAM-ICUbased, incidence rate of POD of 29% in a study conducted on 49 older patients (≥65 years) with bladder cancer following radical cystectomy. Lower incidence rates have been reported for POD following surgeries for other types of cancer, for example; McAlpine et al., 2008 found an incidence rate of POD of 17.5% following surgeries for gynecologic malignancies. For colorectal cancer surgeries, the incidence of POD was ranging from 18% (Patti et al., 2011) (8) to 10.9% (Tei et al., 2010) . Lower incidence rates have been reported following surgeries for esophageal cancer (9.2%) (Markar et al., 2013) , and head and neck cancer (11.5%) (Shah et al., 2012) . Delirium in cancer patients is multi-factorial (cancer byproducts, electrolyte imbalance, paraneoplastic syndrome, endocrine disorder, use of analgesics and psychoactive agents, dehydration, hypoxemia, infection and organ failure) (Bush and Bruera, 2009) . Yager and colleagues, 2011 have found an elevated total choline (tCho) and reduced N-acetyl aspartate (NAA) levels in adult cancer patients with delirium using Proton Magnetic Resonance Spectroscopy (1H-MRS). JOURNAL OF INTERNATIONAL ACADEMIC RESEARCH FOR MULTIDISCIPLINARY Impact Factor 1.393, ISSN: 2320-5083, Volume 2, Issue 5, June 2014 800 Choline elevations indicate demyelination and may be caused by an inflammatory process without cell membrane degradation or demyelination that precedes NAA loss indicating irreversible neuronal damage (Axford, et al., 2001) . In this study, we found a significant relation between age and development of delirium, where more than half (55.9%) of the patients aged 70 years and older developed delirium during the study period. In agreement with this, a lot of studies conducted on patients following cancer surgeries reported a positive correlation between old age and development of postoperative delirium (Large et al. 2013; McAlpine et al., 2008; Patti et al., 2011; Tei et al., 2010; Shah et al., 2012; Markar et al., 2013). In this work, delirium was significantly associated with length of stay at hospital. This finding is in agreement with the work of Marker et al., 2013 in esophageal cancer, and Patti et al., 2011 in colorectal cancer. Contradicting to this, Large et al., 2013 found no significant relation between age and delirium following bladder cancer surgeries. Delirium was considered as an independent predictor of longer hospital of stay (Thomason et al., 2005). Tumor staging, as we found in this study, was not significantly related to the development of postoperative delirium. This agrees with the findings of similar studies conducted on cancer patients. For example, Takeuchi et al., 2012 and Patti et al., 2011 found no relation between postoperative delirium and tumor stage in esophageal and colorectal cancer surgery respectively. Interestingly, Yamagata et al., 2005 have reported that the significant relation between POD and stage IV head and neck tumors is explained by the extensive surgery rather than the advanced lesion. Also our study showed that there was a significant relation between development of postoperative delirium and presence of COPD. This is most appropriately explained by the fact that smoking (cigarette and "goza") is predominant in most of the patients. ASA classification was not significantly related to the development of postoperative delirium in this study. Published data are inconsistent regarding this point, Takeuchi et al., 2012 and Patti et al., 2011 found no significant relation between ASA grade (I-IV) and postoperative delirium. While Veiga et al., 2013 and Tei et al., 2010 found a significant relation of ASA grading (I-IV) to postoperative delirium. JOURNAL OF INTERNATIONAL ACADEMIC RESEARCH FOR MULTIDISCIPLINARY Impact Factor 1.393, ISSN: 2320-5083, Volume 2, Issue 5, June 2014 801 Among the studied intra-operative factors, there was only a significant relation between blood loss and development of POD. Olin et al. 2005 reported that intra-operative bleeding might be a more important risk factor for postoperative delirium than age. Bohner et al., 2003 had also emphasized the importance of blood loss for predicting POD. Contradicting our findings, Tei et al., 2010, found that POD was not affected by intra-operative variables including operative time and blood loss. Our study revealed that development of postoperative delirium is associated with higher mortality rate while in hospital. This agrees with the findings of Tennen et al., 2009, Veiga et al., 2012 and Boogard et al., 2011 where development of delirium was an independent risk factor for hospital mortality and is associated with increased long term chance of dying over 6 months to one year duration. This study is one of the few studies investigating POD in Urologic surgeries, and to our knowledge, the first to study it in Egyptian patients following radical cystectomy. This study has is limited by lacking patient follow up after discharge from hospital, which could have an impact on the overall data. Furthermore, our work is limited by being observational with absence of a solid protocol to use in dealing with delirious patients, further studies with longer post-discharge follow up period and implementing one or more therapeutic modes for POD are required. Conclusion Postoperative delirium is a frequent complication after radical cystectomy for bladder cancer that is associated with certain peri-operative factors, identifying such factors and eliminating or modifying them allows for effective prevention and improved outcome. JOURNAL OF INTERNATIONAL ACADEMIC RESEARCH FOR MULTIDISCIPLINARY Impact Factor 1.393, ISSN: 2320-5083, Volume 2, Issue 5, June 2014 802 Table (1): Demographic data