C International Psychogeriatric Association 2013 International Psychogeriatrics (2014), 26:5, 845–855 doi:10.1017/S1041610213002378
Raised IL-2 and TNF-α concentrations are associated with postoperative delirium in patients undergoing coronary-artery bypass graft surgery ...........................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................
Jakub Kazmierski,1 Andrzej Banys,2 Joanna Latek,3 Julius Bourke4 and Ryszard Jaszewski5 1
Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Lodz, Lodz, Poland Department of Anaesthesiology and Intensive Cardiologic Care, 1st Chair of Cardiology and Cardiac Surgery, Medical University of Lodz, Lodz, Poland 3 Central Veterans Hospital, Lodz, Poland 4 The Centre for Psychiatry at The Wolfson Institute for Preventive Medicine, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK 5 Department of Cardiac Surgery, 1st Chair of Cardiology and Cardiac Surgery, Medical University of Lodz, Lodz, Poland 2
ABSTRACT
Background: The knowledge base regarding the pathogenesis of postoperative delirium is limited. The primary aim of this study is to investigate whether increased levels of IL-2 and TNF-α are associated with delirium in patients who underwent coronary-artery bypass graft (CABG) surgery with cardiopulmonary bypass (CPB). The secondary aim is to establish whether any association between raised cytokine levels and delirium is related to surgical and anesthetic procedures or mediated by pre-existing conditions associated with raised cytokine levels, such as major depressive disorder (MDD), cognitive impairment, or aging. Methods: Patients were examined and screened for MDD and cognitive impairment one day preoperatively, using the Mini International Neuropsychiatric Interview and The Montreal Cognitive Assessment and Trail Making Test Part B. Blood samples were collected postoperatively for cytokine levels. Results: Postoperative delirium screening was found positive in 36% (41 of 113) of patients. A multivariate logistic regression revealed that an increased concentration of pro-inflammatory cytokines is associated with delirium, and related to advancing age, preoperative cognitive decline of participants, and duration of CPB. According to receiver operating characteristic analysis, the most optimal cut-off for IL-2 and TNF-α concentrations in predicting the development of delirium were 907.5 U/ml and 10.95 pg/ml, respectively. Conclusions: The present study suggests that raised postoperative cytokine concentrations are associated with delirium after CABG surgery. Postoperative monitoring of pro-inflammatory markers combined with regular surveillance may be helpful in the early detection of postoperative delirium in this patient group. Key words: delirium, coronary-artery bypass grafting, cardiac surgery, cytokines, interleukins
Introduction Coronary-artery bypass grafting is a lifesaving intervention for severe ischemic heart disease and is frequently performed among elderly patients. It substantially improves patients’ quality of life and prognosis (Velazquez et al., 2012; Vicchio et al., 2012). However, it is often complicated by delirium (Kazmierski et al., 2010a; Mu et al., 2010). Delirium is a common and serious medical problem. Systematic reviews of literature report Correspondence should be addressed to: Jakub Kazmierski, MD, PhD, Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Lodz, Czechoslowacka 8/10, 92-216 Lodz, Poland. Phone: +48 42 675 73 72; Fax: +48 42 675 77 29. Email: [email protected]. Received 8 Aug 2013; revision requested 13 Sep 2013; revised version received 5 Nov 2013; accepted 18 Nov 2013. First published online 17 December 2013.
that prevalence of this syndrome at admission among medical in-patients ranges from 10% to 31%, whereas incidence of new delirium per admission ranges from 3% to 29% (Siddiqi et al., 2006). The prevalence of delirium in medical and surgical intensive care units (ICUs) is even higher and varies from 20% to 80% depending on the severity of illness observed and diagnostic methods used (Girard et al., 2008). A significant number of postoperative cardiac surgery patients develop delirium (from 11% to 50%) and its prevalence is higher at advanced age (Kazmierski et al., 2006; 2010a; 2010b; Rudolph et al., 2006). This complication is associated with higher mortality and morbidity rates (sternum instability, reoperation and sepsis, self-extubation), longer stays in ICU and overall length of admission, as
846
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well as greater cost (Franco et al., 2001; Bucerius et al., 2004; Detroyer et al., 2008; Girard et al., 2008; Kazmierski et al., 2010a). Postoperative delirium may additionally contribute to the development of cognitive decline post-discharge (Saczynski et al., 2012). In the systematic review of 19 cohort studies, delirium was associated with increased mortality at discharge and at 12 months, and post-discharge institutionalization (Siddiqi et al., 2006). Many preoperative predictors of delirium have been uncovered, which may reflect multifactorial etiology of this syndrome. According to the systematic review of studies published in the last ten years, the most established predisposing risk factors for delirium following cardiac intervention include older age, cognitive impairment, depression, and such cardiovascular comorbidity as atrial fibrillation, peripheral vascular disease, and history of stroke (Koster et al., 2011). However, despite its importance, the pathophysiology of delirium developing after major surgery remains poorly understood. One hypothesis suggests that delirium may be due to hyper-responsivity of neuro-immune cells to stimulation by peripheral inflammation, leading to increased neuroinflammation (Hall et al., 2011). The studies support the role of inflammation in the development of delirium in the population of elderly patients hospitalized in general units (Hall et al., 2011; Simone and Tan, 2011). Moreover, an independent relationship between pro-inflammatory interleukin levels and delirium among elderly acutely ill and critically ill inpatients has been reported (de Rooij et al., 2007; Girard et al., 2012). Infectious diseases were common in these cohorts and may partially explain the higher level of cytokines and the association with delirium. However, the data regarding the association between cytokines and delirium after major surgery are limited. In studies conducted among patients presented for hip surgery, differences between individuals with and without delirium were observed in IL-6 and IL8 (Munster et al., 2008; 2010). However, these cohorts included both patients who developed delirium prior and after surgery. Moreover, the above and other available studies use a casecontrol design or univariate analysis only. In the nested case-control study by Lemstra et al. (2008), no relationship was found between levels of preoperative circulating pro-inflammatory markers (C-reactive protein, IL-6, insulin growth factor 1 (IGF-1)) and postoperative delirium in elderly patients. However, IL-6 levels were associated with a measure of preoperative cognitive impairment. Rudolph et al. (2008) reported a case-control study among 24 subjects undergoing different types
of cardiac surgery. In this study, blood samples were analyzed on a dual-channel microsphere flow cytometer and subsequently detected inflammatory markers that were assigned to one of five classes. Twelve subjects who developed delirium had higher increases of postoperative chemokines compared to 12 matched controls. Among the five classes of cytokines, there were no other significant differences between patients with and without delirium. Moreover, the levels of preoperative inflammatory markers did not differ between the groups. The prospective cohort study by Plaschke and colleagues (2010) showed the relationship between raised postoperative IL-6 levels and delirium after cardiac surgery; however, this association was revealed only on univariate analysis. The impact of raised IL-6 concentrations on the development of delirium was not controlled for using other variables related to mental and physical comorbidities of participants or the surgical and anesthetic procedures. Thus, the significance of elevated cytokine concentration was not fully determined, however, the authors speculate that the advanced age of participants could have been responsible for IL-6 elevation and its association with delirium. The aforementioned studies suggest that, although the levels of inflammatory markers are increased prior to surgery in cognitively impaired patients, this increase is not associated with postoperative delirium (Lemstra et al., 2008; Rudolph et al., 2008). According to these studies only postoperative inflammatory markers may be associated with delirium. It should be also noted that previously studied interleukins (IL-1, IL-6, IL8) (de Rooij et al., 2007; Munster et al., 2008; 2010) act as both pro-inflammatory and antiinflammatory cytokines (Xing et al., 1998; Opal and DePalo, 2000). For example, IL-6 is secreted by T-cells and macrophages to stimulate an immune response. However, it also has an inhibitory effect on TNF-α and IL-1, and activates interleukin-1 receptor antagonist (IL-1 inhibitor) and IL-10 (a human cytokine synthesis inhibitory factor). This dual activity of the cytokines studied might have influenced the final associations with postoperative delirium. In light of this, we decided to investigate pro-inflammatory cytokines (IL-2 and TNF-α) alone. IL-2 has been used to treat patients with metastatic malignancies. In a prospective study of consecutive patients who received this treatment, 50% of the individuals experienced severe behavioral and/or cognitive impairment (disorientation, cognitive deterioration) (Denicoff et al., 1987; Kronfol and Remick, 2000). In 34% of the patients, behavioral changes necessitated acute intervention. In the recent animal models, dysregulation of
Cytokines as markers of postoperative delirium
IL-2 expression in the peripheral immune system and the brain was indicated as crucial for injuryinduced neuroimmunological processes that drive responses towards either central nervous system (CNS) neurodegeneration or neuroregeneration (Huang et al., 2012). In addition, Venters et al. (1999) showed that TNF-α exerted its neurotoxicity by inhibiting IGF-1 activity. Although TNF-α fails to cause the cell death in healthy brain, it contributes, similarly to IL2, to neurodegeneration in experimental models (Loddick and Rothwell, 1999). Finally, according to our knowledge, the impact of IL-2 on delirium development has not been investigated to date. The studies revealed that major depressive disorder (MDD), cognitive impairment, and advanced age are the prominent factors contributing to postoperative delirium (Rudolph et al., 2009; Kazmierski et al., 2010a; Kazmierski and Kloszewska, 2011; Kazmierski et al., 2013). Current thinking implicates cortisol and cytokine abnormalities in both MDD and cognitive impairment (Magaki et al., 2007; Simone and Tan, 2011; Maes et al., 2012; Peavy et al., 2012; Kazmierski et al., 2013). Therefore, these conditions should be considered as possible confounders in studies on delirium and cytokines. Moreover, according to the “inflamm-aging” hypothesis diminished ability to cope with stressors, an imbalance between inflammatory and anti-inflammatory networks and a concomitant progressive increase in pro-inflammatory status are major characteristics of the aging process (Franceschi et al., 2000). It is possible, yet, that the age-related inflammatory mechanisms may underlie the association between advanced age and delirium. To date, mechanisms responsible for raised interleukin levels among surgery patients and the putative relationship between inflammation and delirium after cardiac surgery remain unknown. Therefore, our primary aim was to investigate the independent association between raised proinflammatory cytokine levels (IL-2 and TNFα) and delirium diagnosed after CABG surgery. The secondary aim was to establish whether any association between raised cytokine levels and delirium is related to surgical and anesthetic procedures or mediated by pre-existing conditions associated with raised cytokine levels, such as MDD, cognitive impairment, or aging.
Methods This is a prospective, observational cohort study conducted in a 14-bed cardiac surgical ICU of a
847
university teaching hospital (University Hospital, Central Veterans Hospital, Poland). The inclusion criteria were as follows: (1) consecutive adult subjects; (2) patients undergoing elective CABG surgery with cardiopulmonary bypass (CPB); and (3) patients who signed an informed written consent for the participation in the study. The exclusion criteria were: (1) concomitant surgery other than CABG; (2) history of adrenal gland disease; (3) history of systemic inflammatory disease; (4) history of glucocorticoid or cytokine/anti-cytokine therapy within the last year; (5) non-Polish speaking subjects; (6) illiteracy; and (7) patients with pronounced hearing and/or visual impairment. The study was approved by the Ethics Committee of the Medical University of Lodz, Poland and was performed in accordance with the ethical standards of the Declaration of Helsinki. The subjects included in this study have been previously reported in the manuscript regarding the role of cortisol in delirium development (Kazmierski et al., 2013). Preoperative psychiatric assessment The subjects were recruited and examined on the day prior to the scheduled operation. The Montreal Cognitive Assessment (MoCA) and Trail Making Test part B (TMT-B) were used preoperatively to assess global cognition and executive functions, respectively. A diagnosis of dementia was established among patients with abnormal MoCA scores using the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR) criteria. The Mini International Neuropsychiatric Interview (MINI) version 5.0.0 (Polish translation) was used to assess for a diagnosis of MDD (Sheehan et al., 1998; Masiak and Przychoda-Masiak, 2002). These assessments were conducted by an experienced psychiatrist (J.K.). The MoCA was designed as a rapid screening instrument for mild cognitive dysfunction. It assesses different cognitive domains: attention and concentration, executive functions, memory, language, visuospatial skills, conceptual thinking, calculations, and orientation (Nasreddine et al., 2005; Magierska et al., 2012). The TMT-B is a widely used paper-and-pencil task that evaluates the executive functions and cognitive flexibility (War Department Adjutant General’s Office, 1944). In the present study, all the patients who were screened positive for cognitive impairment (MoCA score 6 hours) which resulted in a shorter interval between the end of the intubation and samples collection (
Raised IL-2 and TNF-α concentrations are associated with postoperative delirium in patients undergoing coronary-artery bypass graft surgery ...........................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................
Jakub Kazmierski,1 Andrzej Banys,2 Joanna Latek,3 Julius Bourke4 and Ryszard Jaszewski5 1
Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Lodz, Lodz, Poland Department of Anaesthesiology and Intensive Cardiologic Care, 1st Chair of Cardiology and Cardiac Surgery, Medical University of Lodz, Lodz, Poland 3 Central Veterans Hospital, Lodz, Poland 4 The Centre for Psychiatry at The Wolfson Institute for Preventive Medicine, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK 5 Department of Cardiac Surgery, 1st Chair of Cardiology and Cardiac Surgery, Medical University of Lodz, Lodz, Poland 2
ABSTRACT
Background: The knowledge base regarding the pathogenesis of postoperative delirium is limited. The primary aim of this study is to investigate whether increased levels of IL-2 and TNF-α are associated with delirium in patients who underwent coronary-artery bypass graft (CABG) surgery with cardiopulmonary bypass (CPB). The secondary aim is to establish whether any association between raised cytokine levels and delirium is related to surgical and anesthetic procedures or mediated by pre-existing conditions associated with raised cytokine levels, such as major depressive disorder (MDD), cognitive impairment, or aging. Methods: Patients were examined and screened for MDD and cognitive impairment one day preoperatively, using the Mini International Neuropsychiatric Interview and The Montreal Cognitive Assessment and Trail Making Test Part B. Blood samples were collected postoperatively for cytokine levels. Results: Postoperative delirium screening was found positive in 36% (41 of 113) of patients. A multivariate logistic regression revealed that an increased concentration of pro-inflammatory cytokines is associated with delirium, and related to advancing age, preoperative cognitive decline of participants, and duration of CPB. According to receiver operating characteristic analysis, the most optimal cut-off for IL-2 and TNF-α concentrations in predicting the development of delirium were 907.5 U/ml and 10.95 pg/ml, respectively. Conclusions: The present study suggests that raised postoperative cytokine concentrations are associated with delirium after CABG surgery. Postoperative monitoring of pro-inflammatory markers combined with regular surveillance may be helpful in the early detection of postoperative delirium in this patient group. Key words: delirium, coronary-artery bypass grafting, cardiac surgery, cytokines, interleukins
Introduction Coronary-artery bypass grafting is a lifesaving intervention for severe ischemic heart disease and is frequently performed among elderly patients. It substantially improves patients’ quality of life and prognosis (Velazquez et al., 2012; Vicchio et al., 2012). However, it is often complicated by delirium (Kazmierski et al., 2010a; Mu et al., 2010). Delirium is a common and serious medical problem. Systematic reviews of literature report Correspondence should be addressed to: Jakub Kazmierski, MD, PhD, Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Lodz, Czechoslowacka 8/10, 92-216 Lodz, Poland. Phone: +48 42 675 73 72; Fax: +48 42 675 77 29. Email: [email protected]. Received 8 Aug 2013; revision requested 13 Sep 2013; revised version received 5 Nov 2013; accepted 18 Nov 2013. First published online 17 December 2013.
that prevalence of this syndrome at admission among medical in-patients ranges from 10% to 31%, whereas incidence of new delirium per admission ranges from 3% to 29% (Siddiqi et al., 2006). The prevalence of delirium in medical and surgical intensive care units (ICUs) is even higher and varies from 20% to 80% depending on the severity of illness observed and diagnostic methods used (Girard et al., 2008). A significant number of postoperative cardiac surgery patients develop delirium (from 11% to 50%) and its prevalence is higher at advanced age (Kazmierski et al., 2006; 2010a; 2010b; Rudolph et al., 2006). This complication is associated with higher mortality and morbidity rates (sternum instability, reoperation and sepsis, self-extubation), longer stays in ICU and overall length of admission, as
846
J. Kazmierski et al.
well as greater cost (Franco et al., 2001; Bucerius et al., 2004; Detroyer et al., 2008; Girard et al., 2008; Kazmierski et al., 2010a). Postoperative delirium may additionally contribute to the development of cognitive decline post-discharge (Saczynski et al., 2012). In the systematic review of 19 cohort studies, delirium was associated with increased mortality at discharge and at 12 months, and post-discharge institutionalization (Siddiqi et al., 2006). Many preoperative predictors of delirium have been uncovered, which may reflect multifactorial etiology of this syndrome. According to the systematic review of studies published in the last ten years, the most established predisposing risk factors for delirium following cardiac intervention include older age, cognitive impairment, depression, and such cardiovascular comorbidity as atrial fibrillation, peripheral vascular disease, and history of stroke (Koster et al., 2011). However, despite its importance, the pathophysiology of delirium developing after major surgery remains poorly understood. One hypothesis suggests that delirium may be due to hyper-responsivity of neuro-immune cells to stimulation by peripheral inflammation, leading to increased neuroinflammation (Hall et al., 2011). The studies support the role of inflammation in the development of delirium in the population of elderly patients hospitalized in general units (Hall et al., 2011; Simone and Tan, 2011). Moreover, an independent relationship between pro-inflammatory interleukin levels and delirium among elderly acutely ill and critically ill inpatients has been reported (de Rooij et al., 2007; Girard et al., 2012). Infectious diseases were common in these cohorts and may partially explain the higher level of cytokines and the association with delirium. However, the data regarding the association between cytokines and delirium after major surgery are limited. In studies conducted among patients presented for hip surgery, differences between individuals with and without delirium were observed in IL-6 and IL8 (Munster et al., 2008; 2010). However, these cohorts included both patients who developed delirium prior and after surgery. Moreover, the above and other available studies use a casecontrol design or univariate analysis only. In the nested case-control study by Lemstra et al. (2008), no relationship was found between levels of preoperative circulating pro-inflammatory markers (C-reactive protein, IL-6, insulin growth factor 1 (IGF-1)) and postoperative delirium in elderly patients. However, IL-6 levels were associated with a measure of preoperative cognitive impairment. Rudolph et al. (2008) reported a case-control study among 24 subjects undergoing different types
of cardiac surgery. In this study, blood samples were analyzed on a dual-channel microsphere flow cytometer and subsequently detected inflammatory markers that were assigned to one of five classes. Twelve subjects who developed delirium had higher increases of postoperative chemokines compared to 12 matched controls. Among the five classes of cytokines, there were no other significant differences between patients with and without delirium. Moreover, the levels of preoperative inflammatory markers did not differ between the groups. The prospective cohort study by Plaschke and colleagues (2010) showed the relationship between raised postoperative IL-6 levels and delirium after cardiac surgery; however, this association was revealed only on univariate analysis. The impact of raised IL-6 concentrations on the development of delirium was not controlled for using other variables related to mental and physical comorbidities of participants or the surgical and anesthetic procedures. Thus, the significance of elevated cytokine concentration was not fully determined, however, the authors speculate that the advanced age of participants could have been responsible for IL-6 elevation and its association with delirium. The aforementioned studies suggest that, although the levels of inflammatory markers are increased prior to surgery in cognitively impaired patients, this increase is not associated with postoperative delirium (Lemstra et al., 2008; Rudolph et al., 2008). According to these studies only postoperative inflammatory markers may be associated with delirium. It should be also noted that previously studied interleukins (IL-1, IL-6, IL8) (de Rooij et al., 2007; Munster et al., 2008; 2010) act as both pro-inflammatory and antiinflammatory cytokines (Xing et al., 1998; Opal and DePalo, 2000). For example, IL-6 is secreted by T-cells and macrophages to stimulate an immune response. However, it also has an inhibitory effect on TNF-α and IL-1, and activates interleukin-1 receptor antagonist (IL-1 inhibitor) and IL-10 (a human cytokine synthesis inhibitory factor). This dual activity of the cytokines studied might have influenced the final associations with postoperative delirium. In light of this, we decided to investigate pro-inflammatory cytokines (IL-2 and TNF-α) alone. IL-2 has been used to treat patients with metastatic malignancies. In a prospective study of consecutive patients who received this treatment, 50% of the individuals experienced severe behavioral and/or cognitive impairment (disorientation, cognitive deterioration) (Denicoff et al., 1987; Kronfol and Remick, 2000). In 34% of the patients, behavioral changes necessitated acute intervention. In the recent animal models, dysregulation of
Cytokines as markers of postoperative delirium
IL-2 expression in the peripheral immune system and the brain was indicated as crucial for injuryinduced neuroimmunological processes that drive responses towards either central nervous system (CNS) neurodegeneration or neuroregeneration (Huang et al., 2012). In addition, Venters et al. (1999) showed that TNF-α exerted its neurotoxicity by inhibiting IGF-1 activity. Although TNF-α fails to cause the cell death in healthy brain, it contributes, similarly to IL2, to neurodegeneration in experimental models (Loddick and Rothwell, 1999). Finally, according to our knowledge, the impact of IL-2 on delirium development has not been investigated to date. The studies revealed that major depressive disorder (MDD), cognitive impairment, and advanced age are the prominent factors contributing to postoperative delirium (Rudolph et al., 2009; Kazmierski et al., 2010a; Kazmierski and Kloszewska, 2011; Kazmierski et al., 2013). Current thinking implicates cortisol and cytokine abnormalities in both MDD and cognitive impairment (Magaki et al., 2007; Simone and Tan, 2011; Maes et al., 2012; Peavy et al., 2012; Kazmierski et al., 2013). Therefore, these conditions should be considered as possible confounders in studies on delirium and cytokines. Moreover, according to the “inflamm-aging” hypothesis diminished ability to cope with stressors, an imbalance between inflammatory and anti-inflammatory networks and a concomitant progressive increase in pro-inflammatory status are major characteristics of the aging process (Franceschi et al., 2000). It is possible, yet, that the age-related inflammatory mechanisms may underlie the association between advanced age and delirium. To date, mechanisms responsible for raised interleukin levels among surgery patients and the putative relationship between inflammation and delirium after cardiac surgery remain unknown. Therefore, our primary aim was to investigate the independent association between raised proinflammatory cytokine levels (IL-2 and TNFα) and delirium diagnosed after CABG surgery. The secondary aim was to establish whether any association between raised cytokine levels and delirium is related to surgical and anesthetic procedures or mediated by pre-existing conditions associated with raised cytokine levels, such as MDD, cognitive impairment, or aging.
Methods This is a prospective, observational cohort study conducted in a 14-bed cardiac surgical ICU of a
847
university teaching hospital (University Hospital, Central Veterans Hospital, Poland). The inclusion criteria were as follows: (1) consecutive adult subjects; (2) patients undergoing elective CABG surgery with cardiopulmonary bypass (CPB); and (3) patients who signed an informed written consent for the participation in the study. The exclusion criteria were: (1) concomitant surgery other than CABG; (2) history of adrenal gland disease; (3) history of systemic inflammatory disease; (4) history of glucocorticoid or cytokine/anti-cytokine therapy within the last year; (5) non-Polish speaking subjects; (6) illiteracy; and (7) patients with pronounced hearing and/or visual impairment. The study was approved by the Ethics Committee of the Medical University of Lodz, Poland and was performed in accordance with the ethical standards of the Declaration of Helsinki. The subjects included in this study have been previously reported in the manuscript regarding the role of cortisol in delirium development (Kazmierski et al., 2013). Preoperative psychiatric assessment The subjects were recruited and examined on the day prior to the scheduled operation. The Montreal Cognitive Assessment (MoCA) and Trail Making Test part B (TMT-B) were used preoperatively to assess global cognition and executive functions, respectively. A diagnosis of dementia was established among patients with abnormal MoCA scores using the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR) criteria. The Mini International Neuropsychiatric Interview (MINI) version 5.0.0 (Polish translation) was used to assess for a diagnosis of MDD (Sheehan et al., 1998; Masiak and Przychoda-Masiak, 2002). These assessments were conducted by an experienced psychiatrist (J.K.). The MoCA was designed as a rapid screening instrument for mild cognitive dysfunction. It assesses different cognitive domains: attention and concentration, executive functions, memory, language, visuospatial skills, conceptual thinking, calculations, and orientation (Nasreddine et al., 2005; Magierska et al., 2012). The TMT-B is a widely used paper-and-pencil task that evaluates the executive functions and cognitive flexibility (War Department Adjutant General’s Office, 1944). In the present study, all the patients who were screened positive for cognitive impairment (MoCA score 6 hours) which resulted in a shorter interval between the end of the intubation and samples collection (
