Undrestanding postoperative cognitive dysfunction: novel insights

ABSTRACT: Background: Sleep is integral to biological function and sleep disruption can result in both physiological and psychological dysfunction. The acute cognitive consequences of sleep loss has been an active field of recent investigation, evidence suggests that sleep disruption in critically ill older adults can result in acute decrements in cognitive functioning. Surgery activates the innate immune system, inducing neuroinflammatory changes that interfere with cognition. The fact that patients with sleep disorders have an increased likelihood of exhibiting postoperative delirium encourages us to investigate the contribution of perioperative SF to the neuroinflammatory and cognitive responses of surgery. Methods: The effects of 24h sleep fragmentation (SF) and surgery were explored on adult C57BL/6J male mice. SF procedure started at 7 am with the home-cages being placed on a large platform orbital shaker cycled every 120 seconds (30 sec on/90 sec off). This procedure lasted for 24h. Stabilized tibia fracture was performed either before or after the 24h SF procedure. Separate cohorts of mice were tested for systemic and hippocampal inflammation and cognition. Results: Twenty-four hours of SF induced non-hippocampal memory dysfunction and increase in systemic IL-6. SF and surgery caused hippocampal-dependent memory impairment, although memory impairment was not exacerbated by combining SF with surgery. One day after either SF or surgery there was a significant increase in IL6 mRNA and TNF-alpha mRNA. These increments were more pronounced when either pre or post operative SF was combined with surgery. Conclusions: We show that while SF and surgery can independently produce significant memory impairment, perioperative SF significantly increased hippocampal inflammation without further cognitive impairment. The dissociation between neuroinflammation and cognitive decline may relate to our use of a sole memory paradigm that does not capture other aspects of cognition, especially learning.

Dissecting gastrointestinal dysfunction and inflammation in a “pre-motor” rodent model of Parkinson’s disease

Research on Parkinson’s disease (PD) has mainly focused on the degeneration of the dopaminergic neurons of nigro-striatal (NS) pathway; also, post-mortem studies have demonstrated that the noradrenergic and the serotonergic transmitter systems are also affected (Jellinger, 1999). Degeneration of these neuronal cell bodies is generally thought to start prior to the loss of dopaminergic neurons in the NS pathway and precedes the appearance of the motor symptoms that are the “hallmark” of PD. Gastrointestinal (GI) motility is often disturbed in PD, manifesting chiefly as impaired gastric emptying and constipation. These GI dysfunction symptoms may be the result of a loss in noradrenergic and serotonergic innervation. GI deficits were evaluated using an organ bath technique. Groups treated with different combinations of neurotoxins (6-OHDA alone, 6-OHDA + pCA or 6-OHDA + DSP-4) presented significant differences in gut contractility compared to control groups. Since a substantial body of literature suggests the presence of an inflammatory process in parkinsonian state (Whitton, 2007), changes in pro-inflammatory cytokines in the gut were assessed using a cytokine microarray. It has been found in this work that groups with a combined dopaminergic and noradrenergic lesion have a significant increase in both expressions of IL-13 and VEGF. IL-6 also shows a decrease in treatment groups; however this decrease did not reach statistical significance. The therapeutic value of Exendin-4 (EX-4) was evaluated. It has been previously demonstrated that EX-4, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is neuroprotective in rodent models of PD (Harkavyi et al., 2008). In this thesis it has been found that EX-4 was able to reverse a decrease in gut contractility obtained through intracerebral bilateral 6-OHDA injection. Although more studies are required, EX-4 could be used as a possible therapy for the GI symptoms prominent in the early stages of PD.

Insights into the clinical and functional significance of cardiac autonomic dysfunction in Chagas disease

INTRODUCTION: Exclusive or associated lesions in various structures of the autonomic nervous system occur in the chronic forms of Chagas disease. In the indeterminate form, the lesions are absent or mild, whereas in the exclusive or combined heart and digestive disease forms, they are often more pronounced. Depending on their severity these lesions can result mainly in cardiac parasympathetic dysfunction but also in sympathetic dysfunction of variable degrees. Despite the key autonomic effect on cardiovascular functioning, the pathophysiological and clinical significance of the cardiac autonomic dysfunction in Chagas disease remains unknown. METHODS: Review of data on the cardiac autonomic dysfunction in Chagas disease and their potential consequences, and considerations supporting the possible relationship between this disturbance and general or cardiovascular clinical and functional adverse outcomes. RESULTS: We hypothesise that possible consequences that cardiac dysautonomia might variably occasion or predispose in Chagas disease include: transient or sustained arrhythmias, sudden cardiac death, adverse overall and cardiovascular prognosis with enhanced morbidity and mortality, an inability of the cardiovascular system to adjust to functional demands and/or respond to internal or external stimuli by adjusting heart rate and other hemodynamic variables, and immunomodulatory and cognitive disturbances. CONCLUSIONS: Impaired cardiac autonomic modulation in Chagas disease might not be a mere epiphenomenon without significance. Indirect evidences point for a likely important role of this alteration as a primary predisposing or triggering cause or mediator favouring the development of subtle or evident secondary cardiovascular functional disturbances and clinical consequences, and influencing adverse outcomes.

Sexual dysfunction and dissatisfaction in chronic hepatitis C patients

IntroductionThe prevalence of sexual dysfunction (SD) and dissatisfaction with sexual life (DSL) in patients with chronic hepatitis C virus infection (CHC) was jointly investigated via a thorough psychopathological analysis, which included dimensions such as fatigue, impulsiveness, psychiatric comorbidity, health-related quality of life (HRQL) and sociodemographic and clinical characteristics.MethodsMale and female CHC patients from an outpatient referral center were assessed using the Brief Fatigue Inventory, the Barrat Impulsiveness Scale, the Beck Depression Inventory (BDI), the Hospital Anxiety and Depression Scale, the Hamilton Anxiety Scale (HAM-A), and the World Health Organization Quality of Life Scale-Brief Version (WHOQOL-BREF). Structured psychiatric interviews were performed according to the Mini-International Neuropsychiatric Interview. SD was assessed based on specific items in the BDI (item 21) and the HAM-A (item 12). DSL was assessed based on a specific question in the WHOQOL-BREF (item 21). Multivariate analysis was performed according to an ordinal linear regression model in which SD and DSL were considered as outcome variables.ResultsSD was reported by 60 (57.1%) of the patients according to the results of the BDI and by 54 (51.4%) of the patients according to the results of the HAM-A. SD was associated with older age, female gender, viral genotype 2 or 3, interferon-α use, impulsiveness, depressive symptoms, antidepressant and benzodiazepine use, and lower HRQL. DSL was reported by 34 (32.4%) of the patients and was associated with depressive symptoms, anxiety symptoms, antidepressant use, and lower HRQL.ConclusionsThe prevalence of SD and DSL in CHC patients was high and was associated with factors, such as depressive symptoms and antidepressant use. Screening and managing these conditions represent significant steps toward improving medical assistance and the HRQL of CHC patients.

Exercise-induced ventricular arrhythmias and vagal dysfunction in Chagas disease patients with no apparent cardiac involvement

INTRODUCTION : Exercise-induced ventricular arrhythmia (EIVA) and autonomic imbalance are considered as early markers of heart disease in Chagas disease (ChD) patients. The objective of the present study was to verify the differences in the occurrence of EIVA and autonomic maneuver indexes between healthy individuals and ChD patients with no apparent cardiac involvement. METHODS : A total of 75 ChD patients with no apparent cardiac involvement, aged 44.7 (8.5) years, and 38 healthy individuals, aged 44.0 (9.2) years, were evaluated using echocardiography, symptom-limited treadmill exercise testing and autonomic function tests. RESULTS : The occurrence of EIVA was higher in the chagasic group (48%) than in the control group (23.7%) during both the effort and the recovery phases. Frequent ventricular contractions occurred only in the patient group. Additionally, the respiratory sinus arrhythmia index was significantly lower in the chagasic individuals compared with the control group. CONCLUSIONS : ChD patients with no apparent cardiac involvement had a higher frequency of EIVA as well as more vagal dysfunction by respiratory sinus arrhythmia. These results suggest that even when asymptomatic, ChD patients possess important arrhythmogenic substrates and subclinical disease.

Voiding dysfunction and urodynamic abnormalities in elderly patients

Lower urinary tract dysfunction is a major cause of morbidity and decreased quality of life in elderly men and women. With the progressive aging of the population, it is important to understand common micturitional disorders that may occur in this population. Most urinary problems in the elderly are multifactorial in origin, demanding a comprehensive assessment of the lower urinary tract organs, functional impairments, and concurrent medical diseases. Urodynamics is a highly valuable tool in the investigation of elderly patients with lower urinary tract symptoms. Urodynamic tests are not always necessary, being indicated after excluding potentially reversible conditions outside the urinary tract that may be causing or contributing to the symptoms. Although urodynamic tests may reveal common diagnoses such as bladder outlet obstruction and stress urinary incontinence in the elderly population, findings such as detrusor overactivity and impaired detrusor contractility are common and have important prognostic and therapeutic implications. The purpose of this article is to describe common urologic problems in the elderly and review the indications for and clinical aspects of urodynamic studies in these conditions.

Bethanecol chloride for treatment of clomipramine-induced orgasmic dysfunction in males

PURPOSE: To investigate whether bethanecol chloride may be an alternative for the clinical management of clomipramine-induced orgasmic dysfunction, reported to occur in up to 96% of male users. METHODS: In this study, 12 fully remitted panic disorder patients, complaining of severe clomipramine-induced ejaculatory delay, were randomly assigned to either bethanecol chloride tablets (20 mg, as needed) or placebo in a randomized, double-blind, placebo-controlled, two-period crossover study. A visual analog scale was used to assess severity of the orgasmic dysfunction. RESULTS: A clear improvement was observed in the active treatment period. No placebo or carry-over effects were observed. CONCLUSION: These findings suggest that bethanecol chloride given 45 minutes before sexual intercourse may be useful for clomipramine-induced orgasmic dysfunction in males.

Clinical impact of transesophageal echocardiography in patients with stroke without clinical evidence of cardiovascular sources of emboli

OBJECTIVE: The purpose of this study is to evaluate the impact of transeophageal echocardiography on management of patients at low-risk for cardiogenic embolism to prevent new potential cardiovascular sources of emboli. METHODS: We studied 69 patients with ischemic stroke at low-risk for cardiogenic embolism. Transeophageal echocardiography was performed to access: left atrium enlargement; communication or aneurysm of the interatrial septum; patent foramen ovale; spontaneous echo contrast or intracavitary thrombi; the presence of intraaortic atherosclerotic plaques or thrombi; significant valvar morphologic alteration or dysfunction; left ventricle enlargement, hypertrophy, or contractile abnormality. Transesophageal echocardiography altered clinical management, and we adopted anticoagulant therapy or another procedure apart from the use of acetylsalicylic acid. RESULTS: Transeophageal echocardiography detected at least one abnormality in 40 cases (58%). Clinical conduct was adjusted after the performance of transesophageal echocardiography in 11 patients (15.9%); anticoagulation was added in 10 cases and surgical correction in one patient. CONCLUSION: Transeophageal echocardiography was a very useful tool in the secondary prevention for stroke in patients at low risk for cardiogenic embolism.

Cytokines and troponin-I in cardiac dysfunction after coronary artery grafting with cardiopulmonary bypass

OBJECTIVE: The association between cytokines and troponin-I with cardiac function after cardiac surgery with cardiopulmonary bypass remains a topic of continued investigation. METHODS: Serial measurements, within 24h following surgery, of tumor necrosis factor-alpha, its soluble receptors, and troponin-I were performed in patients with normal ejection fraction undergoing coronary artery bypass grafting. Ejection fraction was measured by radioisotopic ventriculography preoperatively, at 24h and at day 7 postoperatively. RESULTS: Of 19 patients studied (59±8.5 years), 10 (group 1) showed no changes in ejection fraction, 53±8% to 55±7%, and 9 (group 2) had a decrease in ejection fraction, 60±11% to 47±11% (p=0.015) before and 24h after coronary artery bypass grafting, respectively. All immunological variables, except tumor necrosis factor-alpha soluble receptor I at 3h postoperation (5.5± 0.5 in group 1 versus 5.9±0.2 pg/ml in group 2; p=0.048), were similar between groups. Postoperative troponin-I had an inverse correlation with ejection fraction at 24h (r= -0.44). CONCLUSIONS: Inflammatory activity, assessed based on tumor necrosis factor-alpha and its receptors, appears to play a minor role in cardiac dysfunction after cardiac surgery. Troponin I levels are inversely associated with early postoperative ejection fraction.

Reversibility of ventricular dysfunction: clinical experience in a medical office

OBJECTIVE - To describe clinical observations of marked improvement in ventricular dysfunction in a medical office environment under circumstances differing from those in study protocols and multicenter studies performed in hospital or with outpatient cohorts. METHODS - Eleven cardiac failure patients with marked ventricular dysfunction receiving treatment at a doctors office between 1994 and 1999 were studied. Their ages ranged from 20 and 66 years (mean 39.42±14.05 years); 7 patients were men, 4 were women. Cardiopathic etiologies were arterial hypertension in 5 patients, peripartum cardiomyopathy in 2, nondefined myocarditis in 2, and alcoholic cardiomyopathy in 4. Initial echocardiograms revealed left ventricular dilatation (average diastolic diameter, 69.45±8.15mm), reduced left ventricular ejection fraction (0.38±0.08) and left atrial dilatation (43.36±5.16mm). The therapeutic approach followed consisted of patient orientation, elimination of etiological or causal factors of cardiac failure, and prescription of digitalis, diuretics, and angiotensinconverting enzyme inhibitors. RESULTS - Following treatment, left ventricular ejection fraction changed to 0.63±0.09; left ventricular diameters changed to 57.18±8.13mm, and left atrium diameters changed to 37.27±8.05mm. Maximum improvement was noted after 16.9±8.63 (6 to 36) months. CONCLUSION - Patients with serious cardiac failure and ventricular dysfunction caused by hypertension, alcoholism, or myocarditis can experience marked improvement in ventricular dysfunction after undergoing appropriate therapy within the venue of the doctor's office.

Effect of Propafenone on the Contractile Activity of Latissimus Dorsi Muscle Isolated in an Organ Chamber: Experimental Study in Rats

OBJECTIVE: To study the effect of propafenone on the contractile function of latissimus dorsi muscle isolated from rats in an organ chamber. METHODS: We studied 20 latissimus dorsi muscles of Wistar rats and divided them into 2 groups: group I (n=10), or control group - we studied the feasibility of muscle contractility; group II (n=10), in which the contralateral muscles were grouped - we analyzed the effect of propafenone on muscle contractility. After building a muscle ring, 8 periods of sequential 2-minute baths were performed, with intervals of preprogrammed electrical stimulation using a pacemaker of 50 stimuli/min. In group II, propafenone, at the concentration of 9.8 µg/mL, was added to the bath in period 2 and withdrawn in period 4. RESULTS: In group I, no significant depression in muscle contraction occurred up to period 5 (p>0.05). In group II, a significant depression occurred in all periods, except between the last 2 periods (p<0.05). Comparing groups I and II only in period 1, which was a standard period for both groups, we found no significant difference (p>0.05). CONCLUSION: Propafenone had a depressing effect on the contractile function of latissimus dorsi muscle isolated from rats and studied in an organ chamber.

Improvement in left ventricular dysfunction after surgical correction of mitral regurgitation

OBJECTIVE: To evaluate whether left ventricular end-systolic (ESD) diameters £ 51mm in patients (pt) with severe chronic mitral regurgitation (MR) are predictors of a poor prognosis after mitral valve surgery (MVS). METHODS: Eleven pt (aged 36±13 years) were studied in the preoperative period (pre), median of 36 days; in the early postoperative period (post1), median of 9 days; and in the late postoperative period (post2), mean of 38.5±37.6 months. Clinical and echocardiographic data were gathered from each pt with MR and systolic diameter ³51mm (mean = 57±4mm) to evaluate the result of MVS. Ten patients were in NYHA Class III/IV. RESULTS: All but 2 pt improved in functional class. Two pt died from heart failure and infectious endocarditis 14 and 11 months, respectively, after valve replacement. According to ejection fraction (EF) in post2, we identified 2 groups: group 1 (n=6), whose EF decreased in post1, but increased in post2 (p=0.01) and group 2 (n=5), whose EF decreased progressively from post1 to post2 (p=0.10). All pt with symptoms lasting £ 48 months had improvement in EF in post2 (p=0.01). CONCLUSION: ESD ³51mm are not always associated with a poor prognosis after MVS in patients with MR. Symptoms lasting up to 48 months are associated with improvement in left ventricular function.

Right ventricular diastolic dysfunction in the postoperative period of tetralogy of Fallot

OBJECTIVE: To assess right ventricular diastolic function in the intermediate postoperative period of repair of tetralogy of Fallot. METHODS: We carried out a case-control study with 60 patients divided into 2 groups as follows: 1) group I - 30 patients who had undergone repair of tetralogy of Fallot and 2) group II - 30 healthy children. The 2 groups were paired for age, sex, and body surface. The flows in the pulmonary and tricuspid valves were analyzed with Doppler echocardiography. The presence of anterograde flow at the end of diastole in the pulmonary artery defined restrictive right ventricular physiology. Surgical, radiological, electrocardiographic, and echocardiographic variables were analized in the group I. RESULTS: The velocity of the A wave and the E/A ratio for the tricuspid valve showed significant differences between the groups. Cases with E/A < 1.30 predominated in inspiration (group I - 19/30, and group II - 5/30). The duration of the QRS complex on the electrocardiogram was significantly increased in patients with E/A <1.30. Nineteen (63.3%) patients had restrictive right ventricular physiology, which had a longer postoperative period, longer duration of the QRS complex, and a lower E/A ratio in inspiration. The surgical and radiological variables showed no statistical difference. CONCLUSION: Restrictive right ventricular physiology was detected on the intermediate follow-up of most patients undergoing repair of tetralogy of Fallot. The postoperative period and QRS duration were increased in patients with impairment in diastolic function.