Short-term beneficial effects of methylene blue on kidney damage in septic shock patients Objective We previously demonstrated that upregulation of renal inducible nitric oxide synthase -LRB- iNOS -RRB- is associated with proximal tubule injury during systemic inflammation in humans . In this study we investigated the short-term effect of methylene blue -LRB- MB -RRB- , an inhibitor of the NO pathway , on kidney damage and function in septic shock patients . Introduction Refractory septic shock remains the major cause of death in noncoronary intensive care units , especially when accompanied by multiple organ failure , with an estimated mortality rate of 50 -- 60 % -LSB- 1 -RSB- . The incidence of acute renal failure in refractory septic shock is approx. 40 -- 50 % -LSB- 2 -RSB- . Nitric oxide has emerged as an important contributory factor to the pathogenesis of septic shock . We previously demonstrated that induction of renal NO is associated with proximal tubule injury during systemic inflammation in humans -LSB- 3 -RSB- . NO stimulates soluble guanylate cyclase -LRB- sGC -RRB- by binding to its heme moiety , which generates cyclic guanosine monophosphate -LRB- cGMP -RRB- -LSB- 4 -RSB- . In the kidney NO and cGMP production are associated with lipopolysaccharide-induced renal proximal tubular cell toxicity -LSB- 5 -RSB- . Selective sGC inhibition during septic shock in rats resulted in an attenuation of renal dysfunction -LSB- 6 -RSB- , indicating that blocking sGC may be a potential therapeutic strategy to treat septic shock-associated renal failure . Methylene blue -LRB- MB -RRB- binds to sGC , blocks cGMP production and has the ability to scavenge NO and to inhibit NO synthases -LSB- 7 , 8 -RSB- . Although several controlled and uncontrolled clinical studies showed beneficial effects of MB on the hemodynamic instability during septic shock -LRB- reviewed in -LSB- 9 -RSB- -RRB- , there are no studies on the putative protective renal effects . We examined the short-term effects of continuous infusion of low-dose MB -LRB- 1 mg/kg per hour -RRB- in patients with septic shock on urinary excretion of the acute kidney injury markers , cytosolic glutathione S-transferases -LRB- GSTs -RRB- present in proximal tubule -LRB- GSTA1-1 -RRB- and distal tubule -LRB- GSTP1-1 -RRB- -LSB- 10 -RSB- . Material and methods Patients Nine patients received a 4 h continuous infusion of 1 mg/kg per hour MB -LRB- 1 % w/v -RRB- provided by the VieCuri Medical Center pharmacy -LRB- for inclusion criteria see Electronic Supplementary Material , ESM -RRB- . Arterial blood and catheterized urine were collected at several time points during the first 24 h. Clinical parameters , the severity of illness using Acute Physiology and Chronic Health Evaluation II -LRB- APACHE II -RRB- , and Sepsis-Related Organ Failure Assessment -LRB- SOFA -RRB- were recorded . Chemical assays Biochemical parameters were determined by routine clinical chemistry . Hemoglobin , methemoglobin , and bilirubin were measured to assess possible side effects of MB , such as hemolytic anemia and methemoglobinemia -LSB- 11 -- 13 -RSB- . Total amount of the stable NO metabolites , nitrate and nitrite , measure of NO radicals production , and the amounts of GSTA1-1 and GSTP1-1 in urine were assayed as described -LSB- 3 -RSB- . The blue color in urine due to MB excretion did not affect the chemical assays . Statistical analysis Values are given as mean ± S.E. or as median -LRB- 25 -- 75 % range -RRB- depending on their distribution . Differences between experimental groups were tested by analysis of variances for repeated measures . A two-tailed p-value less than 0.05 was considered statistically significant . Results Patients Seven patients ultimately died in the intensive care unit , one of refractory shock -LRB- within 12 h -RRB- and six patients because of multiple organ failure . In the latter group two died within 7 days and the remaining four within 28 days after intervention . The mean calculated predicted mortality rate was 61 % , and all patients had at least three organ failures , reflecting a mean SOFA score of 11.1 ± 0.9 . The median stay at the intensive care unit was 16 days -LRB- range 7 -- 24 -RRB- ; the two survivors stayed 89 days -LRB- 52 -- 121 -RRB- in hospital . Pathogenic organisms isolated by culture and site of infection are illustrated in the ESM . Median C-reactive protein was 178 mg/l -LRB- 118 -- 189 -RRB- ; all patients had lactic acidemia -LRB- median 2.7 mmol/l , range 2.1 -- 3.7 -RRB- and thrombocytopenia -LRB- 68 × 109/l , 50 -- 104 -RRB- . The median MAP increased slightly by 5 mmHg -LRB- 2 -- 11 -RRB- from 69 -LRB- 65 -- 70 -RRB- at baseline to 74 -LRB- 68 -- 82 -RRB- 3 h after the start of MB -LRB- p < 0.05 -RRB- with no change in norepinephrine infusion rate . Methemoglobinemia or hemolytic anemia did not develop after MB -LRB- data not shown -RRB- . All MB-treated patients showed blue-coloring of urine and skin . MB attenuates NO formation The concentration NO metabolites in plasma was higher in septic shock patients than in to healthy volunteers -LSB- 3 -RSB- but did not change after MB administration -LRB- Fig . 1a -RRB- . In contrast , MB significantly attenuated the urinary excretion of NO metabolites by a median 90 % -LRB- 75 -- 95 % , p < 0.05 -RRB- from baseline -LRB- 233 μmol/mmol creatinine , 112 -- 536 -RRB- to 6 h -LRB- 37 , 10 -- 87 -RRB- after the start of MB -LRB- Fig . 1b -RRB- . At 4h the MB infusion was stopped , after which the median excretion of urinary NO metabolites increased by 135 % -LRB- 65 -- 795 % , p < 0.05 -RRB- within 6 -- 24 h after MB treatment -LRB- Fig . 1b -RRB- . Fig. 1NO metabolites in plasma and urine and the urinary excretion of tubular injury markers glutathione S-transferase -LRB- GST -RRB- A1-1 and P1-1 . NO metabolite levels in plasma -LRB- a , n = 9 -RRB- and urine -LRB- b , n = 8 -RRB- and levels of GSTA1-1 -LRB- c , proximal tubule , n = 8 -RRB- and GSTP1-1 -LRB- d , distal tubule , n = 8 -RRB- were measured in urine at various times after MB administration in septic shock patients . The urinary excretion of NO metabolites and GSTs was corrected for creatinine excretion . Data are expressed as median with 25 -- 75 % range and analyzed by analysis of variance with repeated measures over the two time periods . * p < 0.05 vs. baseline , # p < 0.05 vs. 6 h after MB treatment MB attenuates kidney damage All patients showed impaired renal function with oliguria and mild proteinuria -LRB- Table 1 -RRB- . One patient suffered from anuria during the first day . Six patients required continuous venovenous hemofiltration renal replacement therapy with a flow of 35 ml/kg -LRB- for median 8.5 days , 4 -- 13 -RRB- , of which 3 during the MB infusion . The creatinine clearance improved by median 51 % -LRB- 18 -- 173 % , p < 0.05 -RRB- during the first 24 h after MB but was still strongly impaired -LRB- Table 1 -RRB- . The urinary excretion of both GSTA1-1 and GSTP1-1 was elevated in all septic shock patients , indicating both proximal and distal renal tubule damage . During the first 6 h of MB urinary excretion of GSTA1-1 and GSTP1-1 was attenuated by median 45 % -LRB- 10 -- 70 % -RRB- and 70 % -LRB- 40 -- 85 % -RRB- vs. baseline -LRB- Fig . 1c , d , p < 0.05 -RRB- . After ending MB infusion urinary excretion of GSTA1-1 and GSTP1-1 increased again , although not significantly -LRB- Fig . 1c , d -RRB- . Table 1Kidney function parameters of septic shock patients -LRB- n = 8 -RRB- treated with MBMedianRangeTotal urine volume , 0 -- 24 h -LRB- ml -RRB- 495169 -- 885Protein excretion , 0 -- 24 h -LRB- mg/day -RRB- 342245 -- 434Creatinine clearance -LRB- ml/min -RRB- Baseline 8.2 4.2 -- 17.4 24 h 10.6 * 9.6 -- 14.8 Blood urea nitrogen Baseline 17.8 10.8 -- 20.0 24 h 17.3 10.4 -- 22.5 Fractional excretion of sodium -LRB- % -RRB- > 2 % Baseline -LRB- n = 0 -RRB- -- -- 24 h -LRB- n = 3 -RRB- 3.1 2.6 -- 3.6 < 1 % Baseline -LRB- n = 8 -RRB- 0.6 0.3 -- 0.7 24 h -LRB- n = 5 -RRB- 0.4 0.2 -- 0.5 p < 0.05 vs. baseline Discussion Several clinical studies in septic shock patients have investigated the effects of MB on the heart , vascular wall , and lungs -LSB- 9 -RSB- . This is the first report demonstrating that MB attenuates kidney damage in human septic shock . To determine the effect of NO pathway inhibition on renal damage we examined the urinary excretion of early tubular injury markers and found that MB inhibited the NO pathway and preserved the integrity of renal tubules . After termination of MB infusion these parameters returned to their elevated pretreatment levels . Both plasma concentrations -LRB- more than twofold -RRB- and urinary NO metabolites levels in our septic shock patients were much higher than in healthy volunteers , as demonstrated earlier -LSB- 3 -RSB- . Hydrocortisone may have inhibited iNOS activation , however , the patients received a continuous infusion of hydrocortisone that started before MB infusion and continued during the 24 h period . Therefore the observation that urinary NO metabolite excretion was attenuated only in the first 6 h after the start of MB suggests that this effect is not related to steroids . Although urinary NO metabolite excretion was attenuated , we did not find a reduction in plasma NO metabolites . This is in contrast with an earlier report , in which patients received a bolus injection of MB prior to the continuous infusion -LSB- 14 -RSB- . Renal failure in septic shock patients is a complex and multifactorial disease process . During septic shock the systemic vasodilation increases renal sympathetic activity and angiotensin concentration which results in intrarenal vasoconstriction with sodium and water retention and decreased glomerular filtration rate -LSB- 2 -RSB- . We previously demonstrated that induction of renal iNOS , constitutively expressed in the kidney -LSB- 15 -RSB- , is associated with proximal tubule injury during systemic inflammation in humans -LSB- 3 -RSB- . As a result of its active secretory transport function and role in urine concentration , the proximal tubule is a susceptible target and often the first site of damage -LSB- 16 -RSB- . Therefore inhibition of peroxynitrite formation from excessively produced NO and superoxide -LSB- 17 -RSB- by MB may be beneficial for the kidney during septic shock , possibly explained by the local accumulation of MB in renal proximal tubules -LSB- 18 -RSB- . Global hemodynamic variables can influence renal function , however , only a small but statistically significant increase was found for mean arterial pressure , whereas other global hemodynamic parameters did not change during MB treatment . Since the detailed nature of our investigation , obviously these methods are not feasible in a large-scale clinical intervention study . The most elegant way to examine the effects of MB would be in a randomized , placebo-controlled cross-over study . However , with such critically ill patients this design may be considered unethical . We deliberately chose a subgroup of severe septic shock patients with a high chance of sepsis-induced renal damage for two reasons : first , this is the group of patients in which MB is used as a `` last resort therapy '' and , second , to demonstrate the putative beneficial effects of MB on renal damage . With an estimated standard deviation of 36 % in urinary GST excretion , 80 patients would be needed to demonstrate with 80 % power a 10 % reduction in renal injury . This number of patients was not feasible for our investigations . Therefore we decided to determine the parameters before , during and after MB infusion during a 24 h period , which allows each patient to serve as own control . Because of the observational nature and limited size of the present study and the heterogeneity of the patient population , our findings warrant conformation on hard endpoints by a larger clinical trial . However , in our view , first a long-term study is necessary to assess the safety of chronic MB administration in septic patients with refractory shock . Promising effects of MB were found in a trial with vasoplegic patients after cardiac surgery treated with MB -LSB- 19 -RSB- , in which a reduction in both mortality and incidence of renal failure was observed . In conclusion , short-term infusion of MB in septic patients with refractory shock , is associated with a decrease in NO production and an attenuation of the urinary excretion of renal tubular injury markers . Electronic supplementary material Electronic Supplementary Material -LRB- DOC 26K -RRB- Electronic Supplementary Material -LRB- DOC 37K -RRB-

O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

inducible nitric oxide synthase expression


Is there an association between depressive and urinary symptoms during and after pregnancy ? Depressive symptoms and urinary symptoms are both highly prevalent in pregnancy . In the general population , an association is reported between urinary symptoms and depressive symptoms . The association of depressive and urinary symptoms has not yet been assessed in pregnancy . In this study , we assessed -LRB- 1 -RRB- the prevalence of depressive symptoms , over-active bladder -LRB- OAB -RRB- syndrome , urge urinary incontinence -LRB- UUI -RRB- and stress urinary incontinence -LRB- SUI -RRB- during and after pregnancy using the Center for Epidemiologic Studies Depression Scale -LRB- CES-D -RRB- and the Urogenital Distress Inventory -LRB- UDI -RRB- and -LRB- 2 -RRB- the association of depressive symptoms with urinary incontinence and over-active bladder syndrome during and after pregnancy , controlling for confounding socioeconomic , psychosocial , behavioural and biomedical factors in a cohort of healthy nulliparous women . Our data show a significant increase in prevalence of depressive symptoms , UUI , SUI and OAB during pregnancy and a significant reduction in prevalence of depressive symptoms , SUI and OAB after childbirth . UUI prevalence did not significantly decrease after childbirth . In univariate analysis , urinary incontinence and the OAB syndrome were significantly associated with a CES-D score indicative of a possible clinical depression at 36 weeks gestation . However , after adjusting for possible confounding factors , only the OAB syndrome remained significantly associated -LRB- OR 4.4 -LSB- 1.8 -- 10.5 -RSB- -RRB- . No association was found between depressive and urinary symptoms at 1 year post-partum . Only OAB was independently associated with depressive symptoms during pregnancy . Possible explanations for this association are discussed . Introduction The lifetime risk of depressive symptoms in women -LRB- 5.9 -- 21.3 % -RRB- is about twice that in men and symptoms often start in the childbearing years -LSB- 1 -- 3 -RSB- . Prevalence rates of 10 -- 25 % during pregnancy -LSB- 4 -- 9 -RSB- and of 6 -- 16 % post-partum are reported -LSB- 5 , 6 , 8 , 10 -- 12 -RSB- . Prevalence rates vary because of the diversity of populations and diagnostic methodology . Most researchers found higher rates during pregnancy than after childbirth -LSB- 5 , 6 , 8 -RSB- . Urogenital symptoms are also more prevalent in pregnancy than in the general population . Prevalence rates of 9 -- 50 % have been reported for urinary incontinence -LRB- UI -RRB- during first pregnancy and 34 -- 95 % for frequency and urgency symptoms -LRB- over-active bladder -LSB- OAB -RSB- syndrome -RRB- -LSB- 13 , 14 -RSB- . Strong associations are found between depressive symptoms , urinary incontinence and over-active bladder syndrome in non-pregnant women -LSB- 15 -- 19 -RSB- . Whilst the relationship of depressive symptoms and urinary symptoms has not yet been explored in pregnancy , several factors have been found to be associated with depressive symptoms in a general , pregnant and post-partum population . These factors include biomedical factors such as obesity , age , chronic pain -LRB- like back pain -RRB- , previous depressive symptoms -LSB- 12 , 20 , 21 -RSB- , behavioural factors like excessive use of alcohol , smoking , lack of leisure time physical exercise and socioeconomic factors like unemployment and low job satisfaction -LSB- 5 , 7 , 22 -RSB- . Psychosocial factors , such as poorer social support , stressful life events and personality features have also been found related to depressive symptoms -LSB- 11 , 22 -- 25 -RSB- . The aim of this study was to -LRB- 1 -RRB- analyse the prevalence of depressive symptoms and urinary symptoms during and after pregnancy and -LRB- 2 -RRB- assess the association of urinary symptoms with depressive symptoms , controlling for psychosocial , behavioural , socioeconomic and biomedical factors during and after pregnancy . Materials and methods Study population Between January 2002 and July 2003 , 1,366 nulliparous pregnant women from 10 urban midwifery practices in the center of The Netherlands were approached to take part in a prospective longitudinal cohort study assessing pelvic floor problems , sexuality and back pain during first pregnancy until 1 year after delivery . All nulliparous pregnant women received information about the study from the midwives . After 1 week , the women were approached by phone and asked if they wanted to participate in the study . Inclusion criteria were a singleton low risk pregnancy and sufficient knowledge of the Dutch language . One hundred and twenty-two women were excluded due to having a twin pregnancy -LRB- n = 2 -RRB- , miscarriage -LRB- n = 13 -RRB- or insufficient knowledge of the Dutch language -LRB- 107 -RRB- . Thus , 1,244 women met the inclusion criteria . Of these , 672 -LRB- 54 % -RRB- decided to participate in the study . The most common reasons for refusal were lack of time and the intensity and intrusiveness of the questions . The present study is a separate analysis of data collected from the larger study . The Medical Ethics Committee of the University Medical Center Utrecht approved the study . All participants signed an informed consent form . Data collection To assess the prevalence rates at different points in time of depressive symptoms , stress urinary incontinence -LRB- SUI -RRB- , urge urinary incontinence -LRB- UUI -RRB- and over-active bladder -LRB- OAB -RRB- syndrome , we used data obtained from all respondents of questionnaires sent at 12 and 36 weeks gestation and 3 and 12 months post-partum . In addition , we analysed data obtained from the questionnaires sent at 36 weeks gestation and 12 months after delivery to assess the possible association between urinary symptoms and depression . We did so because the prevalence of urinary symptoms peak in the third trimester and because pelvic floor symptoms , occurring in pregnancy and persisting 1 year after delivery , may be associated with depression at this time -LSB- 26 -RSB- . Depressive symptoms were investigated using the Center for Epidemiologic Studies Depression Scale -LRB- CES-D -RRB- . This scale is developed for use in non-psychiatric populations and gives an impression of depressive symptoms -LSB- 27 , 28 -RSB- . The total score ranges from 0 to 60 ; a higher score corresponds with more depressive symptoms . A cut-off score of 16 is frequently used as an indication of a possible clinical depression . We refer in this study to women who scored B16 on the CES-D as having depressive symptoms . Urinary symptoms were assessed with the Urogenital Distress Inventory -LRB- UDI -RRB- -LSB- 29 , 30 -RSB- . The UDI is a validated , standardised questionnaire , translated in Dutch . This questionnaire consists of 19 questions about urogenital symptoms and the experienced discomfort of these symptoms . We looked specifically at self-reported urge and stress urinary incontinence and over-active bladder syndrome . Although the UDI also consists of questions on prolapse , obstructive micturition and pain and heaviness in the pelvic area , these symptoms have not been linked to depression in current literature . Therefore , these questions were not used in the present study . We followed the definitions of the International Continence Society -LRB- ICS -RRB- -LSB- 31 -RSB- . Urge incontinence was determined by a positive answer to the question : `` Do you experience urine leakage related to the feeling of urgency ? '' Stress incontinence was determined by a positive answer to the question : `` Do you experience urine leakage related to physical activity , coughing or sneezing ? '' Over-active bladder syndrome was determined when both of the following questions were answered positively : `` Do you experience frequent urination ? '' and `` Do you experience a strong feeling of urgency to empty your bladder ? '' Validated questionnaires were used to assess potential confounding variables . The Dutch Personality Questionnaire -LRB- DPQ -RRB- contains 133 statements , which are divided into 7 domains : inadequacy , social inadequacy , rigidity , hostility , egoism , dominance and self-esteem -LSB- 32 -RSB- . The higher the score , the more these characteristics are part of the subject 's personality . Personality traits are stable and this questionnaire was completed at 24 weeks gestation for logistic reasons . The Maudsley Marital Questionnaire -LRB- MMQ -RRB- was used to measure the subjective emotional and sexual relationship of the woman with her partner -LSB- 33 -RSB- . The MMQ consists of 15 questions , of which 10 concern emotional aspects -LRB- range 0 -- 80 -RRB- and 5 concern sexual aspects -LRB- range 0 -- 40 -RRB- of the relationship . The higher the score , the worse this specific aspect of the relationship is perceived . In addition , the questionnaires addressed biomedical and socioeconomic variables . Biomedical factors included length and weight at 36 weeks gestation and 1 year after delivery , age at time of delivery , the presence of a chronic illness or back pain and the use of medication . Data on mode of delivery and pregnancy-related complications -LRB- hypertensive disorders , premature delivery , growth retardation and vaginal blood loss -RRB- were obtained from the case files of obstetricians and midwifes . Data on length and weight were transformed into a body mass index -LRB- BMI = weight / -LRB- height -RRB- 2 -RRB- . Socioeconomic factors consisted of level of education , marital state , employment and job satisfaction . For practical reasons , the education level was dichotomised into high school or less and more than high school . Marital state was dichotomised into married and unmarried/divorced . Behavioural factors we studied were whether participants smoked , used alcohol or were involved in leisure time physical activity in early pregnancy . In addition , women were able to add comments to the standard questions . Statistical analyses Changes in prevalence of depressive symptoms , UUI , SUI and OAB between 6 and 12 weeks gestation and between 36 weeks gestation and 3 and 12 months after delivery was determined using the McNemar tests . Possible variables associated with depressive symptoms , including urinary symptoms , were analysed in women that responded to the questionnaire at 36 weeks gestation and 1 year after delivery . Women with and without CES-D B16 were compared in univariate analyses using the independent samples t-test for continuous variables and chi-squared test for categorical variables . The relationship between depressive symptoms -LRB- CES-D _ 16 -RRB- -LRB- dependent variable -RRB- , urinary symptoms and potential confounders was assessed using multivariate logistic regression analysis -LRB- stepwise forward method -RRB- to assess whether urinary symptoms remained associated with depressive symptoms . Only significantly associated variables in univariate analyses -LRB- p < 0.05 -RRB- were put in the model . Odds ratios -LRB- Exp -LRB- B -RRB- -RRB- for continuous variables were calculated when appropriate . The Hosmer and Lemeshow test was used to establish the goodness of fit of the model . A p value of > 0.05 indicates that the model provides a valid representation of data . All analyses were performed with the SPSS for Windows 11.5 . Results Of the 672 women who started in the study at 12 weeks gestation , 642 -LRB- 95 % -RRB- women responded to the personality questionnaire sent at 24 weeks gestation . The questionnaires at 36 weeks gestation and 3 and 12 months after delivery were answered by 511 -LRB- 76 % -RRB- , 503 -LRB- 75 % -RRB- and 509 -LRB- 76 % -RRB- women , respectively . The average age at delivery was 30.0 years -LRB- standard deviation -LRB- SD -RRB- 3.6 years -RRB- . Average BMI at 36 weeks gestation was 27.9 kg/m2 -LRB- SD 4.1 kg/m2 -RRB- . The percentage of women whose education stopped after high school was 52.7 % . None of the women were breast-feeding 1 year after delivery . The percentage of women who did not have a spontaneous vaginal delivery was 33.9 % . Pregnancy-related complications were reported in 18.3 % . In our series , urinary tract infection was not mentioned by any of the women . The prevalence rates of depressive symptoms , UUI , SUI and OAB at different points in time during and after pregnancy are shown in Table 1 . The increase in prevalence during pregnancy -LRB- from 12 to 36 weeks gestation -RRB- and decrease in prevalence after pregnancy -LRB- from 36 weeks gestation to 12 months after delivery -RRB- of all symptoms , except urge urinary incontinence , was statistically significant in the McNemar tests -LRB- p < 0.05 -RRB- . The increase in prevalence of urge incontinence during pregnancy was significant ; however , the seemingly decrease after childbirth was not significant . Factors significantly associated with depressive symptoms at 36 weeks gestation in univariate analyses and in multivariate logistic regression model are shown in Table 2 . Many factors were significantly associated in univariate analysis ; however , in logistic regression only -LRB- social -RRB- inadequacy -LRB- personality traits -RRB- , worse sexual relationship with the partner , not being involved in leisure time physical activity , pregnancy-related complications and OAB syndrome remained independently associated with depressive symptoms . The Hosmer and Lemeshow test provided a p value of 0.214 , which indicates a proper goodness of fit for this model . Explained variance in this model -LRB- R2 -RRB- is 40.9 % . At 1 year post-partum , no significant association was found between depressive and urinary symptoms in the chi-squared tests ; therefore , no logistic regression analysis was performed . Table 1Incidence of depressive symptoms -LRB- CES-D ≥ 16 -RRB- , incontinence and over-active bladder syndrome 12 weeks gestation -LRB- % -RRB- 36 weeks gestation -LRB- % -RRB- 3 months post-partum -LRB- % -RRB- 12 months post-partum -LRB- % -RRB- Depressive symptoms18 .220.716.712.2 Urge incontinence7 .319.116.115.6 Stress incontinence20.142.226.534.3Over-active bladder syndrome54 .260.17.814.4 Table 2Univariate and multivariate associated factors with depressive symptoms at 36 weeks gestation CES-D < 16 -LRB- n = 405 -RRB- CES-D ≥ 16 -LRB- n = 106 -RRB- Crude OR -LRB- 95 % CI -RRB- Adjusted OR -LRB- 95 % CI -RRB- UDIUrge incontinence17 .4 % 26.7 % 1.73 -LRB- 1.05 -- 2.86 -RRB- Stress incontinence39 .2 % 52.4 % 1.71 -LRB- 1.11 -- 2.63 -RRB- Over-active bladder syndrome57 .0 % 73.3 % 2.08 -LRB- 1.29 -- 3.34 -RRB- 4.40 -LRB- 1.84 -- 10.48 -RRB- MMQEmotionality6 .62 -LRB- 6.21 -RRB- 13.74 -LRB- 11.33 -RRB- 1.10 -LRB- 1.07 -- 1.13 -RRB- Sexuality11 .52 -LRB- 6.95 -RRB- 16.53 -LRB- 8.12 -RRB- 1.09 -LRB- 1.06 -- 1.13 -RRB- 1.12 -LRB- 1.06 -- 1.17 -RRB- NPVInadequacy8 .08 -LRB- 5.09 -RRB- 14.50 -LRB- 7.79 -RRB- 1.17 -LRB- 1.13 -- 1.22 -RRB- 1.21 -LRB- 1.13 -- 1.30 -RRB- Social inadequacy6 .89 -LRB- 6.19 -RRB- 9.84 -LRB- 6.96 -RRB- 1.07 -LRB- 1.04 -- 1.10 -RRB- 1.08 -LRB- 1.01 -- 1.16 -RRB- Rigidity24 .65 -LRB- 6.81 -RRB- 26.47 -LRB- 5.91 -RRB- 1.04 -LRB- 1.01 -- 1.08 -RRB- Hostility12 .36 -LRB- 5.36 -RRB- 17.12 -LRB- 6.71 -RRB- 1.14 -LRB- 1.10 -- 1.19 -RRB- Egoism9 .03 -LRB- 4.23 -RRB- 10.56 -LRB- 4.90 -RRB- 1.08 -LRB- 1.03 -- 1.13 -RRB- Self-esteem30.30 -LRB- 4.83 -RRB- 27.09 -LRB- 4.56 -RRB- 0.88 -LRB- 0.84 -- 0.92 -RRB- BMI -LRB- kg/m2 -RRB- 27.59 -LRB- 3.65 -RRB- 29.22 -LRB- 5.24 -RRB- 1.10 -LRB- 1.04 -- 1.15 -RRB- Age -LRB- years -RRB- 30.50 -LRB- 3.67 -RRB- 29.66 -LRB- 4.02 -RRB- 0.94 -LRB- 0.89 -- 1.00 -RRB- Education high school/below46 .9 % 63.2 % 1.95 -LRB- 1.25 -- 3.02 -RRB- Unemployed4 .5 % 12.3 % 3.00 -LRB- 1.42 -- 6.34 -RRB- Low job satisfaction5 .2 % 15.1 % 3.23 -LRB- 1.57 -- 6.68 -RRB- Smoking7 .1 % 16.2 % 2.53 -LRB- 1.33 -- 4.83 -RRB- Use of alcohol16 .0 % 6.7 % 0.38 -LRB- 0.17 -- 0.85 -RRB- No leisure time physical activity43 .2 % 65.1 % 2.46 -LRB- 1.57 -- 3.83 -RRB- 2.83 -LRB- 1.35 -- 5.92 -RRB- Back pain51 .9 % 67.0 % 1.90 -LRB- 1.21 -- 2.98 -RRB- Pregnancy related complications8 .8 % 20.8 % 2.71 -LRB- 1.38 -- 5.34 -RRB- 3.22 -LRB- 1.12 -- 8.87 -RRB- Shown are significantly associated factors at the p < 0.05 level with depressive symptoms . Non-significantly associated factors are left out in this table.CES-D : Center for Epidemiologic Studies Depression Scale , UDI : Urogenital Distress Inventory , MMQ : Maudsley Marital Questionnaire , DPQ : Dutch Personality Questionnaire , BMI : body mass index , OR : odds ratio , 95 % CI : 95 % confidence interval . Discussion In our study , we set out to analyse the prevalence of depressive and urinary symptoms during and after pregnancy and to assess the possible association of urinary symptoms with depression , whilst controlling for psychosocial , behavioural , socioeconomic and biomedical factors . We showed a significant increase in prevalence of depressive symptoms , UUI , SUI and OAB during pregnancy and a significant reduction in the prevalence of depressive symptoms , SUI and OAB after childbirth -LRB- p < 0.05 -RRB- . The prevalence of UUI did not significantly decrease after childbirth . In univariate analysis , UUI , SUI and the OAB syndrome was significantly associated with a CES-D score of B16 at 36 weeks gestation . However , after adjusting for possible confounding factors , only the OAB syndrome remained significantly associated . At 1 year after delivery , no association was found between urinary incontinence , OAB syndrome and depressive symptoms . In non-pregnant women , an association is reported between depression and urinary incontinence , especially urge incontinence , and over-active bladder syndrome with and without urge incontinence -LSB- 15 -- 19 -RSB- . These studies mainly used univariate statistics and did not account for potential confounding factors . Our univariate analysis also showed that urinary incontinence and over-active bladder syndrome were significantly associated with depressive symptoms . However , in multivariate analysis , we did not find an association between depressive symptoms and stress or urge urinary incontinence during or after pregnancy . On the other hand , we did find an independent significant relation between depressive symptoms and over-active bladder syndrome at 36 weeks gestation , though not 1 year after delivery . In a research in a non-pregnant population , several explanations are suggested . Firstly , urinary incontinence as a chronic disorder may lead to depressive symptoms . The finding that depression at 1 year after delivery was not associated with urinary symptoms does not support this explanation . Secondly , it is suggested that psychological factors might influence urgency and detrusor instability -LSB- 34 -RSB- . Thirdly , a mutual pathologic origin of urinary incontinence and depression is proposed : both are suggested to be caused by the reduction of serotonin -LSB- 15 , 35 -RSB- . This suggestion is at the least dubious because serotonergic depletion as the suggested aetiology in depression has been seriously questioned -LSB- 36 -RSB- . Furthermore , the therapeutic effect of selective serotonin re-uptake inhibitors -LRB- SSRIs -RRB- in the treatment of depression is only slightly better than placebo -LSB- 37 -RSB- . In a pregnant population , several other explanations can be considered . First , during the third trimester of pregnancy , the increase in cardiac output , increasing size of the uterus with compression of the bladder and sleep disturbances may all contribute to an increased voiding frequency . Secondly , the definition used for over-active bladder syndrome -LRB- combination of urgency and frequency -RRB- has been developed for use in a non-pregnant population . Because the majority of women will have frequency and urgency symptoms as part of their normal third trimester pregnancy , it is questionable if the diagnosis of OAB in pregnancy has the same meaning and impact as OAB in non-pregnant women . The strength of this study is that we used a prospective , longitudinal design with validated questionnaires in a large number of healthy nulliparous women . By measuring not only urogenital symptoms and depressive symptoms , but also psychosocial , behavioural , socioeconomic and biomedical factors , we were able to perform solid multivariate analysis techniques on the associations between bladder symptoms and depression . Our study has also some potential drawbacks that need to be discussed . First , because of the observational , epidemiological design of the study , all information gathered through the questionnaires is subjective . We used a symptom-based definition of urinary symptoms recommended by the ICS -LSB- 31 -RSB- . Although we could rule out , to a certain extend , urinary tract infection as potential confounding factor for urinary symptoms from the records of the midwife or gynecologist , we were unable to confirm the reported symptoms by means of a clinical diagnosis . However , the sensitivity of clinical tests like the stress test and also urodynamic investigation in relation to urogenital symptoms is still under debate -LSB- 38 , 39 -RSB- . Our data have to be interpreted from a symptom-based point of view , which is most often the best there is to get out of epidemiological studies . It would be worthwhile to test our findings in a clinical setting , although the use of urodynamics during pregnancy in healthy women may turn out to be a difficult ethical question . Secondly , we had a moderate participation rate . Due to the quantity and intimate nature of the questions on sexuality and pelvic floor discomfort , the response rate was 54 % . However , the prevalence rates of pelvic floor problems and back pain found in this cohort are in concordance with prevalence rates in other studies and the obstetrical outcome -LRB- mode of delivery , birth weight , etc. -RRB- of the study population was similar to that of comparable women registered in The Netherlands Perinatal Registry 2001 -LSB- 13 , 40 , 41 -RSB- . In addition , the percentage of women scoring above the cut-off score of 16 on the CES-D is similar to that found in a large American study among pregnant women -LSB- 7 -RSB- . Finally , the associations we found between psychosocial , behavioural , socioeconomic and biomedical factors at 36 weeks gestation have all been reported before in ante-natal and post-natal study populations -LSB- 5 , 7 , 21 , 22 , 42 -- 45 -RSB- . So , the chance that our results are biased by the moderate participation rate is low . A third limitation is that we did not have information on urogenital and depressive symptoms before pregnancy . We decided not to ask about previous symptoms because of the risk of recall bias . Longstanding pre-pregnancy depressive disorders or urogenital symptoms may affect the prevalence rate recorded in pregnancy , but it is questionable if it would affect the associations we studied . Our main conclusion that there is no association between UUI , SUI and depressive symptoms during and after pregnancy was reached after multivariate adjustment in which many factors were accounted for . Finally , the prevalence of depressive symptoms was measured with the CES-D and diagnosis of depression could therefore differ from diagnosis obtained through interview following the DSM-IV criteria . However , the CES-D is a widely used questionnaire with adequate sensitivity and specificity -LSB- 46 -RSB- , gives a good indication of depressive symptoms and is very suitable for large cohort studies . Conclusion We found significantly higher rates of depressive symptoms , SUI and OAB syndrome during pregnancy than after childbirth . After controlling for other associated factors , we found an independent association between depressive symptoms and the OAB syndrome in pregnancy but not with urinary incontinence . This association between OAB syndrome and depressive symptoms is lost after pregnancy , so it is likely that pregnancy-related factors have confounded this association . In general practice , this information on the natural course of the OAB syndrome , and its lack in causing major depressive symptoms after childbirth , can be used to counsel women who are confronted with these problems during pregnancy .

O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O B I I O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O B I I O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O

pregnancy
depression
urge urinary incontinence
stress urinary incontinence


Ocular blood flow in patients with obstructive sleep apnea syndrome -LRB- OSAS -RRB- Background Sleep-related disorders are among the important risk factors for neurovascular diseases . Obstructive sleep apnea syndrome -LRB- OSAS -RRB- is characterized by snoring , excessive daytime sleepiness , and insomnia . Our aim was to investigate the presence of glaucoma in patients with OSAS and to reveal vascular pathology related to the pathogenesis of glaucoma in those patients . Obstructive sleep apnea syndrome -LRB- OSAS -RRB- is characterized by snoring , excessive daytime sleepiness , and insomnia . Epidemiological studies revealed a prevalence between 2 and 20 % . Among the risk factors , obesity , male gender , upper respiratory tract abnormality , consumption of alcohol , snoring , and thick neck are worth mentioning -LSB- 5 , 11 , 12 -RSB- . In previous studies , retinal vascular tortuosity and congestion -LSB- 7 -RSB- , floppy eyelid syndrome -LSB- 3 , 18 , 22 , 27 -RSB- , keratoconus -LSB- 22 -RSB- , papilledema , and optic neuropathy -LSB- 2 , 14 , 20 -RSB- have been described in patients with OSAS . It has been stressed that OSAS may be a predisposing condition for anterior optic neuropathy -LSB- 14 -RSB- . In a study , Mojon et al. , investigating 69 patients with OSAS , found the incidence of glaucoma to be 7.2 % -LSB- 21 -RSB- . Onen et al. found a high incidence -LRB- 14.6 -- 47.6 % -RRB- of primary open-angle glaucoma -LRB- POAG -RRB- in patients with sleep-disordered breathing -LSB- 24 -RSB- . Similarly , in another study by Mojon et al. , the prevalence of low-tension glaucoma -LRB- LTG -RRB- in patients with OSAS was found to be 50 % -LSB- 23 -RSB- . Recently , in a study from Turkey , it was stated that OSAS is correlated with a proportional decrease in retinal nerve fiber layer -LRB- NFL -RRB- -LSB- 15 -RSB- . The study 's aim was to investigate the ocular blood flow in patients with OSAS since pathological ocular blood flow has been suggested as a major mechanism in the etiology of glaucoma and also to detect the glaucoma prevalence in the study group . Patients and methods Patients were recruited from those who were referred for suspected OSAS to the `` Sleep Unit '' of the Neurology Clinic -LRB- Erciyes University Faculty of Medicine , Kayseri , Turkey -RRB- between December 2003 and July 2004 . These were consecutively all patients referred to the Sleep Unit during the 7-month period . A total of 42 patients were evaluated during this period . Among these , 31 patients fulfilled the inclusion criteria . The remaining 11 patients were excluded from the study because they had at least one of the exclusion criteria -LRB- such as those who had previous eye surgery or laser treatment , who had any anterior or posterior segment disease or a history of ocular trauma , those with secondary glaucoma , history of chronic steroid use , history of shock , and diabetes mellitus -RRB- . The study included 31 patients with OSAS and 25 healthy controls . Diagnosis of OSAS was made by the Sleep Unit of the Neurology Clinic . Atherosclerotic risk factors likely to affect ocular blood flow such as hypertension , cigarette smoking , and high blood cholesterol level were investigated in all subjects ; since it was impossible to completely eliminate these factors in both groups , the distribution of these risk factors was investigated and it was found to be similar between the groups -LRB- chi-square : 1.97 ; p = 0.16 -RRB- . Criteria for the diagnosis of POAG were as follows -LRB- all four of the criteria listed had to be present for inclusion in the study -RRB- : A cup to disc ratio -LRB- c/d -RRB- over 0.5 or difference of c/d between two eyes > 0.2 with thinning of the neuroretinal rim ; a careful search was made to detect the presence of any disc hemorrhages to strongly support the diagnosis . The c/d ratio and the optic disc evaluation were derived with a +90 diopter aspherical Volk lens by two independent examiners who were masked to the condition of the patient.Any of the detected visual field defects such as localized defects , paracentral scotoma , Bjerrum scotoma , nasal step , temporal sector defect , and diffuse defect which can not be explained by any neurologic or fundus lesion.Open iridocorneal angle.An intraocular pressure -LRB- IOP -RRB- > 21 mmHg without treatment . Diagnosis of normotensive glaucoma was made with criteria similar to those stated for POAG except for the fact that IOP was < 21 mmHg without treatment . The control group consisted of 25 age - and sex-matched healthy subjects who were recruited from those attending the eye clinic for conditions such as refractive errors , etc. . Control subjects had to meet all of the following ophthalmological criteria for inclusion in the study : No IOP elevation over 21 mmHgNo evidence of glaucomatous optic nerve appearance -LRB- no disc hemorrhages -RRB- and a c/d ratio less than 0.5 Normal anterior chamber angle on slit lamp and gonioscopic examinationNormal visual field test resultsNo previous history of antiglaucomatous drug usage , ocular trauma , ocular surgery , or laser therapy Patients underwent orbital color Doppler ultrasonography -LRB- Toshiba Power Vision 6000 , Osaka , Japan -RRB- at the Radiology Unit of the University . An 11-MHz linear surface probe was used and the measurements were performed between 12:00 a.m. and 13:00 p.m. . The patient was supine ; eyes were closed and aimed at the ceiling under the closed eyelids . Systolic blood velocity -LRB- PSV -RRB- and end-diastolic blood velocity -LRB- EDV -RRB- were calculated in the ophthalmic artery and central retinal artery ; resistivity index -LRB- RI -RRB- was calculated for the central retinal artery -LRB- CRARI -RRB- and ophthalmic artery -LRB- OARI ; RI = PSV-EDV/PSV -RRB- . Polysomnography was performed at the Sleep Research Unit of the University ; it was constituted by two EEG channels , two EOG channels , one EMG channel recording from the submental muscle , one nasal current channel , one thoracic motion channel , one abdominal motion channel , one oximeter channel , a microphone , two leg movement channels from the right and left anterior tibialis muscles , and video recordings made between 2300 and 0700 hours . The parameter used was the apnea-hypopnea index -LRB- AHI -RRB- . Diagnosis of OSAS was made when the AHI was over 5 . When the AHI was between 5 and 15 , OSAS was regarded as `` mild , '' between 16 and 30 as `` moderate , '' and when it was over 30 , it was regarded as `` severe . '' All the subjects in the study underwent a complete ophthalmological examination including visual acuity , slit lamp biomicroscopy , IOP measurement , gonioscopy , and fundus examination . Perimetric examination was made with the Octopus 500 EZ perimeter -LRB- Interzeag AG , Schlieren , Switzerland -RRB- ; stimulus size : white , III , full threshold strategy was used . Only phases 1 and phase 3 of the G1 program were used . The Octopus perimeter has a prior education -LRB- preparation -RRB- program for possibly naive patients , which was used for all patients who were naive to the examination . A factor based on the number of false-positive and false-negative replies to the stimuli , and their ratio -LRB- < 13 % -RRB- , was used to determine reliability . Unreliable results were retested on another day . Disc analysis was made with the Heidelberg Retinal Tomograph II -LRB- Heidelberg Engineering GmbH 2001 , software version 3.0 , Heidelberg , Germany -RRB- . Mean nerve fiber layer thickness , rim area , rim volume , and linear c/d ratio were noted . All statistical analyses were carried out using statistical software -LRB- SPSS , version 10.0 for Windows , SPSS Inc. , Chicago , IL , USA -RRB- . Differences were considered significant at p < 0.05 . Student 's t-test was used for intergroup analysis ; chi-square , and Kruskal-Wallis , and Mann-Whitney U tests for nonparametric tests ; analysis of variance -LRB- ANOVA -RRB- was used for the correlation analysis . The study was conducted in accordance with the Declaration of Helsinki and was approved by an Institutional Ethics Committee . Results This study included 31 patients -LRB- 7 female , 24 male -RRB- and 25 controls -LRB- 7 female , 18 male -RRB- . There was no significant difference among the groups in terms of sex distribution -LRB- Yates corrected chi-square = 0.02 ; p = 0.88 -RRB- . While the mean age of the patient group was 52.07 ± 9.35 years , it was 50.44 ± 6.38 years in the control group ; there was no statistically significant difference between age distributions among the groups -LRB- p = 0.13 , unpaired Student 's t-test -RRB- . There was no statistically significant difference between the two groups with respect to the distribution of arteriosclerotic risk factors and hypertension -LRB- Yates corrected chi-square = 1.97 ; p = 0.16 -RRB- . The prevalence of glaucoma was 4 of 31 OSAS patients -LRB- 12.9 % -RRB- . In two of these four patients , both eyes were affected . One of these patients had normotensive glaucoma and one had POAG . The other two patients had normotensive glaucoma only in one eye . The other eyes had large cupping without any visual field defect . All of these four patients belonged to the severe OSAS group -LRB- AHI > 30 -RRB- . There was no significant difference between mild , moderate , or severe OSAS patients in terms of OARI or CRARI values -LRB- Kruskal-Wallis test p = 0.961 , p = 0.774 -RRB- . The patient and control groups did not differ significantly in terms of CRARI and OARI or IOP -LRB- p > 0.05 ; Table 1 -RRB- . Table 1Comparison of patients and controls with respect to intraocular pressure -LRB- IOP -RRB- , ophthalmic artery resistivity index -LRB- OARI -RRB- , and central retinal artery resistivity index -LRB- CRARI -RRB- ParametersPatient eyes -LRB- mean ± SD -RRB- -LRB- n = 62 -RRB- Control eyes -LRB- mean ± SD -RRB- -LRB- n = 50 -RRB- tpIOP -LRB- mmHg -RRB- 13.37 ± 4.3714.00 ± 4.31 − 1.000.32 OARI0 .72 ± 0.060.71 ± 0.060.7690.44 CRARI0 .69 ± 0.060.70 ± 0.05 − 0.8030.42 There was a statistically significant difference between median IOP values of mild -LRB- 10.5 mmHg ; range : 9 -- 18 mmHg -RRB- and severe -LRB- 14.5 mm Hg ; range : 9 -- 27 mmHg -RRB- OSAS patients -LRB- p = 0.031 ; Mann-Whitney U test -RRB- . When correlation was analyzed between variables , a statistically significant correlation was found between OARI and MD values -LRB- r = 0.339 , p = 0.007 , Fig. 1 -RRB- , CRARI and MD values -LRB- r = 0.246 , p = 0.05 , Fig. 2 -RRB- , CRARI and LV values -LRB- r = 0.253 , p = 0.048 , Fig. 3 -RRB- , and AHI and IOP values -LRB- r = 0.426 , p = 0.001 , Fig. 4 -RRB- . Fig. 1The positive correlation between ophthalmic artery resistivity index -LRB- OARI -RRB- and mean defect -LRB- MD -RRB- in the patient group is statistically significant -LRB- r = 0.339 , p = 0.007 -RRB- Fig. 2The positive correlation between central retinal artery resistivity index -LRB- CRARI -RRB- and mean defect -LRB- MD -RRB- in the patient group is statistically significant -LRB- r = 0.246 , p = 0.05 -RRB- Fig. 3The positive correlation between central retinal artery resistivity index -LRB- CRARI -RRB- and loss variance -LRB- LV -RRB- in the patient group is statistically significant -LRB- r = 0.253 , p = 0.048 -RRB- Fig. 4The positive correlation between apnea-hypopnea index -LRB- AHI -RRB- and intraocular pressure -LRB- IOP -RRB- in the patient group is statistically significant -LRB- r = 0.426 , p = 0.001 -RRB- Discussion This study aimed to investigate the prevalence of glaucoma in patients with OSAS and also to investigate the association of ocular blood flow with OSAS and glaucoma . In previous studies , while the prevalence of glaucoma was found to be 2 % -LSB- 8 -RSB- , no correlation was obtained between respiratory disturbance index -LRB- RDI -RRB- and IOP . However , many other studies found higher incidences and a positive correlation between IOP and RDI . For instance , Mojon et al. stated that there was a positive correlation between IOP and RDI in 114 glaucoma suspects -LSB- 21 -RSB- . In our study , similar to Mojon et al. 's study , there was a significantly positive correlation between IOP and AHI -LRB- r = 0.426 , p = 0.001 -RRB- . In another study by Robert et al. , which was carried out with 69 patients with OSAS , prevalence was found to be 7.2 % -LSB- 27 -RSB- . At the same time , a strong positive correlation was found between OSAS and lid hyperlaxity -LSB- 27 -RSB- . In that study , incidence was 8.7 % and six patients were referred for glaucoma treatment -LSB- 27 -RSB- . In the study of McNab et al. in which 8 patients with floppy eyelid syndrome were investigated for OSAS and 20 other patients with known OSAS were examined for floppy eyelid syndrome and other possibly associated ocular features , it was found that 1 of 8 patients with floppy eyelids had normotensive glaucoma -LSB- 18 -RSB- . Onen et al. found a high prevalence of sleep-disordered breathing -LRB- SDB -RRB- in POAG patients -LSB- 24 -RSB- . When only snoring was taken into consideration , the incidence of `` only snoring '' was 47.6 % , `` snoring and excessive daytime sleeping '' was 27.3 % , and `` snoring , daytime sleepiness , and insomnia '' was 14.6 % -LSB- 24 -RSB- . Marcus et al. also stressed that SDB may be a risk factor for low-tension glaucoma -LRB- LTG -RRB- -LSB- 17 -RSB- . Mojon et al. found that the prevalence of OSAS was 50 % in LTG patients aged between 45 and 64 years and 63 % in those over 64 years of age -LSB- 23 -RSB- . However , Girkin et al. -LSB- 9 -RSB- reported an odds ratio of 2.02 for OSAS patients to develop glaucoma . Similar to most of the above-mentioned studies , the authors of the present study also found a high prevalence of glaucoma -LRB- 12.9 % -RRB- in the study group of 31 patients suggesting that OSAS in conjunction with a vessel disease is an important risk factor for glaucoma . The correlation between RDI and IOP was also investigated by Geyer et al. -LSB- 8 -RSB- ; the authors stated that there was no statistically significant correlation -LSB- 8 -RSB- . On the contrary , Mojon et al. found a positive correlation between two variables -LSB- 21 -RSB- . We found a statistically significant difference between AHI and IOP in mild and severe OSAS patients . In our study , all four glaucomatous patients were in the severe OSAS group with an AHI > 30 . In the patient group , there was a positive correlation between OARI and MD as well as CRARI and MD , and LV . Tsang et al. also found that moderate to severe OSAS patients were associated with a higher incidence of visual field defects -LSB- 29 -RSB- . These results suggest that visual field defects may be caused by optic nerve perfusion insufficiency and that when RI increases , field defects also increase . However , there was no significant difference between OARI and CRARI values of patients and healthy subjects . This may suggest that the effects of OSAS on body systems are seen not only during sleep but also during daytime ; pathological changes may be more clearly documented if recordings and ultrasonography can be made during the sleeping period with a suitable technique to be developed in the future . Hypoxia in OSAS is of intermittent character and the thinning may occur in the progression of the disease in such patients . Long-term follow-up of these patients in terms of NFL thickness changes over time may clarify this issue . Purvin et al. suggested that intracranial pressure increases as a result of episodic nocturnal hypoxemia and hypercapnia , thereby leading to papilledema and increasing the risk of visual loss -LSB- 25 -RSB- . Since intracranial pressure increase in these patients is of intermittent character , cerebrospinal fluid pressure may be normal . In our group of patients , visual field defects were detected in ten patients despite normal ophthalmological examination . This may be due to optic nerve damage caused by cerebral ischemia and intermittent intracranial pressure increase in such patients . Low diastolic pressure and systemic hypertension are reported to be strongly associated with glaucoma -LSB- 4 , 6 , 25 , 26 -RSB- . Some authors suggested that physiological nocturnal hypotension , in the presence of other vascular risk factors , can bring the optic nerve head circulation under the critical levels and thus play a role in the pathogenesis of anterior ischemic neuropathy and glaucoma -LSB- 1 , 10 , 16 , 28 -RSB- . The pathogenesis of LTG is not clear ; however , optic nerve head hypoperfusion has been suggested as the cause -LSB- 30 -RSB- . Hayreh stated that many systemic and ocular paralyses occur at nighttime and may be realized when the patients awaken early in the morning -LSB- 13 -RSB- . Furthermore , Hayreh -LSB- 13 -RSB- and Meyer -LSB- 19 -RSB- suggested that nocturnal hypotension might play a role in the pathogenesis of LTG . In conclusion , in our group of patients with OSAS , a high prevalence was found -LRB- 12.9 % = 4 glaucoma patients of 31 OSAS patients -RRB- and it is interesting to note that all four of the glaucoma patients were in the severe OSAS group . The positive correlation detected between OARI and MD , and also between CRARI and MD as well as LV , suggests that visual field defects may be due to optic nerve perfusion defects and that these field defects also increase as the RI increases . The presence and progression of glaucoma should be investigated particularly in patients with severe OSAS in the long-term follow-up , and changes in retinal nerve fiber layer thickness and ocular Doppler ultrasonographic findings should also be monitored in such patients .

B I I O O O B I I I O O O O O O O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O B I I O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B I I O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

obstructive sleep apnea syndrome
glaucoma
ocular blood flow
polysomnography