obesity is a surging epidemic worldwide . although obesity is a known risk factor for primary cardiovascular events including stroke , its contribution to recurrent vascular risk   and prognoses following an acute vascular event remain controversial . indeed , several studies indicate that a so - called  obesity paradox  might exist because outcomes after an index vascular event ( including stroke ) appear to be better for obese patients compared to their lean counterparts . while several potential underlying mechanisms have been proposed for the obesity paradox , a major critique of data supporting the notion of such a paradox has been the use of body mass index ( bmi ) as the index of obesity . since bmi does not differentiate body composition into muscle , bone or adipose tissue , it is increasingly viewed as an inadequate measure of unhealthy body habitus . on the other hand , urinary creatinine excretion rate ( cer ) is an established marker of muscle mass . over 98% of endogenous creatinine comes from skeletal muscle , which isthen excreted into urine at a constant rate . therefore , urinary cer is proportional to muscle mass , roughly 17 - 20 kilograms of muscle per 1 gram of creatinine . in fact , low cer is an independent predictor of cardiovascular disease and mortality in the general population , and has also been associated with higher all - cause mortality in patients with coronary artery disease . little is known about the role of cer as a prognosticator in stroke patients . in this study , we aimed to assess the relationship of cer with outcome among critically ill acute stroke patients . we prospectively collected data on consecutive patients with acute stroke within 24 hours from symptom onset and admitted to a neurological and neurosurgery intensive care unit in a hospital in taiwan from september 1 , 2007 to august 31 , 2010 . established hospital protocol criteria for admission to our neurological and neurosurgery intensive care unit included hemodynamic instability , acute respiratory failure or intubation for airway protection , unstable neurologic status or glasgow coma score ( gcs ) < 11 . both ischemic stroke and hemorrhagic stroke types wereincluded , but subarachnoid hemorrhage and traumatic intracranial hemorrhage were excluded . patients with end stage renal disease [ defined as estimated glomerular filtration rate ( egfr ) < 15 ml / min/1.73 m ] or known impairment of functional status [ defined as modified rankin scale ( mrs )  3 ] prior to the index stroke were also excluded . we collected baseline demographic for all patients , including age , sex , and medical history of hypertension , diabetes mellitus , atrial fibrillation and prior cerebrovascular disease . neurological deficits were evaluated with the national institute of health stroke scale ( nihss ) , and severity of the disease was evaluated with the acute physiology and chronic health evaluation ii ( apache - ii ) score for each patient on admission . weight and height were measured on admission with subjects in light clothes and without shoes . egfr was estimated by chronic kidney disease epidemiology collaboration ( ckd - epi ) equation adjusted for asians . daily ( 24-hour ) urine volume was recorded by nursing personnel since the admission time to intensive care unit . urine creatinine concentration was measured by spot morning urine on the second day after admission . cer ( mg / day ) was calculated as urine creatinine concentration multiplied by 24-hour urine volume . the primary outcome measure was death or dependence , defined as a mrs of 3 - 6 at 6 month after stroke onset . secondary outcome was death or disability , defined as a mrs of 2 - 6 at 6 month after stroke onset . evaluators of 6-month mrs were unaware of patients in - hospital cer results . the study was performed under a protocol approved by the institutional review board of chang gung memorial hospital , and all examinations were performed after obtaining written informed consent from the patients or appropriate family members . we prospectively collected data on consecutive patients with acute stroke within 24 hours from symptom onset and admitted to a neurological and neurosurgery intensive care unit in a hospital in taiwan from september 1 , 2007 to august 31 , 2010 . established hospital protocol criteria for admission to our neurological and neurosurgery intensive care unit included hemodynamic instability , acute respiratory failure or intubation for airway protection , unstable neurologic status or glasgow coma score ( gcs ) < 11 . both ischemic stroke and hemorrhagic stroke types wereincluded , but subarachnoid hemorrhage and traumatic intracranial hemorrhage were excluded . patients with end stage renal disease [ defined as estimated glomerular filtration rate ( egfr ) < 15 ml / min/1.73 m ] or known impairment of functional status [ defined as modified rankin scale ( mrs )  3 ] prior to the index stroke were also excluded . we collected baseline demographic for all patients , including age , sex , and medical history of hypertension , diabetes mellitus , atrial fibrillation and prior cerebrovascular disease . neurological deficits were evaluated with the national institute of health stroke scale ( nihss ) , and severity of the disease was evaluated with the acute physiology and chronic health evaluation ii ( apache - ii ) score for each patient on admission . weight and height were measured on admission with subjects in light clothes and without shoes . egfr was estimated by chronic kidney disease epidemiology collaboration ( ckd - epi ) equation adjusted for asians . daily ( 24-hour ) urine volume was recorded by nursing personnel since the admission time to intensive care unit . urine creatinine concentration was measured by spot morning urine on the second day after admission . cer ( mg / day ) was calculated as urine creatinine concentration multiplied by 24-hour urine volume . the primary outcome measure was death or dependence , defined as a mrs of 3 - 6 at 6 month after stroke onset . secondary outcome was death or disability , defined as a mrs of 2 - 6 at 6 month after stroke onset . evaluators of 6-month mrs were unaware of patients in - hospital cer results . the study was performed under a protocol approved by the institutional review board of chang gung memorial hospital , and all examinations were performed after obtaining written informed consent from the patients or appropriate family members . statistical analyses were performed using the statistical program for social sciences ( spss ) statistical software ( version 18 , chicago , il , usa ) . the differences between the three groups were analyzed by kruskal - wallis test for skewed variables , analysis of variance ( anova ) for normally distributed variables , and pearson s chi square test for categorical variables . the patients characteristics according to outcome status were compared by mann - whitney u test for skewed variable , student t - test for normally distributed variables , and pearson s chi square test for categorical variables . variables with two - tailed p value less than 0.05 were considered to bestatistically significant and were included in the regression model . multivariate - adjusted odds ratios ( or ) and 95% confidence intervals ( ci ) for the association of cer , using highest tertile as a reference , and 6-month outcome was calculated by a logistic regression analysis . the multivariate model included age , sex , baseline nihss score , apache - ii score on admission , history of stroke , albumin and egfr and classified cer . all p values were two - tailed and a p value < 0.05 was considered statistically significant . among 184 consecutive stroke patients during this period of time , 156 patients met study criteria . overall , mean age was 67.9 ( 13.3 ) years and 83 ( 53.2% ) patients had ischemic stroke . median baseline nihss score was 16 [ interquartile range ( iqr ) 9 - 21 ] , and median apache - ii score on admission was 12 ( iqr 9 - 15 ) . bmi was obtained from 103 patients , with 29 ( 28.2% ) were overweight ( defined as 25  bmi < 30 ) and 6 ( 5.8% ) were obese ( defined as bmi  30 ) . the median cer in the 3 tertiles of highest , middle and lowest cer was 2297.7 mg / d , 1312.4 mg / d and 743.6 mg / d , respectively . patients with the lowest cer were significantly older ( p < 0.001 ) , more often female ( p < 0.001 ) , and had lower bmi ( p < 0.001 ) when compared with the patients with highest cer . also , high baseline nihss score , high apache - ii score , prior stroke , low albumin , and low egfr were associated with poor outcomes at 6 months . ( table 2 ) . in the multivariate logistic regression model , lowest cer , as compared to highest cer , was independently associated with higher possibility of death or dependence at 6 month ( 92.3% vs. 73.1% , or 4.96 , the result was similar when we used death or disability as the endpoint ( table 3 ) . middle cer , as compared to highest cer , showed no difference in the possibility of death or dependence at 6 month ( 75.0% vs. 73.1% , or 2.24 , 95% ci 0.73 to 6.92 , p = 0.160 ) , but was associated with higher possibility of death or disability at 6 months ( 88.5% vs. 78.8% , or 5.74 , 95% ci 1.40 to 23.63 , p = 0.015 ) . in this study , we found that critically ill acute stroke patients in the lowest tertile of cer had greater odds of experiencing death or having severe disability at 6-months post - hospitalization , even after adjusting for confounders . since cer is a marker of muscle mass , the results of this study suggest that low muscle mass may be an independent predictor of poor outcome after a severe acute stroke . some urine biomarkers have been used as prognosticators in cardiovascular and cerebrovascular disea - ses [ 9 - 11 ] . for example , increased urine albumin and igm excretion were supposed to reflect general vascular damage and had been linked to poorer functional outcome after stroke , higher stroke mortality and long - term cardiovascular complications [ 9 - 11 ] . on the other hand , urinary cer is an established urine biomarker to assess total - body muscle mass , and it has advantages in cost - effectiveness , readily availability and accuracy . anthropometry is an alternative but it measures only individual muscle groups and is less accurate . computerized tomography to assess muscle mass is expansive and has to expose the patients inradiation . dual - energy x - ray absorptiometry is also expansive and is possibly inaccurate in patients with altered body water content . cer had been linked to higher cardiovascular risk and mortality in general population , and it also had been related to higher mortality in persons with chronic coronary artery disease , in renal transplant recipients   and in type 2 diabetics with nephropathy . to our knowledge , this is the first study to report a linkbetween low cer and poor outcome in severe acute stroke patients . the mechanisms underlying the association of cer with acute stroke outcomes may be multi - factorial . first of all , muscle is the primary target for insulin action and glucose disposal . it has been reported that low muscle mass is associated with higher fasting glucose and insulin resistance even in non - diabetics ,   and insulin resistance has been shown to be a predictor of cardiovascular and cerebro - vascular diseases . in addition , low muscle mass and insulin resistance were both related to low levels of insulin - like growth factor-1 , which promotes glucose uptake by muscle and low levels of that is associated with poor stroke outcome [ 18 ,   19 ] second , low muscle mass is an indicator of malnutrition . malnutrition was reported in 8 - 34% of acute stroke patients on admission ,   and several studies have demonstrated poor outcomes in terms of length of stay , complications , disability and death in malnourished compared to well - nourished acute stroke patients [ 21 - 24 ] . moreover , some medium - sized studies had shown a benefit of protein - energy supplement on the reduction of poor outcome or death in malnourished acute stroke patients [ 25 ,   26 ] . third , low muscle mass was associated with physical disability and decreased cardiopulmonary fitness in elderly . . it had been reported that individuals with lower cer achieved lower metabolic equivalents and maximum heart rate after the exercise treadmill test , which may indicate poor physical fitness and cardiovascular function . physical inactivity had been recognized as an independent risk factor for stroke , ( 1 ) and pre - stroke physical activity was associated to a less severe stroke and better long - term outcome   there were also increasing evidences showing that stroke survivors may benefit from exercise training to improve the aerobic fitness and functional outcome [ 29 ,   30 ] . first , bmi was not adjusted in our analysis because bmi was only available for some patients . second , ischemic and hemorrhagic stroke were not further analyzed separately because of the modest sample size . third , the study population comprised critically - ill stroke patients , who were in a stressful and metabolically demanding situation . in such a situation , the effect of muscle mass , which represents a metabolic reserve to deal with the demand , on the stroke outcome may be more prominent . whether the predictive value of urine cer on stroke outcome still present in the patients with less severe strokes need further evaluation . fourth , our cohort included only asian patients and the generalizability of the findings to other races is unknown . finally , the cer data in our study was calculated by creatinine in morning spot urine multiply 24-hour urine volume , not measured by the creatinine from 24-hour urine collection . although there have been studies showing that there was good correlation between proteinuria measured by spot urine and 24-hour urine , the correlation between cer measured by spot urine and 24-hour urine still need to be evaluated .   in conclusion , we observed that low baseline cer , a marker of muscle mass , was independently associated with poor 6-month outcome among critically ill acute stroke patients . future studies will need to focus on stroke patients of all levels of severity , assess any differences by stroke type , and include non - asian patients as well . furthermore , the possible mechanisms behind the association between low cer and poor stroke outcome need to be investigated . given that cer might be a potentially modifiable risk factor , future studies could also examine whether pre - morbid modification of this risk factor , potentially through exercise or protein - energy supplement , could be helpful for improving acute stroke outcomes . work was the reported experiments in accordance with the ethical standards of the committee responsible for human experimentation ( institutional and national ) , and with the helsinki declaration of 1975 , as revised in 2008 http://www.wma.net / en/20activities/10ethics/10helsinki/.
urinary creatinine excretion rate ( cer ) is an established marker of muscle mass . 
 low cer has been linked to poor coronary artery disease outcomes , but a link between cer and acute stroke prognosis has not been previously explored . 
 we prospectively collected data from patients with acute stroke ( ischemic 
 or hemorrhagic ) within 24 hours from symptom onset in a neurological and neurosurgery intensive care unit in taiwan . 
 baseline cer ( mg / d ) was calculated by urine creatinine concentration in morning spot urine multiplies 24-hour urine volume on the second day of admission . 
 patients were divided into 3 tertiles with highest , middle , and 
 lowest cer . 
 primary endpoint was poor outcome defined as modified rankin scale 3 - 6 at 6 months . among 156 
 critically ill acute stroke patients meeting study entry criteria , average age was 67.9 years , and 83 ( 53.2% ) patients had ischemic stroke . 
 patients with lowest cer ( vs. highest cer ) had a high risk of poor outcome at 6-month after adjustment ( odds ratio 4.96 , 95% confidence interval 1.22 to 20.15 , p value = 0.025 ) . in conclusion , 
 low baseline cer , a marker of muscle mass , was independently associated with poor 6-month outcome among critically ill acute stroke patients . 
 we speculate that preservation of muscle mass through exercise or protein - energy supplement might be helpful for improving prognosis in severe stroke patients .