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Effect of Intravesical Instillation of Gemcitabine vs Saline Immediately Following Resection of Suspected Low-Grade Non-Muscle-Invasive Bladder Cancer on Tumor Recurrence: SWOG S0337 Randomized Clinical Trial.
Messing, EM, Tangen, CM, Lerner, SP, Sahasrabudhe, DM, Koppie, TM, Wood, DP, Mack, PC, Svatek, RS, Evans, CP, Hafez, KS, et al
JAMA. 2018;(18):1880-1888
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Abstract
IMPORTANCE Low-grade non-muscle-invasive urothelial cancer frequently recurs after excision by transurethral resection of bladder tumor (TURBT). OBJECTIVE To determine whether immediate post-TURBT intravesical instillation of gemcitabine reduces recurrence of suspected low-grade non-muscle-invasive urothelial cancer compared with saline. DESIGN, SETTING, AND PARTICIPANTS Randomized double-blind clinical trial conducted at 23 US centers. Patients with suspected low-grade non-muscle-invasive urothelial cancer based on cystoscopic appearance without any high-grade or without more than 2 low-grade urothelial cancer episodes within 18 months before index TURBT were enrolled between January 23, 2008, and August 14, 2012, and followed up every 3 months with cystoscopy and cytology for 2 years and then semiannually for 2 years. Patients were monitored for tumor recurrence, progression to muscle invasion, survival, and toxic effects. The final date of follow-up was August 14, 2016. INTERVENTIONS Participants were randomly assigned to receive intravesical instillation of gemcitabine (2 g in 100 mL of saline) (n = 201) or saline (100 mL) (n = 205) for 1 hour immediately following TURBT. MAIN OUTCOMES AND MEASURES The primary outcome was time to recurrence of cancer. Secondary end points were time to muscle invasion and death due to any cause. RESULTS Among 406 randomized eligible patients (median age, 66 years; 84.7% men), 383 completed the trial. In the intention-to-treat analysis, 67 of 201 patients (4-year estimate, 35%) in the gemcitabine group and 91 of 205 patients (4-year estimate, 47%) in the saline group had cancer recurrence within 4.0 years (hazard ratio, 0.66; 95% CI, 0.48-0.90; P<.001 by 1-sided log-rank test for time to recurrence). Among the 215 patients with low-grade non-muscle-invasive urothelial cancer who underwent TURBT and drug instillation, 34 of 102 patients (4-year estimate, 34%) in the gemcitabine group and 59 of 113 patients (4-year estimate, 54%) in the saline group had cancer recurrence (hazard ratio, 0.53; 95% CI, 0.35-0.81; P = .001 by 1-sided log-rank test for time to recurrence). Fifteen patients had tumors that progressed to muscle invasion (5 in the gemcitabine group and 10 in the saline group; P = .22 by 1-sided log-rank test) and 42 died of any cause (17 in the gemcitabine group and 25 in the saline group; P = .12 by 1-sided log-rank test). There were no grade 4 or 5 adverse events and no significant differences in adverse events of grade 3 or lower. CONCLUSIONS AND RELEVANCE Among patients with suspected low-grade non-muscle-invasive urothelial cancer, immediate postresection intravesical instillation of gemcitabine, compared with instillation of saline, significantly reduced the risk of recurrence over a median of 4.0 years. These findings support using this therapy, but further research is needed to compare gemcitabine with other intravesical agents. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00445601.
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Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial.
Hanley, DF, Lane, K, McBee, N, Ziai, W, Tuhrim, S, Lees, KR, Dawson, J, Gandhi, D, Ullman, N, Mould, WA, et al
Lancet (London, England). 2017;(10069):603-611
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BACKGROUND Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. METHODS In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134. FINDINGS Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1·06 [95% CI 0·88-1·28; p=0·554]). A difference of 3·5% (RR 1·08 [95% CI 0·90-1·29], p=0·420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0·60 [95% CI 0·41-0·86], p=0·006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1·99 [95% CI 1·22-3·26], p=0·007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0·55 [95% CI 0·31-0·97], p=0·048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0·76 [95% CI 0·64-0·90], p=0·002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1·21 [95% CI 0·37-3·91], p=0·771) was similar. INTERPRETATION In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status. FUNDING National Institute of Neurological Disorders and Stroke.
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Urinary Sodium-to-Potassium Ratio Tracks the Changes in Salt Intake during an Experimental Feeding Study Using Standardized Low-Salt and High-Salt Meals among Healthy Japanese Volunteers.
Yatabe, MS, Iwahori, T, Watanabe, A, Takano, K, Sanada, H, Watanabe, T, Ichihara, A, Felder, RA, Miura, K, Ueshima, H, et al
Nutrients. 2017;(9)
Abstract
The Na/K ratio is considered to be a useful index, the monitoring of which allows an effective Na reduction and K increase, because practical methods (self-monitoring devices and reliable individual estimates from spot urine) are available for assessing these levels in individuals. An intervention trial for lowering the Na/K ratio has demonstrated that a reduction of the Na/K ratio mainly involved Na reduction, with only a small change in K. The present study aimed to clarify the relationship between dietary Na intake and the urinary Na/K molar ratio, using standardized low- and high-salt diets, with an equal dietary K intake, to determine the corresponding Na/K ratio. Fourteen healthy young adult volunteers ingested low-salt (3 g salt per day) and high-salt (20 g salt per day) meals for seven days each. Using a portable urinary Na/K meter, participants measured their spot urine at each voiding, and 24-h urine was collected on the last day of each diet period. On the last day of the unrestricted, low-salt, and high-salt diet periods, the group averages of the 24-h urine Na/K ratio were 4.2, 1.0, and 6.9, while the group averages of the daily mean spot urine Na/K ratio were 4.2, 1.1, and 6.6, respectively. The urinary Na/K ratio tracked changes in dietary salt intake, and reached a plateau approximately three days after each change in diet. Frequent monitoring of the spot urine Na/K ratio may help individuals adhere to an appropriate dietary Na intake.
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Efficacy of nasal irrigation in the treatment of acute sinusitis in atopic children.
Wang, YH, Ku, MS, Sun, HL, Lue, KH
Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi. 2014;(1):63-9
Abstract
BACKGROUND Nasal irrigation has been used as adjunctive therapy for sinonasal disease but is under-researched in children. The study aim was to evaluate the effectiveness of nasal irrigation with normal saline in the management of acute sinusitis in atopic children. METHODS We enrolled 60 atopic children with acute sinusitis, of whom 29 received nasal irrigation with normal saline and 31 did not receive nasal irrigation. All participants underwent a nasal peak expiratory flow rate (nPEFR) test, a nasal smear examination, and radiography (Water's projection) and were requested to complete a Pediatric Rhinoconjunctivitis Quality-of-Life Questionnaire (PRQLQ) during the baseline visit. All participants were requested to record symptoms in a daily diary and were followed up at 1-week intervals. A physical examination, nasal smear, and nPEFR were performed at each visit, and all daily diaries were collected. At the final visit (after 3 weeks), the symptom diaries were reviewed and participants were requested to complete the PRQLQ again. nPEFR, radiography, and a nasal smear were also repeated. RESULTS There were significant improvements in mean PRQLQ and nPEFR values (p < 0.05) for the irrigation compared to the non-irrigation group. There was no significant difference in radiographic findings between the groups (p > 0.05). The irrigation group recorded significant improvements in eye congestion, rhinorrhea, nasal itching, sneezing, and cough symptoms compared with the non-irrigation group. CONCLUSION Nasal irrigation is an effective adjunctive treatment for acute sinusitis in atopic children.
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Comparison of low-abundance biomarker levels in capillary-collected nonstimulated tears and washout tears of aqueous-deficient and normal patients.
Guyette, N, Williams, L, Tran, MT, Than, T, Bradley, J, Kehinde, L, Edwards, C, Beasley, M, Fullard, R
Investigative ophthalmology & visual science. 2013;(5):3729-37
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PURPOSE Low tear volume limits the use of nonstimulated (NS) microcapillary tear collection in aqueous-deficient (AD) patients. Adding a small amount of "washout" fluid to the eye prior to tear collection is a potentially viable alternative method for abundant proteins, but is relatively untested for low-abundance biomarkers. This study determined the feasibility of the washout (WO) method as an NS alternative for low-abundance biomarkers. NS and WO biomarker profiles were compared between AD patients and non-AD controls to determine if the two methods identify the same intergroup differences. METHODS Matching NS and WO tears were collected from 48 patients by micropipette, the WO sample after instillation of 10 μL saline. Tear cytokine levels were measured by 27-Plex Bio-Rad assay. Bland-Altman analyses for each biomarker determined the agreement between tear sample types. Patients were grouped as AD or non-AD based on Schirmer score to determine if NS profile between-group differences were preserved in WO tears. RESULTS Bland-Altman plots showed good biomarker level agreement between NS and WO tears for most cytokines. Five biomarkers, among those most often cited as differing in AD dry eye, differed significantly between non-AD and AD groups in both tear types. Additional biomarker differences were seen in NS tears only. CONCLUSIONS The WO tear collection method is a viable alternative to NS tears for many low-abundance biomarkers and is able to replicate major NS tear differences between dry eye groups. More subtle intergroup differences are lost in WO samples because of reduced statistical power.
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Sodium chloride 0.9% versus Lactated Ringer in the management of severely dehydrated patients with choleriform diarrhoea.
Cieza, JA, Hinostroza, J, Huapaya, JA, León, CP
Journal of infection in developing countries. 2013;(7):528-32
Abstract
INTRODUCTION Although experience within Peru suggests clinical and physiological benefits of treating dehydration caused by diarrhoea with Lactated Ringer's solution (LR) over sodium chloride 0.9%, (NaCl) there is little documented scientific evidence supporting this view. It is important to clarify this issue and determine the best solution for use during epidemics. METHODOLOGY Forty patients suffering from dehydration due to choleriform diarrhoea were enrolled in the study. Twenty patients were treated using NaCl (Group A) and the other twenty with LR (Group B). After diuresis recovery was achieved, the patients were continued on a course of oral rehydration salts. Serum electrolytes, arterial pH, HCO3-, and pCO2 were measured at three stages: at admission, after diuresis recovery, and after 12 hours. RESULTS Acidosis was corrected more quickly with LR that NaCl. The hyperosmolality and hypernatremic states were corrected with both solutions. CONCLUSION LR use resulted in a better clinical response than NaCl, illustrated by more rapid physiological correction, showing that mixed metabolic acidosis was corrected more quickly and more appropriately with this treatment.
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Hemodynamic responses to rapid saline loading: the impact of age, sex, and heart failure.
Fujimoto, N, Borlaug, BA, Lewis, GD, Hastings, JL, Shafer, KM, Bhella, PS, Carrick-Ranson, G, Levine, BD
Circulation. 2013;(1):55-62
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BACKGROUND Hemodynamic assessment after volume challenge has been proposed as a way to identify heart failure with preserved ejection fraction. However, the normal hemodynamic response to a volume challenge and how age and sex affect this relationship remain unknown. METHODS AND RESULTS Sixty healthy subjects underwent right heart catheterization to measure age- and sex-related normative responses of pulmonary capillary wedge pressure and mean pulmonary arterial pressure to volume loading with rapid saline infusion (100-200 mL/min). Hemodynamic responses to saline infusion in heart failure with preserved ejection fraction (n=11) were then compared with those of healthy young (<50 years of age) and older (≥50 years of age) subjects. In healthy subjects, pulmonary capillary wedge pressure increased from 10±2 to 16±3 mm Hg after ~1 L and to 20±3 mm Hg after ~2 L of saline infusion. Older women displayed a steeper increase in pulmonary capillary wedge pressure relative to volume infused (16±4 mm Hg·L(-1)·m(2)) than the other 3 groups (P≤0.019). Saline infusion resulted in a greater increase in mean pulmonary arterial pressure relative to cardiac output in women compared with men regardless of age. Subjects with heart failure with preserved ejection fraction exhibited a steeper increase in pulmonary capillary wedge pressure relative to infused volume (25±12 mm Hg·L(-1)·m(2)) than healthy young and older subjects (P≤0.005). CONCLUSIONS Filling pressures rise significantly with volume loading, even in healthy volunteers. Older women and patients with heart failure with preserved ejection fraction exhibit the largest increases in pulmonary capillary wedge pressure and mean pulmonary arterial pressure.
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Randomized clinical trial evaluating intravitreal ranibizumab or saline for vitreous hemorrhage from proliferative diabetic retinopathy.
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JAMA ophthalmology. 2013;(3):283-93
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IMPORTANCE Vascular endothelial growth factor plays a role in proliferative diabetic retinopathy (PDR). Intravitreal injection of saline has been shown potentially to lead to improved visual acuity compared with observation alone in eyes with vitreous hemorrhage. Therefore, it is important to determine if intravitreal anti-vascular endothelial growth factor can reduce vitrectomy rates (and risks associated with vitrectomy) compared with saline for vitreous hemorrhage from PDR that precludes placement or confirmation of complete panretinal photocoagulation. OBJECTIVE To evaluate intravitreal ranibizumab compared with intravitreal saline injections on vitrectomy rates for vitreous hemorrhage from PDR. DESIGN Phase 3, double-masked, randomized, multicenter clinical trial. Data reported were collected from June 2010 to March 2012 and include 16 weeks of follow-up. SETTING Community-based and academic-based ophthalmology practices specializing in retinal diseases. PARTICIPANTS Two hundred sixty-one eyes of 261 study participants, who were at least 18 years of age with type 1 or type 2 diabetes mellitus. Study eyes had vitreous hemorrhage from PDR precluding panretinal photocoagulation completion. INTERVENTION Eyes were randomly assigned to 0.5-mg intravitreal ranibizumab (n = 125) or intravitreal saline (n = 136) at baseline and 4 and 8 weeks. MAIN OUTCOME MEASURE Cumulative probability of vitrectomy within 16 weeks. RESULTS Cumulative probability of vitrectomy by 16 weeks was 12% with ranibizumab vs 17% with saline (difference, 4%; 95% CI, -4% to 13%) and of complete panretinal photocoagulation without vitrectomy by 16 weeks was 44% and 31%, respectively (P = .05). The mean (SD) visual acuity improvement from baseline to 12 weeks was 22 (23) letters and 16 (31) letters, respectively (P = .04). Recurrent vitreous hemorrhage occurred within 16 weeks in 6% and 17%, respectively (P = .01). One eye developed endophthalmitis after saline injection. CONCLUSIONS AND RELEVANCE Overall, the 16-week vitrectomy rates were lower than expected in both groups. This study suggests little likelihood of a clinically important difference between ranibizumab and saline on the rate of vitrectomy by 16 weeks in eyes with vitreous hemorrhage from PDR. Short-term secondary outcomes including visual acuity improvement, increased panretinal photocoagulation completion rates, and reduced recurrent vitreous hemorrhage rates suggest biologic activity of ranibizumab. Long-term benefits remain unknown. Whether vitrectomy rates after saline or ranibizumab injection are different than observation alone cannot be determined from this study. TRIAL REGISTRATION The study is listed on www.clinicaltrials.gov, under identifier NCT00996437 (website registration date October 14, 2009).
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Pre-hospital cooling of patients following cardiac arrest is effective using even low volumes of cold saline.
Skulec, R, Truhlár, A, Seblová, J, Dostál, P, Cerný, V
Critical care (London, England). 2010;(6):R231
Abstract
INTRODUCTION Pre-hospital induction of therapeutic mild hypothermia (TH) may reduce post-cardiac arrest brain injury in patients resuscitated from out-of-hospital cardiac arrest. Most often, it is induced by a rapid intravenous administration of as much as 30 ml/kg of cold crystalloids. We decided to assess the pre-hospital cooling effectivity of this approach by using a target dose of 15-20 ml/kg of 4°C cold normal saline in the setting of the physician-staffed Emergency Medical Service. The safety and impact on the clinical outcome have also been analyzed. METHODS We performed a prospective observational study with a retrospective control group. A total of 40 patients were cooled by an intravenous administration of 15-20 ml/kg of 4°C cold normal saline during transport to the hospital (TH group). The pre-hospital decrease of tympanic temperature (TT) was analyzed as the primary endpoint. Patients in the control group did not undergo any pre-hospital cooling. RESULTS In the TH group, administration of 12.6 ± 6.4 ml/kg of 4°C cold normal saline was followed by a pre-hospital decrease of TT of 1.4 ± 0.8°C in 42.8 ± 19.6 min (p < 0.001). The most effective cooling was associated with a transport time duration of 38-60 min and with an infusion of 17 ml/kg of cold saline. In the TH group, a trend toward a reduced need for catecholamines during transport was detected (35.0 vs. 52.5%, p = 0.115). There were no differences in demographic variables, comorbidities, parameters of the cardiopulmonary resuscitation and in other post-resuscitation characteristics. The coupling of pre-hospital cooling with subsequent in-hospital TH predicted a favorable neurological outcome at hospital discharge (OR 4.1, CI95% 1.1-18.2, p = 0.046). CONCLUSIONS Pre-hospital induction of TH by the rapid intravenous administration of cold normal saline has been shown to be efficient even with a lower dose of coolant than reported in previous studies. This dose can be associated with a favorable impact on circulatory stability early after the return of spontaneous circulation and, when coupled with in-hospital continuation of cooling, can potentially improve the prognosis of patients. TRIAL REGISTRATION ClinicalTrials (NCT): NCT00915421.
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Normotensive sodium loading in normal man: regulation of renin secretion during beta-receptor blockade.
Mølstrøm, S, Larsen, NH, Simonsen, JA, Washington, R, Bie, P
American journal of physiology. Regulatory, integrative and comparative physiology. 2009;(2):R436-45
Abstract
Saline administration may change renin-angiotensin-aldosterone system (RAAS) activity and sodium excretion at constant mean arterial pressure (MAP). We hypothesized that such responses are elicited mainly by renal sympathetic nerve activity by beta1-receptors (beta1-RSNA), and tested the hypothesis by studying RAAS and renal excretion during slow saline loading at constant plasma sodium concentration (Na+ loading; 12 micromol Na+.kg(-1).min(-1) for 4 h). Normal subjects were studied on low-sodium intake with and without beta1-adrenergic blockade by metoprolol. Metoprolol per se reduced RAAS activity as expected. Na+ loading decreased plasma renin concentration (PRC) by one-third, plasma ANG II by one-half, and plasma aldosterone by two-thirds (all P < 0.05); surprisingly, these changes were found without, as well as during, acute metoprolol administration. Concomitantly, sodium excretion increased indistinguishably with and without metoprolol (16 +/- 2 to 71 +/- 14 micromol/min; 13 +/- 2 to 55 +/- 13 micromol/min, respectively). Na+ loading did not increase plasma atrial natriuretic peptide, glomerular filtration rate (GFR by 51Cr-EDTA), MAP, or cardiac output (CO by impedance cardiography), but increased central venous pressure (CVP) by approximately 2.0 mmHg (P < 0.05). During Na+ loading, sodium excretion increased with CVP at an average slope of 7 micromol.min(-1).mmHg(-1). Concomitantly, plasma vasopressin decreased by 30-40% (P < 0.05). In conclusion, beta1-adrenoceptor blockade affects neither the acute saline-mediated deactivation of RAAS nor the associated natriuretic response, and the RAAS response to modest saline loading seems independent of changes in MAP, CO, GFR, beta1-mediated effects of norepinephrine, and ANP. Unexpectedly, the results do not allow assessment of the relative importance of RAAS-dependent and -independent regulation of renal sodium excretion. The results are compatible with the notion that at constant arterial pressure, a volume receptor elicited reduction in RSNA via receptors other than beta1-adrenoceptors, decreases renal tubular sodium reabsorption proximal to the macula densa leading to increased NaCl concentration at the macula densa, and subsequent inhibition of renin secretion.