How a positive fluid balance develops in acute kidney injury: A binational, observational study.

PURPOSE: A positive fluid balance (FB) is associated with harm in intensive care unit (ICU) patients with acute kidney injury (AKI). We aimed to understand how a positive balance develops in such patients. METHODS: Multinational, retrospective cohort study of critically ill patients with AKI not requiring renal replacement therapy. RESULTS: AKI occurred at a median of two days after admission in 7894 (17.3%) patients. Cumulative FB became progressively positive, peaking on day three despite only 848 (10.7%) patients receiving fluid resuscitation in the ICU. In those three days, persistent crystalloid use (median:60.0 mL/h; IQR 28.9-89.2), nutritional intake (median:18.2 mL/h; IQR 0.0-45.9) and limited urine output (UO) (median:70.8 mL/h; IQR 49.0-96.7) contributed to a positive FB. Although UO increased each day, it failed to match input, with only 797 (10.1%) patients receiving diuretics in ICU. After adjustment, a positive FB four days after AKI diagnosis was associated with an increased risk of hospital mortality (OR 1.12;95% confidence intervals 1.05-1.19;p-value <0.001). CONCLUSION: Among ICU patients with AKI, cumulative FB increased after diagnosis and was associated with an increased risk of mortality. Continued crystalloid administration, increased nutritional intake, limited UO, and minimal use of diuretics all contributed to positive FB. KEY POINTS: Question How does a positive fluid balance develop in critically ill patients with acute kidney injury? Findings Cumulative FB increased after AKI diagnosis and was secondary to persistent crystalloid fluid administration, increasing nutritional fluid intake, and insufficient urine output. Despite the absence of resuscitation fluid and an increasing cumulative FB, there was persistently low diuretics use, ongoing crystalloid use, and a progressive escalation of nutritional fluid therapy. Meaning Current management results in fluid accumulation after diagnosis of AKI, as a result of ongoing crystalloid administration, increasing nutritional fluid, limited urine output and minimal diuretic use.

Excess burden of critical illness related to inflammatory bowel disease.

BACKGROUND: Although inflammatory bowel disease (IBD) is associated with major morbidity and mortality, few studies have evaluated its associated burden of critical illness. AIMS: To examine the epidemiology and outcome of intensive care unit (ICU) admission among patients with IBD in North Brisbane, Australia. METHODS: A population-based cohort design was used. All admissions to ICU serving the Metro North Hospital and Health Service among adult residents during 2017-2019 were included. Data were obtained from ICU clinical information systems with linkages to statewide admissions and death registries. RESULTS: Among 9011 ICU admissions, 101 (1.1%) were among patients with IBD, of which 57 (0.6%) and 44 (0.5%) had ulcerative colitis (UC) and Crohn disease (CD) respectively. The incidence of ICU admission was 379, 1336, 1514 and 1429 per 100 000 annually among those without IBD, CD, UC and IBD respectively. Patients with IBD were at excess risk for admission across all age groups, with women aged <50 years at highest risk and men thereafter. The all-cause 90-day case-fatality rates following ICU admission were not significantly different among patient groups and were 18%, 12%, 15% and 12% for CD, UC, IBD and non-IBD respectively. However, as compared with non-IBD patients, those with CD (151.8 vs 39.4 per 100 000; relative risk (RR) 3.85; 95% confidence interval (CI) 1.25-9.02; P = 0.013), UC (159.4 vs 39.4 per 100 000; RR 4.05; 95% CI 1.48-8.84; P = 0.005) and IBD (155.6 vs 39.4 per 100 000; RR 3.95; 95% CI 1.96-7.10; P = 0.002) were at significantly higher risk for mortality. CONCLUSIONS: Patients with IBD suffer a major burden of critical illness.

Long-term outcome of prolonged critical illness: A multicentered study in North Brisbane, Australia.

BACKGROUND: Although critical illness is usually of high acuity and short duration, some patients require prolonged management in intensive care units (ICU) and suffer long-term morbidity and mortality. OBJECTIVE: To describe the long-term survival and examine determinants of death among patients with prolonged ICU admission. METHODS: A retrospective cohort of adult Queensland residents admitted to ICUs for 14 days or longer in North Brisbane, Australia was assembled. Comorbid illnesses were classified using the Charlson definitions and all cause case fatality established using statewide vital statistics. RESULTS: During the study a total of 28,742 adult Queensland residents had first admissions to participating ICUs of which 1,157 (4.0%) had prolonged admissions for two weeks or longer. Patients with prolonged admissions included 645 (55.8%), 243 (21.0%), and 269 (23.3%) with ICU lengths of stay lasting 14-20, 21-27, and ≥28 days, respectively. Although the severity of illness at admission did not vary, pre-existing comorbid illnesses including myocardial infarction, congestive heart failure, kidney disease, and peptic ulcer disease were more frequent whereas cancer, cerebrovascular accidents, and plegia were less frequently observed among patients with increasing ICU lengths of stay lasting 14-20, 21-27, and ≥28 days. The ICU, hospital, 90-day, and one-year all cause case-fatality rates were 12.7%, 18.5%, 20.2%, and 24.9%, respectively, and were not different according to duration of ICU stay. The median duration of observation was 1,037 (interquartile range, 214-1888) days. Although comorbidity, age, and admitting diagnosis were significant, neither ICU duration of stay nor severity of illness at admission were associated with overall survival outcome in a multivariable Cox regression model. CONCLUSIONS: Most patients with prolonged stays in our ICUs are alive at one year post-admission. Older age and previous comorbidities, but not severity of illness or duration of ICU stay, are associated with adverse long-term mortality outcome.

Allopurinol in combination with thiopurine induces mucosal healing and improves clinical and metabolic outcomes in IBD.

BACKGROUND: Thiopurines, azathioprine (AZA) and 6-mercaptopurine (6-MP) are common maintenance medications for inflammatory bowel disease (IBD). Excessive methylation via thiopurine methyltransferase (TPMT) frequently causes therapeutic failure. Allopurinol reduces excessive 6-methyl-mercaptopurine (6-MMP) while enhancing 6-thioguanine (6-TGN) levels. The aim of this study was to evaluate clinical, metabolic and endoscopic impact of allopurinol in combination with low-dose thiopurine in IBD. METHODS: Retrospective review of consecutive cases treated with allopurinol. Metabolites and their ratios (6-MMP/6-TGN) were compared pre- and post-allopurinol. Clinical and endoscopic remission were assessed. RESULTS: Allopurinol (n = 66) reduced mean dose of AZA by 70% (p < 0.01). Baseline levels (SD) 6-TGN, 6-MMP and 6-MMP/6-TGN were 165 (64), 9388 (5234) and 59.8 (30.3), respectively. These values improved on allopurinol to 297 (102), 896 (1031) and 3.4 (4.0), respectively (p < 0.0001). Therapeutic 6-TGN level (>235) was achieved in 49/58 cases on allopurinol combination therapy, versus 9/58 monotherapy (p = 0.0001). Among the thiopurine failure group (40 patients), clinical remission or response was observed in 65% and 22% of patients, respectively. In the asymptomatic group with excessive 6-MMP, 11/14 achieved sustained remission on allopurinol. Repeat colonoscopy (n = 28) showed mostly endoscopic remission (67.9%) or improvement (17.8%). Few had unimproved lesions (14.3%). Importantly, 46% of cases had complete mucosal healing. Two patients had cancer on combination therapy (de novo pancreatic cancer and fatal recurrence of metastatic testicular cancer). Elevated transaminases were reduced on allopurinol (48.2 versus 6.9%) (p < 0.001); no change in leukopenic or infectious events occurred. CONCLUSION: Allopurinol in combination with low-dose thiopurine corrected excessive 6-MMP levels, resulting in clinical remission and mucosal healing in the majority of cases. The potential cancer risk of allopurinol and thiopurine combination therapy needs further research.

BP101 Peptide Promotes Female Sexual Receptivity in the Rat.

INTRODUCTION: Low sexual desire is a frequent sexual problem in women, with only one drug for the condition approved by the Food and Drug Administration. AIM: To evaluate the ability of a novel synthetic peptide, BP101, to facilitate sexual behavior after intranasal administration or infusion into certain brain areas in female rats. METHODS: Bilaterally ovariectomized female rats, primed with a suboptimal combination of estradiol benzoate (EB) and progesterone, were used as a model of low sexual motivation. Sexual behavior was tested with stud male rats after acute (experiment 1) or long-term (experiment 2) intranasal administration of BP101 or peptide infusion into the olfactory bulb, medial preoptic area, ventromedial hypothalamic nucleus, or ventral tegmental area (experiment 3). MAIN OUTCOME MEASURES: Frequency of solicitations (SF), as an indicator of sexual motivation in female rats, and lordosis frequency and ratio, as measurements of female consummatory sexual behavior. RESULTS: Acute intranasal BP101 administration moderately increased SF, with the highest tested dose of 300 µg/kg causing an 80% increase. Female rats receiving BP101 75 or 300 µg/kg daily on days 6 to 16 of the peptide administration displayed twofold higher SF compared with the placebo-treated animals, an increase comparable to optimally hormone-primed female rats. Infusion of BP101 1 and 5 µg per rat into the medial preoptic area, but not into the olfactory bulb, ventromedial hypothalamic nucleus, or ventral tegmental area, increased SF in female rats supplemented with EB 10 or 20 µg. The effect was relatively more pronounced in female rats receiving EB 10 µg (≈300%) compared with EB 20 µg (≈50%) with direct brain infusions. CONCLUSION: BP101 displays a potent stimulatory effect on sexual motivation in the female rat, and the medial preoptic area seems to be the site of its action. BP101 is effective in female rats receiving different hormone supplementations, making the present data generalizable to pre- and postmenopausal women with hypoactive sexual desire. Andreev-Andrievskiy A, Lomonosov M, Popova A, et al. BP101 Peptide Promotes Female Sexual Receptivity in the Rat. J Sex Med 2017;14:336-346.

Acute oral metformin enhances satiation and activates brainstem nesfatinergic neurons.

OBJECTIVE: The study was designed to determine metformin effects on meal pattern, gastric emptying, energy expenditure, and to identify metformin-sensitive neurons and their phenotype. METHODS: This study was performed on C57BL/6J and obese/diabetic (db/db) mice. Metformin (300 mg/kg) was administered by oral gavage. Food intake, meal pattern, oxygen consumption (VO2 ), and carbon dioxide production (VCO2 ) were obtained using an Oxylet Physiocage System. Gastric emptying assay and real-time RT-PCR from dorsal vagal complex extracts were also performed. C-Fos expression was used as a marker of neuronal activation. Phenotypic characterization of activated neurons was performed using either proopiomelanocortin (POMC)-Tau-Topaz GFP transgenic mice or NUCB2/nesfatin-1 and tyrosine hydroxylase (TH) labeling. RESULTS: Acute per os metformin treatment slowed down gastric emptying, reduced meal size, but not meal number in a leptin-independent manner, and transiently decreased energy expenditure in a leptin-dependent manner. Metformin specifically activated central circuitry within the brainstem, independently of vagal afferents. Finally, while POMC neurons seemed sparsely activated, we report that a high proportion of the c-Fos positive cells were nesfatinergic neurons, some of which coexpressing TH. CONCLUSIONS: Altogether, these results show that metformin modifies satiation by activating brainstem circuitry and suggest that NUCB2/nesfatin-1 could be involved in this metformin effect.

Brain neuronal activation induced by flibanserin treatment in female rats.

RATIONALE: Flibanserin, a 5-HT1A agonist and 5-HT2A antagonist, is developed for the treatment of hypoactive sexual desire disorder in women, and its efficacy has been evidenced in several clinical studies. Flibanserin prosexual effects have been also evidenced in preclinical animal models. However, the mechanism of action of flibanserin remains not fully understood. OBJECTIVE: The aim of the present study was to examine brain neuronal activation in female rats treated with flibanserin, using single immunocytochemical labeling of Fos protein, a marker of neuronal activation, and co-localization of Fos and catecholaminergic marker. METHOD: Six groups of female rats received either acute or chronic administrations of vehicle, flibanserin 15 mg/kg or flibanserin 45 mg/kg. The brains were collected and processed for immunocytochemical labeling. RESULTS: Acute flibanserin increased levels of Fos immunoreactivity in the nucleus accumbens, arcuate hypothalamic nucleus, locus coeruleus, lateral paragigantocellular nucleus, and nucleus of the solitary tract. Chronic 22-day treatment with flibanserin increased Fos expression in the medial preoptic area and arcuate nucleus of the hypothalamus, ventral tegmental area, locus coeruleus, and lateral paragigantocellular nucleus. Both acute and chronic flibanserin increased the density of activated catecholaminergic neurons in the ventral tegmental area but not in the locus coeruleus. CONCLUSION: Altogether, our results showed that flibanserin, at the dose known to enhance female sexual motivation, preferentially activated the brain regions belonging to the mesolimbic dopaminergic pathway and hypothalamic structures involved in the integration of sexual cues related to sexual motivation.

Serotonin and premature ejaculation: from physiology to patient management.

INTRODUCTION: Premature ejaculation (PE), whose pathophysiology is still not clearly identified, is the most common male sexual dysfunction, yet it remains underdiagnosed and undertreated. The aims of this paper are to provide a scientific and pharmacologic rationale, and to discuss to what extent selective serotonin reuptake inhibitors (SSRIs) can help patients with PE. MATERIALS AND METHODS: A comprehensive evaluation of available published data included analysis of published full-length papers that were identified with Medline and Cancerlit from January 1981 to January 2006. Official proceedings of internationally known scientific societies held in the same time period were also assessed. RESULTS: The central ejaculatory neural circuit comprises spinal and cerebral areas that form a highly interconnected network. The sympathetic, parasympathetic, and somatic spinal centers, under the influence of sensory genital and cerebral stimuli integrated and processed at the spinal cord level, act in synergy to command physiologic events occurring during ejaculation. Experimental evidence indicates that serotonin (5-HT), throughout brain descending pathways, exerts an inhibitory role on ejaculation. To date, three 5-HT receptor subtypes (5-HT1A, 5-HT1B, and 5-HT2C) have been postulated to mediate 5-HT's modulating activity on ejaculation. Pharmacologic manipulation of the serotonergic system has been performed in rats, with the antidepressant selective serotonin reuptake inhibitors (SSRIs) exhibiting the greatest efficacy in delaying ejaculation. The mechanism of action by which SSRIs modulate central 5-HT tone has been studied in depth, but gaps in this knowledge prevent an explanation of the efficacy of acute treatment in delaying ejaculation. Emerging clinical evidence indicates chronic and on-demand dosing of SSRIs has a beneficial effect for the treatment of men with PE, at least for paroxetine. On-demand dapoxetine, and SSRI with a short half-life, recently has been shown to significantly increase intravaginal latency time and PE patient-related outcomes in phase 3 clinical trials. CONCLUSIONS: Nowadays there is no doubt that PE can be treated effectively by SSRIs. Nevertheless their mechanism of action is not yet well understood and deserves more research. In particular it is not understood why all the SSRIs are not equal in terms of their ability to delay ejaculation. Therefore, there is a need for more research to better characterize the mechanism of action of SSRIs as well their clinical benefit in patients affected by PE.