Water Conservation Overrides Osmotic Diuresis During SGLT2 Inhibition in Patients With Heart Failure.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors are believed to improve cardiac outcomes due to their osmotic diuretic potential. OBJECTIVES: The goal of this study was to test the hypothesis that vasopressin-driven urine concentration overrides the osmotic diuretic effect of glucosuria induced by dapagliflozin treatment. METHODS: DAPA-Shuttle1 (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment) was a single-center, double-blind, randomized, placebo-controlled trial, in which patients with chronic heart failure NYHA functional classes I/II and reduced ejection fraction were randomly assigned to receive dapagliflozin 10 mg daily or placebo (1:1) for 4 weeks. The primary endpoint was change from baseline in urine osmolyte concentration. Secondary endpoints included changes in copeptin levels and solute free water clearance. RESULTS: Thirty-three randomized, sodium-glucose cotransporter 2 inhibitor-naïve participants completed the study, 29 of whom (placebo: n = 14; dapagliflozin: n = 15) provided accurate 24-hour urine collections (mean age 59 ± 14 years; left ventricular ejection fraction 31% ± 9%). Dapagliflozin treatment led to an isolated increase in urine glucose excretion by 3.3 mmol/kg/d (95% CI: 2.51-4.04; P < 0.0001) within 48 hours (early) which persisted after 4 weeks (late; 2.7 mmol/kg/d [95% CI: 1.98-3.51]; P < 0.0001). Dapagliflozin treatment increased serum copeptin early (5.5 pmol/L [95% CI: 0.45-10.5]; P < 0.05) and late (7.8 pmol/L [95% CI: 2.77-12.81]; P < 0.01), leading to proportional reductions in free water clearance (early: -9.1 mL/kg/d [95% CI: -14 to -4.12; P < 0.001]; late: -11.0 mL/kg/d [95% CI: -15.94 to -6.07; P < 0.0001]) and elevated urine concentrations (late: 134 mmol/L [95% CI: 39.28-229.12]; P < 0.01). Therefore, urine volume did not significantly increase with dapagliflozin (mean difference early: 2.8 mL/kg/d [95% CI: -1.97 to 7.48; P = 0.25]; mean difference late: 0.9 mL/kg/d [95% CI: -3.83 to 5.62]; P = 0.70). CONCLUSIONS: Physiological-adaptive water conservation eliminated the expected osmotic diuretic potential of dapagliflozin and thereby prevented a glucose-driven increase in urine volume of approximately 10 mL/kg/d · 75 kg = 750 mL/kg/d. (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment [DAPA-Shuttle1]; NCT04080518).

Cardioprotective Properties of Mannitol-Involvement of Mitochondrial Potassium Channels.

Cardiac preconditioning (PC) and postconditioning (PoC) are powerful measures against the consequences of myocardial ischemia and reperfusion (I/R) injury. Mannitol-a hyperosmolar solution-is clinically used for treatment of intracranial and intraocular pressure or promotion of diuresis in renal failure. Next to these clinical indications, different organ-protective properties-e.g., perioperative neuroprotection-are described. However, whether Mannitol also confers cardioprotection via a pre- and/or postconditioning stimulus, possibly reducing consequences of I/R injury, remains to be seen. Therefore, in the present study we investigated whether (1) Mannitol-induced pre- and/or postconditioning induces myocardial infarct size reduction and (2) activation of mitochondrial ATP-sensitive potassium (mKATP) channels is involved in cardioprotection by Mannitol. Experiments were performed on isolated hearts of male Wistar rats via a pressure controlled Langendorff system, randomized into 7 groups. Each heart underwent 33 min of global ischemia and 60 min of reperfusion. Control hearts (Con) received Krebs-Henseleit buffer as vehicle only. Pre- and postconditioning was achieved by administration of 11 mmol/L Mannitol for 10 min before ischemia (Man-PC) or immediately at the onset of reperfusion (Man-PoC), respectively. In further groups, the mKATP channel blocker 5HD, was applied with and without Mannitol, to determine the potential underlying cardioprotective mechanisms. Primary endpoint was infarct size, determined by triphenyltetrazolium chloride staining. Mannitol significantly reduced infarct size both as a pre- (Man-PC) and postconditioning (Man-PoC) stimulus compared to control hearts (Man-PC: 31 ± 4%; Man-PoC: 35 ± 6%, each p < 0.05 vs. Con: 57 ± 9%). The mKATP channel inhibitor completely abrogated the cardioprotective effect of Mannitol-induced pre- (5HD-PC-Man-PC: 59 ± 8%, p < 0.05 vs. Man-PC) and postconditioning (5HD-PoC-Man-PoC: 59 ± 10% vs. p < 0.05 Man-PoC). Infarct size was not influenced by 5HD itself (5HD-PC: 60 ± 14%; 5HD-PoC: 54 ± 14%, each ns vs. Con). This study demonstrates that Mannitol (1) induces myocardial pre- and postconditioning and (2) confers cardioprotection via activation of mKATP channels.

Effect of mannitol on acute kidney injury induced by cisplatin.

PURPOSE: Acute kidney injury (AKI) is a frequent dose-limiting toxicity induced by cisplatin. Mannitol has been used in hydration protocols to mitigate this adverse event but its role remains controversial. The aim of this study is to define the impact of mannitol on AKI in patients receiving cisplatin. METHODS: This retrospective observational study was conducted in cancer patients who received at least one dose of cisplatin between September 2010 and December 2016 at the Centre hospitalier de l'Université de Montréal. The primary outcome of this study was the comparison of all grade cisplatin-associated AKI between hydration protocols with or without mannitol. RESULTS: A total of 1821 patients were included of which 658 received mannitol whilst 1163 received hydration alone. The risk of all grade cisplatin-associated AKI was significantly lower for the mannitol group (Hazard Ratio (HR) = 0.62; 95% CI [0.42, 0.89]). This result was mainly driven by gynecologic (HR = 0.50), upper gastrointestinal (HR = 0.32), urinary tract malignancies (HR = 0.29) and lymphoma (HR = 0.33). No significant difference was seen for head and neck (HN), lung, germ cells and other cancers. However, HN cancers patients receiving mannitol had fewer grade 2 and 3 AKI. Significantly fewer AKI events were observed in HN, lung, upper gastrointestinal and urinary tract cancer when mannitol was added for cisplatin dose <75 mg/m2. CONCLUSION: Although the results were generally driven by a decrease of grade 1 AKI for most cancers, the greatest benefit of mannitol was seen with cisplatin doses lower than 75 mg/m2 and should probably be reinstated in this setting.

Comparison of equiosmolar doses of 10% hypertonic saline and 20% mannitol for controlling intracranial hypertention in patients with large hemispheric infarction.

OBJECTIVE: We conducted this prospective self-crossover controlled trial to compare the efficacy and safety of 10 % hypertonic saline (HS) and 20 % mannitol in doses of similar osmotic burden for the treatment of increased intracranial pressure (ICP) in patients with large hemispheric infarction (LHI). PATIENTS AND METHODS: Patients with LHI were enrolled from January 2017 to January 2018. We used an alternating treatment protocol to compare the effects of HS with mannitol given for episodes of increased ICP in patients with LHI. Indicators such as ICP, mean arterial pressure (MAP) and cerebral perfusion pressure (CPP) were continuously monitored at regular intervals for 240 min after initiation of infusion. Electrolytes, plasma osmolality and renal functions were measured before and 240 min after initiation of infusion to compare the efficacy and safety of the two drugs. RESULTS: A total of 49 episodes of increased ICP occurred in 14 patients with LHI, of which 24 were infused with 10 % HS and 25 with 20 % mannitol. Both the treatments were equally effective in reducing ICP (P < 0.01). The differences in the duration and degree of reduction were not significant between the groups (P > 0.05). Although both the osmolar agents decreased MAP, the degree was greater in the mannitol group (P < 0.05) at T120. The increase in CPP was greater in the HS group compared with the mannitol group (P < 0.05) at T120. However, HS was associated with faster heart rate (HR) and higher serum chloride levels (P < 0.05). Changes in serum sodium levels and osmolality were not significant between the groups in spite of being higher in the HS group. CONCLUSIONS: Both the drugs can serve as first-line agents for treating intracranial hypertension caused by LHI and should be selected rationally according to the differences in efficacy and adverse effects.

Rg1 in combination with mannitol protects neurons against glutamate-induced ER stress via the PERK-eIF2 α-ATF4 signaling pathway.

AIMS: Ginseng and ginsenosides are known for their remarkable effects on the central nervous system. However, pharmacokinetic studies have suggested that the Ginsenoside Rg1 (Rg1) cannot be efficiently transported through the blood-brain barrier. To investigate the effects of Rg1 in combination with mannitol protects neurons against glutamate-induced ER stress via the PERK-eIF2 -ATF4 signaling pathway. MAIN METHODS: Rg1, along with the BBB permeabilizer mannitol, exhibited a potent neuroprotective effect by significantly reducing the neurological scores and infarct volume in rats exposed to middle cerebral artery occlusion. We evaluated the effect of Rg1 on neuroprotection after MCAO, and also explored its potential mechanism of action. KEY FINDINGS: Our results show that Rg1 reduced the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive neurons. This neuroprotection may be dependent, at least in part, on the preservation of the endoplasmic reticulum and mitochondrial function. Ischemia-induced brain injury is largely caused by the excessive release of glutamate, which results in excitotoxicity and cell death. Neurons were pretreated with Rg1 before inducing endoplasmic reticulum stress with glutamate. A reduction in the expression of Bax and a concomitant increase in Bcl2 expression prevented the induction of apoptosis. Furthermore, Rg1 downregulated the expression of endoplasmic reticulum stress genes. SIGNIFICANCE: Our results indicate that Rg1 modulation of stress-responsive genes helps prevent glutamate-induced endoplasmic reticulum stress in neurons through the PERK-eIF2-α-ATF4 signaling pathway.

Hypertonic saline and mannitol in patients with traumatic brain injury: A systematic and meta-analysis.

BACKGROUND: To compare the effects of 3% hypertonic saline solution and 20% mannitol solution on intracranial hypertension. METHODS: WAN-FANGDATA, CNKI, and CQVIP databases were searched, and relevant literatures of randomized controlled trials comparing 3% hypertonic saline solution with mannitol in reducing intracranial hypertension from 2010 to October 2019 were collected. Meta-analysis was performed using RevMan software. RESULTS: As a result, 10 articles that met the inclusion criteria were finally included. A total of 544 patients were enrolled in the study, 270 in the hypertonic saline group and 274 in the mannitol group. There was no significant difference in the decrease of intracranial pressure and the onset time of drug between the 2 groups after intervention (all P > .05). There was a statistically significant difference between the hypertonic saline group and the mannitol group in terms of duration of effect in reducing intracranial pressure (95% confidence interval: 0.64-1.05, Z = 8.09, P < .00001) and cerebral perfusion pressure after intervention (95% confidence interval: 0.15-0.92, Z = 2.72, P = .007). CONCLUSION: Both 3% hypertonic saline and mannitol can effectively reduce intracranial pressure, but 3% hypertonic saline has a more sustained effect on intracranial pressure and can effectively increase cerebral perfusion pressure.

Osmotic diuresis by SGLT2 inhibition stimulates vasopressin-induced water reabsorption to maintain body fluid volume.

Most of the filtered glucose is reabsorbed in the early proximal tubule by the sodium-glucose cotransporter SGLT2. The glycosuric effect of the SGLT2 inhibitor ipragliflozin is linked to a diuretic and natriuretic effect that activates compensatory increases in fluid and food intake to stabilize body fluid volume (BFV). However, the compensatory mechanisms that are activated on the level of renal tubules remain unclear. Type 2 diabetic Goto-Kakizaki (GK) rats were treated with vehicle or 0.01% (in diet) ipragliflozin with free access to fluid and food. After 8 weeks, GK rats were placed in metabolic cages for 24-hr. Ipragliflozin decreased body weight, serum glucose and systolic blood pressure, and increased fluid and food intake, urinary glucose and Na+ excretion, urine volume, and renal osmolar clearance, as well as urine vasopressin and solute-free water reabsorption (TcH2O). BFV, measured by bioimpedance spectroscopy, and fluid balance were similar among the two groups. Urine vasopressin in ipragliflozin-treated rats was negatively and positively associated with fluid balance and TcH2O, respectively. Ipragliflozin increased the renal membrane protein expression of SGLT2, aquaporin (AQP) 2 phosphorylated at Ser269 and vasopressin V2 receptor. The expression of SGLT1, GLUT2, AQP1, and AQP2 was similar between the groups. In conclusion, the SGLT2 inhibitor ipragliflozin induced a sustained glucosuria, diuresis, and natriuresis, with compensatory increases in fluid intake and vasopressin-induced TcH2O in proportion to the reduced fluid balance to maintain BFV. These results indicate that the osmotic diuresis induced by SGLT2 inhibition stimulates compensatory fluid intake and renal water reabsorption to maintain BFV.

Mannitol Improves Intraoperative Brain Relaxation in Patients With a Midline Shift Undergoing Supratentorial Tumor Surgery: A Randomized Controlled Trial.

BACKGROUND: Mannitol is widely used to reduce brain tissue swelling and improve brain relaxation during neurosurgery. However, the optimal dosage for patients with midline shift undergoing supratentorial tumor resection remains unclear. METHODS: In this randomized, controlled double-blinded study, 204 patients with preoperative midline shift who underwent elective supratentorial brain tumor surgery were equally allocated to receive placebo or 0.7, 1.0, or 1.4 g/kg mannitol infusion. The primary outcome was the proportion of satisfactory brain relaxation. RESULTS: Demographics and baseline characteristics were similar among the 4 groups. Trend analysis showed that mannitol infusion increased satisfactory brain relaxation (P<0.0001), relaxed dural tension (P<0.0001) and adequate surgical exposure (P<0.0001), and decreased the requirement for rescue therapy for brain swelling (P<0.0005), all in a dose-dependent manner. Tumor size (odds ratio [OR]: 0.99 per 1 mm, 95% confidence interval [CI]: 0.989-0.998, P=0.004), peritumoral edema classification (OR: 0.60, 95% CI: 0.37-0.97; P=0.038) as well as mannitol dose (OR: 2.81, 95% CI: 1.97-4.02, P<0.0001) were significantly associated with satisfactory brain relaxation. An increased risk of moderate to severe postoperative cerebral edema was found in the group receiving 1.4 g/kg mannitol (P=0.025) in a dose-dependent manner (P=0.018). CONCLUSIONS: An optimal mannitol infusion dosage of 1.0 g/kg is recommended to improve brain relaxation with lower risk of moderate to severe postoperative cerebral edema in patients with midline shift undergoing supratentorial tumor resections. The effect of mannitol on brain relaxation is affected by tumor size and severity of peritumoral edema, rather than by midline shift.

Examining Mannitol Use in Kidney Cancer Surgery: A Cautionary Tale of Extrapolated Surgical Data.

Mannitol for renal protection during partial nephrectomy is common but unsupported by evidence from clinical trials. The impact of mannitol on renal physiology includes both beneficial and harmful effects. Current understanding of renal ischemia reperfusion injury suggests potentially targetable processes that have a lower potential risk.

Phase III Trial of Intravenous Mannitol Versus Placebo During Nephron-sparing Surgery: Post Hoc Analysis of 3-yr Outcomes.

Our recently reported phase III trial demonstrated that patients undergoing nephron-sparing surgery (NSS) with an estimated glomerular filtration rate (eGFR) of ≥45 ml/min/1.73 m2 who received mannitol had no improvement in renal function at 6 mo compared with those who received placebo. Some authors have suggested that benefit is restricted to subgroups, such as those with comorbidities. We assessed whether preoperative eGFR, or other patient and surgical factors modified the effect of mannitol on postoperative outcomes at 6 mo and with extended follow-up. We also assessed whether mannitol was associated with differences in long-term GFR years after surgery. No significant difference between the mannitol or placebo groups (mean eGFR difference: 1.4; 95% confidence interval: -2.6, 5.3; p = 0.5) was found in the 134 patients with known eGFR at 3 yr after NSS. At both 6 mo and 3 yr, the effect of mannitol was not significantly modified by patient or surgical factors including preoperative eGFR. In summary, we validated our original trial conclusions by finding that intraoperative use of mannitol does not improve either short- or long-term renal function in patients undergoing NSS. Specifically, there is no evidence that comorbidities, including lower preoperative eGFR, modify the effect of mannitol. PATIENT SUMMARY: Use of mannitol at the time of partial nephrectomy does not improve either short- or long-term renal function even in patients with comorbidities, including lower preoperative renal function. The routine use of intraoperative mannitol should be discontinued.

Osmotic stress activates nif and fix genes and induces the Rhizobium tropici CIAT 899 Nod factor production via NodD2 by up-regulation of the nodA2 operon and the nodA3 gene.

The symbiosis between rhizobia and legumes is characterized by a complex molecular dialogue in which the bacterial NodD protein plays a major role due to its capacity to activate the expression of the nodulation genes in the presence of appropiate flavonoids. These genes are involved in the synthesis of molecules, the nodulation factors (NF), responsible for launching the nodulation process. Rhizobium tropici CIAT 899, a rhizobial strain that nodulates Phaseolus vulgaris, is characterized by its tolerance to multiple environmental stresses such as high temperatures, acidity or elevated osmolarity. This strain produces nodulation factors under saline stress and the same set of CIAT 899 nodulation genes activated by inducing flavonoids are also up-regulated in a process controlled by the NodD2 protein. In this paper, we have studied the effect of osmotic stress (high mannitol concentrations) on the R. tropici CIAT 899 transcriptomic response. In the same manner as with saline stress, the osmotic stress mediated NF production and export was controlled directly by NodD2. In contrast to previous reports, the nodA2FE operon and the nodA3 and nodD1 genes were up-regulated with mannitol, which correlated with an increase in the production of biologically active NF. Interestingly, in these conditions, this regulatory protein controlled not only the expression of nodulation genes but also the expression of other genes involved in protein folding and synthesis, motility, synthesis of polysaccharides and, surprinsingly, nitrogen fixation. Moreover, the non-metabolizable sugar dulcitol was also able to induce the NF production and the activation of nod genes in CIAT 899.

Sequential changes in urine production, glomerular filtration rate, and electrolyte excretion after mannitol administration.

INTRODUCTION: Acute kidney injury (AKI) leading to severe uremia is associated with high morbidity and mortality. Mannitol is an osmotic diuretic, widely used in the management of AKI, both as a bolus injection and as a constant rate infusion (CRI). OBJECTIVES: To determine the plasma concentration of mannitol after a bolus injection and CRI at the recommended dosages, and to assess the effect of mannitol on renal function variables including urine production, glomerular filtration rate (GFR), and solute excretion. METHODS: Prospective cross-over design study, using 6 healthy dogs. Each dog underwent 3 protocols with at least a 7-day washout period between protocols. The first protocol included bolus injection of mannitol, the second protocol included bolus injection followed by CRI of mannitol and the third protocol (control) included injection of 5% dextrose in water (D5W). Urine production, GFR, and fractional excretion (FE) of solutes were measured for 10 hours. RESULTS: For all protocols, urine production significantly (P < .001) increased after bolus injection, but no significant difference in urine production or GFR was observed among the treatment groups. Mannitol injection increased the FE of sodium and urea nitrogen, but these effects were short-lived. CONCLUSIONS: Mannitol has minimal effect on urine production and GFR but does increase FE of urea nitrogen and sodium, immediately after bolus injection. Constant rate infusion at a conventional dosage of 1 mg/kg/min cannot maintain these effects in dogs with normal renal function, because mannitol concentration decreases rapidly.

Mannitol decreases neocortical epileptiform activity during early brain development via cotransport of chloride and water.

Seizures and brain injury lead to water and Cl- accumulation in neurons. The increase in intraneuronal Cl- concentration ([Cl-]i) depolarizes the GABAA reversal potential (EGABA) and worsens seizure activity. Neocortical neuronal membranes have a low water permeability due to the lack of aquaporins necessary to move free water. Instead, neurons use cotransport of ions including Cl- to move water. Thus, increasing the extracellular osmolarity during seizures should result in an outward movement of water and salt, reducing [Cl-]i and improving GABAA receptor-mediated inhibition. We tested the effects of hyperosmotic therapy with a clinically relevant dose of mannitol (20 mM) on epileptiform activity, spontaneous multiunit activity, spontaneous inhibitory post-synaptic currents (sIPSCs), [Cl-]i, and neuronal volume in layer IV/V of the developing neocortex of C57BL/6 and Clomeleon mice. Using electrophysiological techniques and multiphoton imaging in acute brain slices (post-natal day 7-12) and organotypic neocortical slice cultures (post-natal day 14), we observed that mannitol: 1) decreased epileptiform activity, 2) decreased neuronal volume and [Cl-]i through CCCs, 3) decreased spontaneous multi-unit activity frequency but not amplitude, and 4) restored the anticonvulsant efficacy of the GABAA receptor modulator diazepam. Increasing extracellular osmolarity by 20 mOsm with hypertonic saline did not decrease epileptiform activity. We conclude that an increase in extracellular osmolarity by mannitol mediates the efflux of [Cl-]i and water through CCCs, which results in a decrease in epileptiform activity and enhances benzodiazepine actions in the developing neocortex in vitro. Novel treatments aimed to decrease neuronal volume may concomitantly decrease [Cl-]i and improve seizure control.

Effects of Osmotic Therapy on Pupil Reactivity: Quantification Using Pupillometry in Critically Ill Neurologic Patients.

BACKGROUND: Osmotic therapy is a critical component of medical management for cerebral edema. While up to 90% of neurointensivists report using these treatments, few quantitative clinical measurements guide optimal timing, dose, or administration frequency. Its use is frequently triggered by a qualitative assessment of neurologic deterioration and/or pupil size, and anecdotally appears to improve pupil asymmetry suggestive of uncal herniation. However, subjective pupil assessment has poor reliability, making it difficult to detect or track subtle changes. We hypothesized that osmotic therapy reproducibly improves quantitative pupil metrics. METHODS: We included patients at two centers who had recorded quantitative pupil measurements within 2 h before and after either 20% mannitol or 23.4% hypertonic saline in the neurosciences intensive care unit. The primary outcome was the Neurologic Pupil Index (NPi), a composite metric ranging from 0 to 5 in which > 3 is considered normal. Secondary outcomes included pupil size, percent change, constriction and dilation velocity, and latency. Results were analyzed with Wilcoxon signed-rank tests, Chi-square and multi-level linear regression to control for other edema-reducing interventions. RESULTS: Out of 72 admissions (403 paired pupil observations), NPi significantly differed within 2 h of osmotic therapy when controlling for other commonly used interventions in our whole cohort (ß = 0.08, p = 0.0168). The effect was most pronounced (ß = 0.57) in patients with abnormal NPi prior to intervention (p = 0.0235). CONCLUSIONS: Pupil reactivity significantly improves after osmotic therapy in a heterogenous critically ill population when controlling for various other interventions. Future work is necessary to determine dose-dependent effects and clinical utility.

Mannitol and Hypertonic Saline Reduce Swelling and Modulate Inflammatory Markers in a Rat Model of Intracerebral Hemorrhage.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) leaves most survivors dependent at follow-up. The importance of promoting M2-like microglial responses is increasingly recognized as a key element to ameliorate brain injury following ICH. The osmotherapeutic agents, mannitol and hypertonic saline (HTS), which are routinely used to reduce intracranial pressure, have been shown to reduce neuroinflammation in experimental ischemic and traumatic brain injury, but anti-inflammatory effects of osmotherapies have not been investigated in ICH. METHODS: We studied the effects of iso-osmotic mannitol and HTS in rat models of ICH utilizing high-dose and moderate-dose collagenase injections into the basal ganglia, associated with high and low mortality, respectively. We studied the effects of osmotherapies, first given 5 h after ICH induction, and then administered every 12 h thereafter (4 doses total). Immunohistochemistry was used to quantify microglial activation and polarization. RESULTS: Compared to controls, mannitol and HTS increased plasma osmolarity 1 h after infusion (301 ± 1.5, 315 ± 4.2 and 310 ± 2.0 mOsm/kg, respectively), reduced mortality at 48 h (82, 36 and 53%, respectively), and reduced hemispheric swelling at 48 h (32, 21, and 17%, respectively). In both perihematomal and contralateral tissues, mannitol and HTS reduced activation of microglia/macrophages (abundance and morphology of Iba1 + cells), and in perihematomal tissues, they reduced markers of the microglia/macrophage M1-like phenotype (nuclear p65, TNF, and NOS2), increased markers of the microglia/macrophage M2-like phenotype (arginase, YM1, and pSTAT3), and reduced infiltration of CD45 + cells. CONCLUSIONS: Repeated dosing of osmotherapeutics at regular intervals may be a useful adjunct to reduce neuroinflammation following ICH.

Mannitol reduces nephron loss after warm renal ischemia in a porcine model.

BACKGROUND: Mannitol has been employed to ameliorate renal warm ischemia damage during partial nephrectomy, however, there is limited scientific evidence to support the use of mannitol during partial nephrectomy. The objective of the present study was to investigate the glomerular number after renal warm ischemia, with and without the use of mannitol in a Pig Model. METHODS: Twenty-four male pigs were assigned into three groups. Eight animals were allocated to the sham group that was subjected to laparoscopic dissection of the left renal hilum, without renal ischemia. Eight animals were allocated to the ischemia group that had the left renal hilum clamped for 30 min through laparoscopic access. Eight animals received mannitol (250 mg/kg) before the occlusion of renal hilum for 30 min. The kidneys were collected after the euthanasia of the pigs 21 days post surgery. The right kidney was utilized as a self-control for each animal. Serum creatinine, urea levels, the weight and volume of the kidneys were measured. Glomerular volumetric density, volume-weighted glomerular volume, and cortical volume were quantified through stereological methods and employed to determine the number of nephrons per kidney. Student's t test and ANOVA were used for statistical analysis. RESULTS: In the ischemia group, the left kidney recorded a reduction of 24.6% (290, 000 glomeruli) in the number of glomeruli in comparison to the right kidney. Kidneys subjected to ischemia also displayed decreased weight and volume in comparison to the sham and mannitol groups. No difference was observed between the left and right kidneys from the sham and mannitol groups. Further, no distinction in serum creatinine and urea among the groups was observed. CONCLUSION: The use of mannitol significantly reduces nephron loss during warm ischemia in pigs.

Effect of Mannitol on Ultrasonographically Measured Optic Nerve Sheath Diameter as a Surrogate for Intracranial Pressure During Robot-Assisted Laparoscopic Prostatectomy with Pneumoperitoneum and the Trendelenburg Position.

INTRODUCTION: CO2 pneumoperitoneum and the steep Trendelenburg position during robot-assisted laparoscopic prostatectomy (RALP) can increase intracranial pressure (ICP). Mannitol is widely used to treat increased ICP. However, no studies to date have specifically evaluated the effect of mannitol on ICP in patients undergoing RALP. Ultrasonographic measurement of the optic nerve sheath diameter (ONSD) is considered a reliable technique to noninvasively evaluate the ICP. Therefore, this study compared ONSDs as a surrogate for ICP before and after mannitol administration in prostate cancer patients undergoing RALP. METHODS: Mannitol (0.5 g/kg) was administered after pneumoperitoneum establishment and shifting to the Trendelenburg position. ONSDs were measured at six predetermined time points: 10 minutes after anesthesia induction (T0); 5 minutes after pneumoperitoneum and the Trendelenburg position before mannitol administration (T1); 30 minutes (T2), 60 minutes (T3), and 90 minutes (T4) after completion of mannitol administration during pneumoperitoneum and the Trendelenburg position; and at skin closure in the supine position (T5). Moreover, intraoperative hemodynamic and respiratory variables were evaluated simultaneously. RESULTS: Thirty-six patients were analyzed. ONSDs were significantly lower at T2, T3, and T4 than at T1 (all p < 0.001), with the greatest decrease observed at T4 compared with T1 (4.46 ± 0.2 mm vs 4.81 ± 0.3 mm, p < 0.001). Regional cerebral oxygen saturation, cardiac output, corrected flow time, peak velocity, body temperature, arterial CO2 partial pressure, peak airway pressure, plateau airway pressure, dynamic compliance, and static compliance were not significantly different during pneumoperitoneum and the Trendelenburg position; however, mean arterial blood pressure and heart rate were significantly different. CONCLUSIONS: Mannitol decreases the ONSD in patients undergoing RALP with CO2 pneumoperitoneum and the steep Trendelenburg position. This result provides useful information on the beneficial effects of mannitol administration on prostate cancer patients who may develop increased ICP during RALP.

Renal tubular epithelial cells injury induced by mannitol and its potential mechanism.

Administration of mannitol with high dose could induce extensive isometric renal proximal tubular vacuolization and acute renal failure in clinic. We previously demonstrated that mannitol-induced human kidney tubular epithelial cell (HK-2) injury. The objective of our present work was to further study the cytotoxicity of mannitol in HK-2 cells and its potential mechanism. Cell viability was assessed by an MTT method. Cell morphological changes were observed. Furthermore, levels of malondialdehyde (MDA) and glutathione (GSH) were measured. Flow cytometry was performed to determine cell apoptosis by using Annexin V-FITC and PI. In addition, the F-actin of cells was labeled by FITC-Phalloidin for observation of cytoskeleton. The MTT assay displayed that the cell viability decreased significantly in a dose- and time-dependent manner. The morphological changes were observed, including cell membrane rapture and cell detachment. The GSH concentration in HK-2 cells decreased dramatically in mannitol treatment group, while MDA content increased significantly. The results of flow cytometry indicated that apoptotic percentages of HK-2 cells increased in 250 mmol/L mannitol treatment group. After treatment with 250 mmol/L mannitol for 48 h, HK-2 cells showed disorganization of cytoskeleton and even exhibited a totally destroyed cytoskeleton. Therefore, high dose of mannitol has a toxic effect on renal tubular epithelial cells, which might be attributed to oxidative stress, destroyed cellular cytoskeleton and subsequent cell apoptosis.

Cardiac output changes after osmotic therapy in neurosurgical and neurocritical care patients: a systematic review of the clinical literature.

AIM: Osmotherapy constitutes a first-line intervention for intracranial hypertension management. However, hyperosmolar solutes exert various systematic effects, among which their impact on systemic haemodynamics is poorly clarified. This review aims to appraise the clinical evidence of the effect of mannitol and hypertonic saline (HTS) on cardiac performance in neurosurgical and neurocritical care patients. METHOD: A database search was conducted to identify randomized clinical trials and observational studies reporting HTS or mannitol use in acute brain injury setting. The primary end-points were alterations of cardiac output (CO) and other haemodynamic variables, while the impact of osmotic agents on intracranial pressure, brain relaxation, plasma osmolality, electrolyte levels and urinary output constituted secondary outcomes. RESULTS: Eight studies, enrolling 182 patients in total, were included. HTS exerted a more profound cardiac output augmentation than mannitol, but no distinct difference between groups occurred. Central venous pressure, stroke volume and stroke volume variation were favourably affected by both osmotic agents, whilst the reported changes in blood pressure were inconclusive. HTS infusion yielded a larger intracranial pressure reduction than mannitol but had an equivalent effect on brain relaxation. Mannitol presented a more potent diuretic effect than HTS. Effect on serum osmolality was alike in both osmotic agents, but contrary to HTS-promoted hypernatraemia, mannitol use induced transient hyponatraemia. CONCLUSIONS: Mannitol or HTS administration seems to induce an enhancement of cardiac performance; being more prominent after HTS infusion. This effect combined with mannitol-induced enhancement of diuresis and HTS-promoted increase of plasma sodium concentration could partially explain the effects of osmotherapy on cerebral haemodynamics.