Effects of intrarenal pelvic infusion of tumour necrosis factor-α and interleukin 1-ß on reno-renal reflexes in anaesthetised rats.

OBJECTIVE: Reno-renal reflexes are disturbed in cardiovascular and hypertensive conditions when elevated levels of pro-inflammatory mediators/cytokines are present within the kidney. We hypothesised that exogenously administered inflammatory cytokines tumour necrosis factor alpha (TNF-α) and interleukin (IL)-1ß modulate the renal sympatho-excitatory response to chemical stimulation of renal pelvic sensory nerves. METHODS: In anaesthetised rats, intrarenal pelvic infusions of vehicle [0.9% sodium chloride (NaCl)], TNF-α (500 and 1000 ng/kg) and IL-1ß (1000 ng/kg) were maintained for 30 min before chemical activation of renal pelvic sensory receptors was performed using randomized intrarenal pelvic infusions of hypertonic NaCl, potassium chloride (KCl), bradykinin, adenosine and capsaicin. RESULTS: The increase in renal sympathetic nerve activity (RSNA) in response to intrarenal pelvic hypertonic NaCl was enhanced during intrapelvic TNF-α (1000 ng/kg) and IL-1ß infusions by almost 800% above vehicle with minimal changes in mean arterial pressure (MAP) and heart rate (HR). Similarly, the RSNA response to intrarenal pelvic adenosine in the presence of TNF-α (500 ng/kg), but not IL-1ß, was almost 200% above vehicle but neither MAP nor HR were changed. There was a blunted sympatho-excitatory response to intrapelvic bradykinin in the presence of TNF-α (1000 ng/kg), but not IL-1ß, by almost 80% below vehicle, again without effect on either MAP or HR. CONCLUSION: The renal sympatho-excitatory response to renal pelvic chemoreceptor stimulation is modulated by exogenous TNF-α and IL-1ß. This suggests that inflammatory mediators within the kidney can play a significant role in modulating the renal afferent nerve-mediated sympatho-excitatory response.

Arginine or Hypertonic Saline-Stimulated Copeptin to Diagnose AVP Deficiency.

BACKGROUND: Distinguishing between arginine vasopressin (AVP) deficiency and primary polydipsia is challenging. Hypertonic saline-stimulated copeptin has been used to diagnose AVP deficiency with high accuracy but requires close sodium monitoring. Arginine-stimulated copeptin has shown similar diagnostic accuracy but with a simpler test protocol. However, data are lacking from a head-to-head comparison between arginine-stimulated copeptin and hypertonic saline-stimulated copeptin in the diagnosis of AVP deficiency. METHODS: In this international, noninferiority trial, we assigned adult patients with polydipsia and hypotonic polyuria or a known diagnosis of AVP deficiency to undergo diagnostic evaluation with hypertonic-saline stimulation on one day and with arginine stimulation on another day. Two endocrinologists independently made the final diagnosis of AVP deficiency or primary polydipsia with use of clinical information, treatment response, and the hypertonic-saline test results. The primary outcome was the overall diagnostic accuracy according to prespecified copeptin cutoff values of 3.8 pmol per liter after 60 minutes for arginine and 4.9 pmol per liter once the sodium level was more than 149 mmol per liter for hypertonic saline. RESULTS: Of the 158 patients who underwent the two tests, 69 (44%) received the diagnosis of AVP deficiency and 89 (56%) received the diagnosis of primary polydipsia. The diagnostic accuracy was 74.4% (95% confidence interval [CI], 67.0 to 80.6) for arginine-stimulated copeptin and 95.6% (95% CI, 91.1 to 97.8) for hypertonic saline-stimulated copeptin (estimated difference, -21.2 percentage points; 95% CI, -28.7 to -14.3). Adverse events were generally mild with the two tests. A total of 72% of the patients preferred testing with arginine as compared with hypertonic saline. Arginine-stimulated copeptin at a value of 3.0 pmol per liter or less led to a diagnosis of AVP deficiency with a specificity of 90.9% (95% CI, 81.7 to 95.7), whereas levels of more than 5.2 pmol per liter led to a diagnosis of primary polydipsia with a specificity of 91.4% (95% CI, 83.7 to 95.6). CONCLUSIONS: Among adult patients with polyuria polydipsia syndrome, AVP deficiency was more accurately diagnosed with hypertonic saline-stimulated copeptin than with arginine-stimulated copeptin. (Funded by the Swiss National Science Foundation; CARGOx ClinicalTrials.gov number, NCT03572166.).

Management of noncytotoxic extravasation injuries: A focused update on medications, treatment strategies, and peripheral administration of vasopressors and hypertonic saline.

Extravasation is the leakage of intravenous solutions into surrounding tissues, which can be influenced by drug properties, infusion techniques, and patient-related risk factors. Although peripheral administration of vesicants may increase the risk of extravasation injuries, the time and resources required for central venous catheter placement may delay administration of time-sensitive therapies. Recent literature gathered from the growing use of peripheral vasopressors and hypertonic sodium suggests low risk of harm for initiating these emergent therapies peripherally, which may prevent delays and improve patient outcomes. Physiochemical causes of tissue injury include vasoconstriction, pH-mediated, osmolar-mediated, and cytotoxic mechanisms of extravasation injuries. Acidic agents, such as promethazine, amiodarone, and vancomycin, may cause edema, sloughing, and necrosis secondary to cellular desiccation. Alternatively, basic agents, such as phenytoin and acyclovir, may be more caustic due to deeper tissue penetration of the dissociated hydroxide ions. Osmotically active agents cause cellular damage as a result of osmotic shifts across cellular membranes in addition to agent-specific toxicities, such as calcium-induced vasoconstriction and calcifications or arginine-induced leakage of potassium causing apoptosis. A new category has been proposed to identify absorption-refractory mechanisms of injury in which agents such as propofol and lipids may persist in the extravasated space and cause necrosis or compartment syndrome. Pharmacological antidotes may be useful in select extravasations but requires prompt recognition and frequently complex administration strategies. Historically, intradermal phentolamine has been the preferred agent for vasopressor extravasations, but frequent supply shortages have led to the emergence of terbutaline, a ß2 -agonist, as an acceptable alternative treatment option. For hyperosmolar and pH-related mechanisms of injuries, hyaluronidase is most commonly used to facilitate absorption and dispersion of injected agents. However, extravasation management is largely supportive and requires a protocolized multidisciplinary approach for early detection, treatment, and timely surgical referral when required to minimize adverse events.

Nursing Progress of Hypertonic Saline Inhalation in the Treatment of Infantile Bronchitis Based on Image Enhancement.

The onset of bronchiolitis is closely related to the anatomical characteristics of the bronchi in children of this age. This kind of injury is caused by epithelial necrosis, nasal mucosa, and mucosal edema caused by narrowing and blockage of the trachea. Children with this serious phenomenon will have respiratory and heart failure, which threatens the life of children to a large extent. In this paper, based on image enhancement technology, hypertonic saline aerosol inhalation treatment of pediatric bronchiolitis nursing care, through related cases, the application of image enhancement technology in hypertonic saline aerosol inhalation therapy and pediatric bronchiolitis is analyzed, and the tone mapping function is used. Tone mapping functions, hereditary arithmetics, and slope regimes for experimental field capture and detection were used for the objective of therapeutic approaches for the treatment of pediatric capillary pneumonia by hypertonic inhalation. Experimental results show that imaging technology hypertonic inhalation can control the main symptoms of bronchiolitis in infants and young children. Inhalation of 3% saline can shorten the course of moderately chronic children to half a year and can reduce the length of hospital stay by a quarter of the original requires hospitalization time, and the cure rate of pediatric bronchiolitis is increased to 93.7%.

Hypertonic lactate for the treatment of intracranial hypertension in patients with acute brain injury.

Hypertonic lactate (HL) is emerging as alternative treatment of intracranial hypertension following acute brain injury (ABI), but comparative studies are limited. Here, we examined the effectiveness of HL on main cerebral and systemic physiologic variables, and further compared it to that of standard hypertonic saline (HS). Retrospective cohort analysis of ABI subjects who received sequential osmotherapy with 7.5% HS followed by HL-given at equi-osmolar (2400 mOsmol/L) and isovolumic (1.5 mL/kg) bolus doses-to reduce sustained elevations of ICP (> 20 mmHg). The effect of HL on brain (intracranial pressure [ICP], brain tissue PO2 [PbtO2], cerebral microdialysis [CMD] glucose and lactate/pyruvate ratio [LPR]) and blood (chloride, pH) variables was examined at different time-points (30, 60, 90, 120 min vs. baseline), and compared to that of HS. A total of 34 treatments among 17 consecutive subjects (13 traumatic brain injury [TBI], 4 non-TBI) were studied. Both agents significantly reduced ICP (p < 0.001, at all time-points tested): when comparing treatment effectiveness, absolute ICP decrease in mmHg and the duration of treatment effect (median time with ICP < 20 mmHg following osmotherapy 183 [108-257] vs. 150 [111-419] min) did not differ significantly between HL and HS (all p > 0.2). None of the treatment had statistically significant effects on PbtO2 and CMD biomarkers. Treatment with HL did not cause hyperchloremia and resulted in a more favourable systemic chloride balance than HS (Δ blood chloride - 1 ± 2.5 vs. + 4 ± 3 mmol/L; p < 0.001). This is the first clinical study showing that HL has comparative effectiveness than HS for the treatment of intracranial hypertension, while at the same time avoiding hyperchloremic acidosis. Both agents had no significant effect on cerebral oxygenation and metabolism.

AVP-eGFP was significantly upregulated by hypovolemia in the parvocellular division of the paraventricular nucleus in the transgenic rats.

Arginine vasopressin (AVP) is produced in the paraventricular (PVN) and supraoptic nuclei (SON). Peripheral AVP, which is secreted from the posterior pituitary, is produced in the magnocellular division of the PVN (mPVN) and SON. In addition, AVP is produced in the parvocellular division of the PVN (pPVN), where corticotrophin-releasing factor (CRF) is synthesized. These peptides synergistically modulate the hypothalamic-pituitary-adrenal (HPA) axis. Previous studies have revealed that the HPA axis was activated by hypovolemia. However, the detailed dynamics of AVP in the pPVN under hypovolemic state has not been elucidated. Here, we evaluated the effects of hypovolemia and hyperosmolality on the hypothalamus, using AVP-enhanced green fluorescent protein (eGFP) transgenic rats. Polyethylene glycol (PEG) or 3% hypertonic saline (HTN) was intraperitoneally administered to develop hypovolemia or hyperosmolality. AVP-eGFP intensity was robustly upregulated at 3 and 6 h after intraperitoneal administration of PEG or HTN in the mPVN. While in the pPVN, eGFP intensity was significantly increased at 6 h after intraperitoneal administration of PEG with significant induction of Fos-immunoreactive (-ir) neurons. Consistently, eGFP mRNA, AVP hnRNA, and CRF mRNA in the pPVN and plasma AVP and corticosterone were significantly increased at 6 h after intraperitoneal administration of PEG. The results suggest that AVP and CRF syntheses in the pPVN were activated by hypovolemia, resulting in the activation of the HPA axis.

Effect of extracellular hyperosmolality on sweat rate during metaboreflex activation in passively heated young men.

Metaboreflex activation augments sweating during mild-to-moderate hyperthermia in euhydrated (isosmotic isovolemic) individuals. Recent work indicates that extracellular hyperosmolality may augment metaboreflex-mediated elevations in sympathetic nervous activity. Our primary objective was, therefore, to test the hypothesis that extracellular hyperosmolality would exacerbate metaboreflex-mediated increases in sweat rate. On two separate occasions, 12 young men [means (SD): 25 (5) yr] received a 90-min intravenous infusion of either 0.9% saline (isosmotic condition, ISO) or 3.0% saline (hyperosmotic condition, HYP), resulting in a postinfusion serum osmolality of 290 (3) and 301 (7) mosmol/kgH2O, respectively. A whole body water perfusion suit was then used to increase esophageal temperature by 0.8°C above resting. Participants then performed a metaboreflex activation protocol consisting of 90-s isometric handgrip exercise (40% of their predetermined maximum voluntary contraction), followed by 150 s of brachial occlusion (trapping produced metabolites within the limb). Metaboreflex-induced sweating was quantified as the change in global sweat rate (from preisometric handgrip exercise to brachial occlusion), estimated as the surface area-weighted average of local sweat rate on the abdomen, axilla, chest, bicep, quadriceps, and calf, measured using ventilated capsules (3.8 cm2). We also explored whether this response differed between body regions. The change in global sweat rate due to metaboreflex activation was significantly greater in HYP compared with ISO (0.03 mg/min/cm2 [95% confidence interval: 0.00, 0.06]; P = 0.047), but was not modulated by body region (site × condition interaction: P = 0.679). These findings indicate that extracellular hyperosmolality augments metaboreflex-induced increases in global sweat rate, with no evidence for region-specific differences.

Exploring the appropriate dose of nebulized hypertonic saline for bronchiolitis: a dose-response meta-analysis.

Nebulized hypertonic saline (HS) has gathered increasing attention in bronchiolitis. This study aims to evaluate the relationship between the dose of nebulized HS and the effects on bronchiolitis. Five electronic databases-PubMed, EMBASE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and ISRCTN-were searched until May 2021. Randomized controlled trials (RCTs) that investigated the effect of HS on bronchiolitis were included. A total of 35 RCTs met the eligibility criteria. HS nebulization may shorten the length of stay (LOS) in hospital (mean difference -0.47, 95% CI -0.71 to -0.23) and improve the 24-hour, 48-hour, and 72-hour Clinical Severe Score (CSS) in children with bronchiolitis. The results showed that there was no significant difference between 3% HS and the higher doses (>3%) of HS in LOS and 24-hour CSS. Although the dose-response meta-analysis found that there may be a linear relationship between different doses and effects, the slope of the linear model changed with different included studies. Besides, HS nebulization could reduce the rate of hospitalization of children with bronchiolitis (risk ratio 0.88, 95% CI 0.78 to 0.98), while the trial sequential analysis indicated the evidence may be insufficient and potentially false positive. This study showed that nebulized HS is an effective and safe therapy for bronchiolitis. More studies are necessary to be conducted to evaluate the effects of different doses of HS on bronchiolitis.

Inverse neurovascular coupling contributes to positive feedback excitation of vasopressin neurons during a systemic homeostatic challenge.

Neurovascular coupling (NVC), the process that links neuronal activity to cerebral blood flow changes, has been mainly studied in superficial brain areas, namely the neocortex. Whether the conventional, rapid, and spatially restricted NVC response can be generalized to deeper and functionally diverse brain regions remains unknown. Implementing an approach for in vivo two-photon imaging from the ventral surface of the brain, we show that a systemic homeostatic challenge, acute salt loading, progressively increases hypothalamic vasopressin (VP) neuronal firing and evokes a vasoconstriction that reduces local blood flow. Vasoconstrictions are blocked by topical application of a VP receptor antagonist or tetrodotoxin, supporting mediation by activity-dependent, dendritically released VP. Salt-induced inverse NVC results in a local hypoxic microenvironment, which evokes positive feedback excitation of VP neurons. Our results reveal a physiological mechanism by which inverse NVC responses regulate systemic homeostasis, further supporting the notion of brain heterogeneity in NVC responses.

Safety of airway clearance combined with bronchodilator and hypertonic saline in non-hospitalized infants with acute bronchiolitis.

BACKGROUND: Acute viral bronchiolitis (AVB) is associated with significant morbidity and no study has addressed the safety of airway clearance techniques (ACT) for non-hospitalized infants. This study aimed to evaluate the safety of the use of ACT combined with bronchodilator and hypertonic saline in non-hospitalized children with the first episode of AVB. METHODS: A quasi-experimental study of infants aged 2-12 months, with a clinical diagnosis of AVB (mild to moderate), was performed. The Wang score, breathing frequency, oxygen saturation (SpO2), heart rate (HR), and the presence of adverse events were evaluated before, 10 and 20 min after the application of a protocol including ACT (nasal irrigation, prolonged slow expiration, and provoked cough), bronchodilator and hypertonic saline inhalation. A total of 265 infants, mean age 6.86±3.01 months, were included. RESULTS: A reduction (p<0.001) in the Wang score and in the breathing frequency as well as an increase in SpO2 were found. There was also a transient HR increment at 10 min followed by a reduction at 20 min (p<0.05). The proportion of patients presenting with chest retraction and wheezing decreased (p<0.001) after treatment. Most of the children (88.3%) did not experience adverse events. A post-treatment increment (p<0.001) of patients classified as having normal values, as well as a decrease in those with mild and moderate AVB, was found for the Wang score levels. CONCLUSION: The use of ACT combined with bronchodilator and hypertonic saline was safe, immediately after treatment, for non-hospitalized children with mild to moderate AVB. No clinically important deterioration or adverse events were identified in the follow-up period.

Suppression of ventral hippocampal CA1 pyramidal neuronal activities enhances water intake.

Thirst is an important interoceptive response and drives water consumption. The hippocampus actively modulates food intake and energy metabolism, but direct evidence for the exact role of the hippocampus in modulating drinking behaviors is lacking. We observed decreased number of c-Fos-positive neurons in the ventral hippocampal CA1 (vCA1) after water restriction or hypertonic saline injection in rats. Suppressed vCA1 neuronal activities under the hypertonic state were further confirmed with in vivo electrophysiological recording, and the level of suppression paralleled both the duration and the total amount of water consumption. Chemogenetic inhibition of vCA1 pyramidal neurons increased water consumption in rats injected with both normal and hypertonic saline. These findings suggest that suppression of vCA1 pyramidal neuronal activities enhances water intake.

Sodium chloride injection to treat opioid overdose; Does it work? A preclinical study.

Opioid overdoses (ODs) are increasing in Mexico's northern border. Because naloxone is usually not available, witnesses inject common salt (NaCl) into a vein of OD victims in an attempt to help them regain consciousness. Despite this widespread practice, no preclinical studies have addressed the efficacy of NaCl as an opioid antidote. Here we tested saline solutions at different concentrations. Because the highest (31.6 %) caused tail necrosis, we selected 17.7 % as a hypertonic saline solution (HSS) to determine if it could prevent the lethal effect of morphine (Mor), fentanyl (Fen), or Mor + Fen in adult Wistar male rats. We also evaluated if NaCl could modify the opioid antagonist effect of naloxone. Our results show that HSS: a) sensitizes animals to thermal but not mechanical stimuli; b) does not prevent mortality caused by high morphine or fentanyl doses; c) decreases the latency to recovery from the sedative effects caused by low doses of morphine or fentanyl; and d) increases naloxone's efficacy to prevent the lethality produced by Mor or Fen, but not by Mor + Fen. These results suggest that HSS is marginally effective in shortening the recovery time from nonfatal opioid ODs and increases naloxone's efficacy to counteract opioid-induced ODs.

Hypertonic saline in people with cystic fibrosis: review of comparative studies and clinical practice.

Cystic fibrosis (CF) is a multisystem disorder, caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. These cause a reduced secretion of chloride, a marked absorption of sodium and, therefore, of water, through the epithelium, resulting in the formation of thickened secretions in organs such as lung or pancreas. These viscous secretions lead to airway obstruction, chronic infection and inflammation resulting in progressive lung damage, bronchiectasis and eventual respiratory failure. Although the average life expectancy has increased over the last 30 years, lung disease is the most common cause of death in people with CF. For these reasons, the improvement of sputum clearance is a major therapeutic aim in CF and early initiation of airway clearance is widely recommended and implemented. Symptomatic mucolytic therapy today is mainly based on inhalation of DNase, hypertonic saline or mannitol, in combination with physiotherapy. Mucolytic agents break down the gel structure of mucus and therefore decrease its elasticity and viscosity, reducing the pulmonary exacerbation frequency and to improve and stabilize lung function. Nevertheless, high quality studies comparing these mucolytic drugs are still few, and the individual experiences of patients and caregivers explain the high variability of their use globally. This review will summarize the current knowledge on hypertonic saline in the treatment of CF lung disease. Furthermore, we report the real-world prescription of inhaled mucolytic agents in CF.

Effectiveness of Continuous Hypertonic Saline in Acute Ischemic Infarcts: A Radiographic and Clinical Evaluation.

OBJECTIVE: The role of continuous hypertonic saline (HS) infusion in the management of malignant cerebral edema is controversial. We evaluated patients presenting with large anterior circulation territory infarcts and compared radiographic and clinical outcomes to evaluate the effects of continuous HS. METHODS: This was a retrospective review of patients with malignant ischemic strokes who were initially managed with continuous HS versus routine medical management. Radiographic parameters of cerebral edema and clinical parameters were collected at different time intervals after admission. Rates and timing of surgery, mortality, and complications were also collected. RESULTS: The study included 43 patients: 26 in group 1 (HS) and 17 in group 2 (no HS). Both cohorts had comparable baseline clinical and radiographic parameters. There was no difference between rates and timing of surgery, complications, and mortality. Mean midline shift was significantly greater in the HS group at interval 1 (12-36 hours, P = 0.003) and interval 2 (36-60 hours, P = 0.030), and mean change in midline shift from initial interval to interval 1 was significantly greater in the HS group (P = 0.019). CONCLUSIONS: Despite the widespread use of continuous HS in acute ischemic infarcts, only a limited number of studies have evaluated its efficacy, and virtually no studies have studied its effect on radiographic progression and rates of decompressive surgery. Results of this study indicate that there is no benefit of continuous HS. In fact, there may be worsening of cerebral edema with administration of continuous HS. In addition, there are no differences in prevention or delay of decompressive surgery or in overall mortality.

Adjuvant administration of hypertonic saline in lumbar epidural intervention may be associated with successful response in patients with probable neuropathic radicular pain Screened by Douleur Neuropathique 4.

Background: Chronic lumbar radicular pain often accompanies neuropathic pain. The treatment may follow a screening for probable neuropathic pain rather than the definitive diagnosis, which is often difficult in daily practice. However, interventional management may have limited effects on symptoms in patients with neuropathic radicular pain refractory to conservative treatments. The purpose of this study is to evaluate the factors associated with successful responses after lumbar epidural intervention in patients with chronic lumbar neuropathic radicular pain determined by Douleur Neuropathique 4 (DN4). Methods: We retrospectively reviewed 221 chronic lumbar radicular pain patients using a DN4 questionnaire prior to the epidural interventional procedure. The patients were divided into two groups according to the DN4 questionnaire: <4-point DN4 and ≥4 DN4. The numerical rating scale (NRS) for pain intensity, changes in physical functional status, and the use of pain medication were obtained before and 1 month after the procedure. Successful responder was defined based on robust combination of outcome parameters. The factors associated with successful response were analyzed using univariate and multivariate regression. Results: We found 170 (76.9%) patients with DN4 <4 and 51 (23.1%) with a score ≥4. Among the total 221 patients, 129 (58.4%) were successful responders and 92 (41.6%) were non-responders regardless of DN4 score. We observed a significantly lower proportion of successful responders among patients with a DN4 score ≥4 (22, 43.1%) than patients with a score <4 (107, 62.9%) (P=0.012). After adjusting in multivariate regression analysis, the DN4 score was independently associated with response after lumbar epidural intervention (odds ratio [OR]=0.838; 95% confidence interval [CI]=0.718-0.978; P=0.025). In subgroup logistic regression analysis according to the DN4 score, adjuvant administration of hypertonic saline during epidural interventions in patients with a DN4 score ≥4 (OR=3.71; CI=1.142-12.457; P=0.029) was associated with the success of the lumbar epidural procedure at 1 month. Conclusion: The adjuvant use of hypertonic saline in lumbar epidural interventions may be effective at least 1 month after the intervention in patients with probable neuropathic lumbar radicular pain ≥4 using the DN4.

Oxytocin levels in response to pituitary provocation tests in healthy volunteers.

OBJECTIVE: Oxytocin, secreted into circulation through the posterior pituitary, regulates lactation, weight, and socio-behavioral functioning. Oxytocin deficiency has been suggested in patients with hypopituitarism; however, diagnostic testing for oxytocin deficiency has not been developed. The aim of this study was to investigate known pituitary provocation tests to stimulate plasma oxytocin. DESIGN: Sixty-five healthy volunteers underwent either the hypertonic saline or arginine infusion test, known to stimulate copeptin, or the oral macimorelin test, known to stimulate growth hormone. Plasma oxytocin was measured before and once plasma sodium level ≥ 150 mmol/L for the hypertonic saline, after 60 min for the arginine infusion, and after 45 min for the oral macimorelin test (expected peak of copeptin and growth hormone levels, respectively). Primary outcome was a change from basal to stimulated oxytocin levels using paired t-tests. RESULTS: As expected, copeptin increased in response to hypertonic saline and arginine infusion (P < 0.001), and growth hormone increased to oral macimorelin (P < 0.001). Oxytocin increased in response to hypertonic saline infusion from 0.4 (0.2) to 0.6 pg/mL (0.3) (P = 0.003) but with a high variance. There was no change to arginine infusion (P = 0.4), and a trend to lower stimulated levels to oral macimorelin (P = 0.05). CONCLUSION: Neither the arginine infusion nor the oral macimorelin test stimulates plasma oxytocin levels, whereas there was an increase with high variance upon hypertonic saline infusion. As a predictable rise in most participants is required for a reliable pituitary provocation test, none of the investigated pituitary provocation tests can be recommended diagnostically to identify patients with an oxytocin deficiency.

Effect of Continuous Infusion of Hypertonic Saline vs Standard Care on 6-Month Neurological Outcomes in Patients With Traumatic Brain Injury: The COBI Randomized Clinical Trial.

Importance: Fluid therapy is an important component of care for patients with traumatic brain injury, but whether it modulates clinical outcomes remains unclear. Objective: To determine whether continuous infusion of hypertonic saline solution improves neurological outcome at 6 months in patients with traumatic brain injury. Design, Setting, and Participants: Multicenter randomized clinical trial conducted in 9 intensive care units in France, including 370 patients with moderate to severe traumatic brain injury who were recruited from October 2017 to August 2019. Follow-up was completed in February 2020. Interventions: Adult patients with moderate to severe traumatic brain injury were randomly assigned to receive continuous infusion of 20% hypertonic saline solution plus standard care (n = 185) or standard care alone (controls; n = 185). The 20% hypertonic saline solution was administered for 48 hours or longer if patients remained at risk of intracranial hypertension. Main Outcomes and Measures: The primary outcome was Extended Glasgow Outcome Scale (GOS-E) score (range, 1-8, with lower scores indicating worse functional outcome) at 6 months, obtained centrally by blinded assessors and analyzed with ordinal logistic regression adjusted for prespecified prognostic factors (with a common odds ratio [OR] >1.0 favoring intervention). There were 12 secondary outcomes measured at multiple time points, including development of intracranial hypertension and 6-month mortality. Results: Among 370 patients who were randomized (median age, 44 [interquartile range, 27-59] years; 77 [20.2%] women), 359 (97%) completed the trial. The adjusted common OR for the GOS-E score at 6 months was 1.02 (95% CI, 0.71-1.47; P = .92). Of the 12 secondary outcomes, 10 were not significantly different. Intracranial hypertension developed in 62 (33.7%) patients in the intervention group and 66 (36.3%) patients in the control group (absolute difference, -2.6% [95% CI, -12.3% to 7.2%]; OR, 0.80 [95% CI, 0.51-1.26]). There was no significant difference in 6-month mortality (29 [15.9%] in the intervention group vs 37 [20.8%] in the control group; absolute difference, -4.9% [95% CI, -12.8% to 3.1%]; hazard ratio, 0.79 [95% CI, 0.48-1.28]). Conclusions and Relevance: Among patients with moderate to severe traumatic brain injury, treatment with continuous infusion of 20% hypertonic saline compared with standard care did not result in a significantly better neurological status at 6 months. However, confidence intervals for the findings were wide, and the study may have had limited power to detect a clinically important difference. Trial Registration: ClinicalTrials.gov Identifier: NCT03143751.

Administration of 3% Sodium Chloride Through Peripheral Intravenous Access: Development and Implementation of a Protocol for Clinical Practice.

BACKGROUND: Patients with traumatic brain injury, cerebral edema, and severe hyponatremia require rapid augmentation of serum sodium levels. Three percent sodium chloride is commonly used to normalize or augment serum sodium level, yet there are limited data available concerning the most appropriate route of administration. Traditionally, 3% sodium chloride is administered through a central venous catheter (CVC) due to the attributed theoretical risk of phlebitis and extravasation injuries when hyperosmolar solution is administered peripherally. CVCs are associated with numerous complications, including arterial puncture, pneumothorax, infection, thrombosis, and air embolus. Peripherally infused 3% sodium chloride may bypass these concerns. AIMS: To explore the evidence for peripherally infused 3% sodium chloride and to implement the findings. METHODS: The Iowa Model of Evidence-Based Practice (EBP) was used to guide the project. A multidisciplinary team was established, and they developed an evidence-based protocol for the administration of 3% sodium chloride using peripheral intravenous catheters (PIVs), identified potential barriers to implementation, and developed targeted education to implement this practice change in a large academic medical center. RESULTS: Of the 103 patients in this project, only three (2.9%) identified adverse events. Two were associated with continuous infusions, and one was associated with a bolus infusion. LINKING ACTION TO EVIDENCE: This is the first study to describe a multidisciplinary protocol development and implementation process for the administration of 3% sodium chloride peripherally. Utilizing a multidisciplinary team is critical to the success of an EBP project. Implementing an evidence-based PIV protocol with stringent monitoring criteria for the administration of 3% sodium chloride has the potential to reduce adverse events related to CVC injury.

Preeclampsia and low sodium: A retrospective cohort analysis and literature review.

BACKGROUND: The aim of this study was to retrospectively analyze the prevalence of severe preeclampsia and low sodium (PALS) among the pregnant population admitted at the University Hospital of Udine in the past 4 years and to compare these data with the current literature. METHODS: Only women with a diagnosis of preeclampsia were included. According to the lowest sodium level measured either 5 days before or 5 days after delivery, patients were divided in two groups: women with hyponatremia (<135 mmol/L; severe <120 mmol/L) and women with normonatremia (>135 mmol/L). Moreover, a search literature was performed. RESULTS: Of 59 patients with preeclampsia, 20 (34%) had hyponatremia. Only one case (1.6%) of severe maternal hyponatremia (sodium level 117 mmol/L) in the setting of preeclampsia was identified. After literature search, a total of 22 manuscripts including 60 case reports of PALS were identified. The lowest sodium level was 113 mmol/L, at 25 weeks of gestation. In most cases hyponatremia was treated with fluid restriction. In only 5 cases hyponatremia was treated with a saline hypertonic solution. Hyponatremia resolution, when reported, occurred in about 48 h. Sodium level in neonates ranged from 118 and 128 mmol/L. CONCLUSIONS: PALS may occur in about a third of women with severe preeclampsia. Severe maternal hyponatremia should be treated with fluid restriction and with hypertonic saline solution. Moreover neonatologists should be alerted in order to treat the neonate for the best outcome.