Sodium Repletion Research Articles

RISK FACTORS FOR INTRAOPERATIVE AND POSTSURGICAL HYPERTENSIVE CRISIS IN PATIENTS WITH PHEOCHROMOCYTOMAS AND SYMPATHETIC PARAGANGLIOMAS: RESULTS FROM THE PHEO-RISK STUDY

Objective: To identify presurgical and surgical risk factors for intraoperative and postoperative hypertensive crisis in patients with pheochromocytomas and sympathetic paragangliomas (PGLs) (PPGLs). Design and method: A retrospective multicenter cohort study of patients with PPGLs from 18 tertiary hospitals was performed. Results: A total of 296 surgeries performed in 289 patients with PPGLs (276 pheochromocytomas and 13 sympathetic PGL) were included. Laparoscopic PPGL resection was performed in 85.1% (n = 252) of the whole cohort. Alpha presurgical blockade was employed in 93.2% of the cases (n = 276) and beta-adrenergic in 53.4% (n = 158). Phenoxybenzamine was the treatment of choice in 126, doxazosin in 148 and the other 7 were treated with amlodipine and 4 with other antihypertensive drugs. Presurgical intravenous volume expansion was performed in 79% (n = 218) of the cases. In addition, 77.2% (n = 169/219) received oral sodium repletion. Hypertensive crisis occurred in 20.3% (n = 60) of the surgeries: intraoperative crisis in 56 and postoperative crisis in 6 cases. We identified as risk factors of hypertensive crisis (intraoperative and postoperative), a higher presurgical body mass index (BMI) (OR 1.16 per each kg/m2 increase CI 1.01-1.33) and HbA1c levels (OR 3.79 per each unit increase, CI 1.44-9.99), presurgical glucocorticoid therapy (OR 2.9, CI 1.08-7.59), higher presurgical SBP (OR 1.22 per each 10-mmHg increase, CI 1.03-1.45) and absence of oral sodium repletion (OR 2.3, CI 1.11-4.65). Patients with hypertensive crisis had a higher rate of intraoperative bleeding (18.3% vs. 3.4%, P<0.001), intraoperative hemodynamic instability (36.7% vs. 8.5%, P<0.001) and of intraoperative hypotensive episodes (41.7% vs. 11.4%, P<0.001) than those without hypertensive crisis. Hospital stay was longer in patients experienced hypertensive crisis (9.7 vs. 6.8 days, P = 0.007) than those without crisis Conclusions: Intraoperative and postoperative hypertensive crisis occurs in up to 20% of the PPGL resections. Patients with higher BMI, HbA1c levels, pretreated with glucocorticoid therapy before surgery, with higher presurgical SBP and who do not receive oral sodium repletion had a higher risk for developing hypertensive crisis during and after PPGL surgery.

Sex differences in body fluid composition in humans with obstructive sleep apnea before and after CPAP therapy.

Obstructive sleep apnea (OSA) is common in heart and kidney disease, both conditions prone to fluid retention. Nocturnal rostral fluid shift contributes to the pathogenesis of OSA in men more than women, suggesting a potential role for sex differences in body fluid composition in the pathogenesis of OSA, with men having a predisposition to more severe OSA due to an underlying volume expanded state. Continuous positive airway pressure (CPAP) increases intraluminal pressure in the upper airway and mitigates the rostral fluid shift; this, in turn, may prevent fluid redistribution from other parts of the body to the upper airway. We sought to determine the impact of CPAP on sex differences in body fluid composition. Twenty-nine (10 women, 19 men) incident, sodium replete, otherwise healthy participants who were referred with symptomatic OSA (oxygen desaturation index >15/h) were studied pre- and post-CPAP (>4 h/night × 4 weeks) using bioimpedance analysis. Bioimpedance parameters including fat-free mass (FFM, %body mass), total body water (TBW, %FFM), extracellular and intracellular water (ECW and ICW, %TBW), and phase angle (°) were measured and evaluated for sex differences before and after CPAP. Pre-CPAP, despite TBW being similar between sexes (74.6 ± 0.4 vs. 74.3 ± 0.2%FFM, p = 0.14; all values women vs. men), ECW (49.7 ± 0.7 vs. 44.0 ± 0.9%TBW, p < 0.001) was increased, while ICW (49.7 ± 0.5 vs. 55.8 ± 0.9%TBW, p < 0.001) and phase angle (6.7 ± 0.3 vs. 8.0 ± 0.3°, p = 0.005) were reduced in women compared to men. There were no sex differences in response to CPAP (∆TBW -1.0 ± 0.8 vs. 0.7 ± 0.7%FFM, p = 0.14; ∆ECW -0.1 ± 0.8 vs. -0.3 ± 1.0%TBW, p = 0.3; ∆ICW 0.7 ± 0.4 vs. 0.5 ± 1.0%TBW, p = 0.2; ∆Phase Angle 0.2 ± 0.3 vs. 0.0 ± 0.1°, p = 0.7). Women with OSA had baseline parameters favoring volume expansion (increased ECW, reduced phase angle) compared to men. Changes in body fluid composition parameters in response to CPAP did not differ by sex.

Respiratory Distress in an Adolescent Girl.

1. Bobby Kumar, MD* 2. Katie Meyer, DO* 3. Leon Rosenberg, DO* 4. Alyson Trillo, DO* 5. Ashley Van Putten, DO, PGY3* 1. *Salah Foundation Children’s Hospital, Fort Lauderdale, FL A 17-year-old girl with past medical history of iron deficiency anemia and depression presented with 6 days of fever (maximum temperature of 103.6°F), cough, congestion, and mild shortness of breath. Other symptoms included nonbloody, nonbilious emesis, decreased appetite, diarrhea, chest pain, body aches, and abdominal pain. When her shortness of breath worsened, she presented to the emergency department for evaluation. On presentation, she was febrile, with oral temperature of 103.1°F, tachycardia, and in severe respiratory distress with subcostal and supraclavicular retractions, decreased breath sounds on the bases, and significant crackles on the right side. Initial oxygen saturation was 89% on room air, with improvement to 98% on 2 L/min of oxygen via nasal cannula. Chest radiograph shows extensive right-sided infiltrates as well as a focal patchy infiltrate on the left (Fig 1). Figure 1. Anteroposterior (a) and lateral (b) chest radiographs showing extensive right-sided infiltrates with patchy infiltrates on the left. Due to right upper quadrant abdominal pain and persistent diarrhea, an abdominal ultrasound was performed, which was unremarkable. Initial laboratory testing on admission revealed no elevated white blood cell count, mild microcytic anemia (hemoglobin 11.3 g/dL, mean corpuscular volume 60.6), hyponatremia (sodium 125 mmol/L), hypokalemia (potassium 3.3 mmol/L), elevated aspartate aminotransferase (141 units/L) and alanine aminotransferase (57 units/L), elevated γ -glutamyl transferase (52 units/L), prolonged coagulation studies (prothrombin time 17.7 seconds and partial thromboplastin time 30.0 seconds), minimally elevated lipase (200 units/L), positive toxicology for cannabis, elevated C-reactive protein of 36.6 mg/dL, negative urine pregnancy test, urinalysis with 100 mg/dL of protein, and a specific gravity of 1.024. Screening for sexually transmitted infections was negative. The …

Hypertonic Saline For The Treatment of Diuretic Resistance In Advanced Heart Failure: A Retrospective Analysis From The Cleveland Clinic

Background Recent studies demonstrated that intravenous hypertonic saline solution (HSS) in combination with high-dose furosemide for the management of diuretic resistance in heart failure can lead to improved diuresis, reduction in length of hospitalization and mortality. Objective The objective of this study was to analyze real world use and safety of HSS administration in advanced heart failure patients in the Cleveland Clinic and identify factors for improvement for the development of an institutional protocol. Methods A retrospective chart analysis was performed in all advanced heart failure patients in whom HSS was administer and who were admitted to the intensive heart failure care unit from 2008 to 2019. Results In our study cohort of 34 patients who received HSS (median age 64 [IQR 53,68] years, 56% male, median LVEF 23 [IQR 15,39]%, median Cr 1.4 [IQR 1.1,2.1]mg/dL, median Na 121 [IQR 116,125]mg/dL), all subjects except one received 3% sodium chloride as HSS regimen. There was large variability in amount of NaCl administered (median 5,5 [IQR 3.4,18]g), infusion speed (median 50 [25,71]ml/min) and concurrent intravenous administration of loop diuretics (75%) and their dosages (furosemide median dose 240 [100-490]mg). The change in serum sodium serum sodium (3 [IQR 1, 5] mmol/L) after HSS was significant (p Conclusion Hypertonic saline solution administered has largely restricted to a relatively small cohort of end-stage heart failure patients with significant hyponatremia, and demonstrated increase in serum sodium without detrimental effects on renal function or complications related to sodium repletion or volume overload. However, the lack of a standardized precluded meaningful assessment of safety and efficacy of such interventions.

Renal Dopamine Oxidation and Inflammation in High Salt Fed Rats.

BackgroundOxidative stress and high salt intake could be independent or intertwined risk factors in the origin of hypertension. Kidneys are the major organ to regulate sodium homeostasis and blood pressure and the renal dopamine system plays a pivotal role in sodium regulation during sodium replete conditions. Oxidative stress has been implicated in renal dopamine dysfunction and development of hypertension, especially in salt‐sensitive animal models. Here we show the nexus between high salt intake and oxidative stress causing renal tubular dopamine oxidation, which leads to mitochondrial and lysosomal dysfunction and subsequently causes renal inflammation and hypertension.Methods and ResultsMale Sprague Dawley rats were divided into the following groups, vehicle (V)—tap water, high salt (HS)—1% NaCl, L‐buthionine‐sulfoximine (BSO), a prooxidant, and HS plus BSO without and with antioxidant resveratrol (R) for 6 weeks. Oxidative stress was significantly higher in BSO and HS+BSO–treated rat compared with vehicle; however, blood pressure was markedly higher in the HS+BSO group whereas an increase in blood pressure in the BSO group was modest. HS+BSO–treated rats had significant renal dopamine oxidation, lysosomal and mitochondrial dysfunction, and increased renal inflammation; however, HS alone had no impact on organelle function or inflammation. Resveratrol prevented oxidative stress, dopamine oxidation, organelle dysfunction, inflammation, and hypertension in BSO and HS+BSO rats.ConclusionsThese data suggest that dopamine oxidation, especially during increased sodium intake and oxidative milieu, leads to lysosomal and mitochondrial dysfunction and renal inflammation with subsequent increase in blood pressure. Resveratrol, while preventing oxidative stress, protects renal function and mitigates hypertension.

Short-term cross-sensitizion of need-free sugar intake by combining sodium depletion and hypertonic NaCl intake

History of sodium depletion cross-sensitizes the effects of drugs of abuse. The objective of the present study was to find out if history of sodium depletion also cross-sensitizes a natural reward such as sugar intake in the rat. Sodium depletion was induced by furosemide combined with removal of ambient sodium for 24 h; it was repeated seven days later. The depletion was immediately followed by 0.3 M NaCl intake in a sodium appetite test (active sodium repletion). Seven days after the last depletion, hydrated and fed (need-free) sucrose-naïve animals were offered 10% sucrose in a first 2-h sucrose test. The sucrose test was repeated once a day in a series of five consecutive days. History of sodium depletion enhanced sucrose intake in the first and second tests; it had no effect from the third to fifth sucrose test. The effect on the initial sucrose intake tests disappeared if the rats did not ingest 0.3 M NaCl in the sodium appetite test. Prior experience with sucrose intake in need-free conditions had no effect on sodium appetite. History of intracellular dehydration transiently influenced sucrose intake in the first sucrose test. We found no evidence for thirst sensitization. We conclude that history of dehydration, particularly that resulting from sodium depletion, combined to active sodium repletion, produced short-term cross-sensitization of sucrose intake in sucrose-naïve rats. The results suggest that the cross-sensitization of sucrose intake related with acquisition of sugar as a novel nutrient rather than production of lasting effects on sugar rewarding properties.

Dehydration: Isonatremic, Hyponatremic, and Hypernatremic Recognition and Management.

1. Karen S. Powers, MD, FCCM* 1. *Pediatric Critical Care, Golisano Children’s Hospital, University of Rochester School of Medicine, Rochester, NY. Clinicians need to recognize the signs and symptoms of dehydration to safely restore fluid and electrolytes. After completing this article, readers should be able to: 1. Understand that the signs and symptoms of dehydration are related to changes in extracellular fluid volume. 2. Recognize the different clinical and laboratory abnormalities in isonatremic, hyponatremic, and hypernatremic dehydration. 3. Know how to manage isonatremic dehydration. 4. Know how to manage hyponatremic dehydration. 5. Know how to manage hypernatremic dehydration. 6. Recognize how to avoid as well as treat complications of fluid and sodium repletion. 7. Understand which patients are candidates for oral rehydration. 8. Know the proper fluids and methods for oral rehydration. Dehydration is one of the leading causes of pediatric morbidity and mortality throughout the world. Diarrheal disease and dehydration account for 14% to 30% of worldwide deaths among infants and toddlers. (1) In the United States, as recently as 2003, gastroenteritis was the source for more than 1.5 million office visits, 200,000 hospitalizations, and 300 deaths per year. The rotavirus vaccine has significantly decreased the incidence of rotaviral gastroenteritis, and now norovirus is the leading cause in the United States. Water, which is essential for cellular homeostasis, comprises about 75% of body weight in infants and up to 60% in adolescents and adults. Without water intake, humans would die within a few days. (2) The human body has an efficient mechanism of physiologic controls to maintain fluid and electrolyte balance, including thirst. These mechanisms can be overwhelmed in disease states such as gastroenteritis because of rapid fluid and electrolyte losses, leading to dysnatremia, which is the most common electrolyte abnormality in hospitalized patients. (3) Infants and young children are …

Sensitivity to Aldosterone

See related article, p 1212–1218 In this issue, Tu et al1 show clear differences in sensitivity of blood pressure (BP) to aldosterone between blacks and those of predominantly white ancestry, in both children and adults. It has long been known that blacks are more salt sensitive than whites: this contribution thus complements the previous findings and has ramifications for the role of aldosterone across the board. The article reports the unusual combination of a long-term (>20 years) observational study on children aged 5 to 17 years starting in 1986 and an acute intervention study comparing the effects of fludrocortisone administration for 2 weeks on BP, weight, and hormonal parameters in black and white adults. The long-term study enrolled 580 children (266 blacks, 314 whites). Age, height, weight, systolic and diastolic BP (DBP), concentrations of plasma electrolytes (Na+ K+), plasma aldosterone (PAC), and renin activity (PRA) were measured, plus urinary excretion of Na+, K+, and creatinine. At baseline, black children were on average 18 months older, with a higher body mass index and slightly but significantly higher BP (103/43 versus 100/41 mm Hg). They also showed significantly lower PAC (9 versus 14 ng/dL) and PRA levels (2.8 versus 3.3 ng/mL per hour), with indistinguishable plasma [K+] and overnight urinary excretion levels of K+ and Na+. In the subsequently re-enrolled adult subcohort, the blacks were 17 months younger, with higher body mass index (31 versus 28) but identical systolic and DBP (116/74 mm Hg). They had lower levels of PRA (1.0 versus 1.5 ng/mL per hour) and PAC (5 versus 9 ng/dL), with levels of plasma K+ and BP indistinguishable from those in whites. Urinary Na+ excretion was similar (78 versus 81 nmol/mg creatinine), but K+ excretion …

5-HT neurons of the area postrema become c-Fos-activated after increases in plasma sodium levels and transmit interoceptive information to the nucleus accumbens.

Serotonergic (5-hydroxytryptamine, 5-HT) neurons of the area postrema (AP) represent one neuronal phenotype implicated in the regulation of salt appetite. Tryptophan hydroxylase (Tryp-OH, synthetic enzyme-producing 5-HT) immunoreactive neurons in the AP of rats become c-Fos-activated following conditions in which plasma sodium levels are elevated; these include intraperitoneal injections of hypertonic saline and sodium repletion. Non-Tryp-OH neurons also became c-Fos-activated. Sodium depletion, which induced an increase in plasma osmolality but caused no significant change in the plasma sodium concentration, had no effect on the c-Fos activity in the AP. Epithelial sodium channels are expressed in the Tryp-OH-immunoreactive AP neurons, possibly functioning in the detection of changes in plasma sodium levels. Since little is known about the neural circuitry of these neurons, we tested whether the AP contributes to a central pathway that innervates the reward center of the brain. Stereotaxic injections of pseudorabies virus were made in the nucleus accumbens (NAc), and after 4 days, this viral tracer produced retrograde transneuronal labeling in the Tryp-OH and non-Tryp-OH AP neurons. Both sets of neurons innervate the NAc via a multisynaptic pathway. Besides sensory information regarding plasma sodium levels, the AP→NAc pathway may also transmit other types of chemosensory information, such as those related to metabolic functions, food intake, and immune system to the subcortical structures of the reward system. Because these subcortical regions ultimately project to the medial prefrontal cortex, different types of chemical signals from visceral systems may influence affective functions.

ENaC-expressing neurons in the sensory circumventricular organs become c-Fos activated following systemic sodium changes

The sensory circumventricular organs (CVOs) are specialized collections of neurons and glia that lie in the midline of the third and fourth ventricles of the brain, lack a blood-brain barrier, and function as chemosensors, sampling both the cerebrospinal fluid and plasma. These structures, which include the organum vasculosum of the lamina terminalis (OVLT), subfornical organ (SFO), and area postrema (AP), are sensitive to changes in sodium concentration but the cellular mechanisms involved remain unknown. Epithelial sodium channel (ENaC)-expressing neurons of the CVOs may be involved in this process. Here we demonstrate with immunohistochemical and in situ hybridization methods that ENaC-expressing neurons are densely concentrated in the sensory CVOs. These neurons become c-Fos activated, a marker for neuronal activity, after various manipulations of peripheral levels of sodium including systemic injections with hypertonic saline, dietary sodium deprivation, and sodium repletion after prolonged sodium deprivation. The increases seen c-Fos activity in the CVOs were correlated with parallel increases in plasma sodium levels. Since ENaCs play a central role in sodium reabsorption in kidney and other epithelia, we present a hypothesis here suggesting that these channels may also serve a related function in the CVOs. ENaCs could be a significant factor in modulating CVO neuronal activity by controlling the magnitude of sodium permeability in neurons. Hence, some of the same circulating hormones controlling ENaC expression in kidney, such as angiotensin II and atrial natriuretic peptide, may coordinate ENaC expression in sensory CVO neurons and could potentially orchestrate sodium appetite, osmoregulation, and vasomotor sympathetic drive.

Use of conivaptan for management of hyponatremia following surgery for Cushing's disease

BackgroundHyponatremia due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common osmoregulatory complication following surgery for Cushing's disease. Conventional management includes water restriction and sodium repletion, however this regimen does not address the underlying pathophysiology of excessive vasopressin production. Vaptans are arginine vasopressin receptor antagonists shown to be effective in correcting water excess in other disease states of euvolemic and hypervolemic hyponatremia. The use of these agents has not been reported in Cushing's patients. MethodsWe retrospectively studied Cushing's patients at our institution with post-surgical hyponatremia (Na<130mEq/L) treated with and without conivaptan between 2005 and 2011. We report rates of serum sodium normalization and compare length-of-stay (LOS) between the groups. ResultsHyponatremia developed in six of 98 patients (6.1%) undergoing resection of ACTH-positive pituitary adenomas. Three patients received conivaptan and fluid restriction±sodium supplementation, and three received conventional therapy alone. The rate of serum sodium normalization with conivaptan was 5.8±2.3mEq/L/20mg IV bolus given every 24h. All patients receiving conivaptan were discharged with normal serum sodium values and no instances of rapid overcorrection occurred. A trend toward longer LOS occurred in patients treated with conivaptan (4.6±0.3 days, mean±SE) versus conventional therapy alone (1.6±0.3 days). ConclusionsConivaptan is a potentially useful treatment option for hyponatremia in the setting of Cushing's disease patients after pituitary surgery.

Effect of Contrasted Sodium Diets on the Pharmacokinetics and Pharmacodynamic Effects of Renin–Angiotensin System Blockers

Dietary sodium, the main determinant of the pharmacodynamic response to renin-angiotensin system blockade, influences the pharmacokinetics of various cardiovascular drugs. We compared the effect of contrasted sodium diets on the pharmacokinetics of single oral doses of 8 mg candesartan cilexetil, 160 mg valsartan, 10 mg ramipril, and 50 mg atenolol administered to 64 (16 per group) normotensive male subjects randomly assigned to sodium depletion (SD) or sodium repletion (SR) in a crossover study. Pharmacodynamic response was assessed as the increase in plasma renin concentration for renin-angiotensin system blockers and electrocardiographic changes in PR interval duration for atenolol. The area under the curve (AUC) for plasma candesartan and atenolol concentrations was significantly lower for SR than for SD (respective ratios of AUC0-∞: 0.74; [90% CI, 0.66-0.82] and 0.69 [90% CI, 0.54-0.88], respectively), indicating a lack of bioequivalence between SR and SD. SR did not affect the pharmacokinetics of valsartan or ramipril. The increase in plasma renin concentration with the 3 renin-angiotensin system blockers was 10 times lower during the SR than the SD period. In the multiple regression analysis, the AUC0-24 of plasma drug concentration explained <1% and 21% of the variance of the AUC0-24 of delta plasma renin concentration for candesartan (P=0.8882/P=0.0368) during the SR and SD periods, respectively. The atenolol-induced lengthening of PR interval was fully reversed by SR. Thus, sodium balance modulates the pharmacokinetics of candesartan cilexetil and atenolol, with measurable effects on the selected pharmacodynamic end points.

Hyponatremia-Associated Rhabdomyolysis Following Exercise in an Adolescent With Cystic Fibrosis

Adolescents with well-controlled cystic fibrosis, including good lung function and appropriate growth, commonly participate in competitive athletic activities. We present the case of an adolescent male with cystic fibrosis, hyponatremia, dehydration, and rhabdomyolysis after participating in football practice on a summer morning. The patient presented with severe myalgia and serum sodium of 129 mmol/L, chloride 90 mmol/L, and creatine phosphokinase 1146 U/L. Aggressive hydration with intravenous 0.9% saline resulted in clinical improvement with no renal or muscular sequelae. Health care providers need to educate patients with cystic fibrosis about maintaining adequate hydration and sodium repletion during exercise. Research is needed regarding the appropriate amount and composition of oral rehydration fluids in exercising individuals with cystic fibrosis, as the physiology encountered in these patients provides a unique challenge to maintaining electrolyte balance and stimulation of thirst.

Opioid mechanisms that mediate the palatability of and appetite for salt in sodium replete and deficient states

Sodium deficiency reliably produces a robust intake of saline in rats, which is associated with an increased preference for sodium solutions at hypertonic concentrations that would normally be avoided. The mechanisms underlying the shift to an increased preference for sodium in the deficient state are not well understood. The current experiments examined the role of opioids on changes of behavioral responses that are modified as a function of body sodium status by studying the intake of 0.3M saline in a free access drinking test and by characterizing the changes in orofacial-related behaviors in response to intra-orally delivered 0.3M NaCl. In intake tests, systemic treatment with morphine and naltrexone respectively, enhanced and attenuated intake of 0.3M saline in sodium depleted rats. In taste reactivity tests systemic treatment with morphine significantly decreased negative responses to 0.3M saline infusions in both sodium replete and sodium depleted rats. Systemically administered naltrexone significantly decreased positive hedonic responses to 0.3M saline infusions only in sodium depleted rats. These results indicate that peripheral administration of opioid agonists and antagonists alter both hypertonic saline ingestion in a free access situation and taste reactivity responses to hypertonic saline under sodium replete and deplete conditions. The results indicate that endogenous opioids alter the processing of central information to affect hedonic mechanisms that influence behaviors related to sodium consumption and palatability.

Renal salt-wasting syndrome in children with intracranial disorders

Hypotonic hyponatremia, a serious and recognized complication of any intracranial disorder, results from extra-cellular fluid volume depletion, inappropriate anti-diuresis or renal salt-wasting. The putative mechanisms by which intracranial disorders might lead to renal salt-wasting are either a disrupted neural input to the kidney or the elaboration of a circulating natriuretic factor. The key to diagnosis of renal salt-wasting lies in the assessment of extra-cellular volume status: the central venous pressure is currently considered the yardstick for measuring fluid volume status in subjects with intracranial disorders and hyponatremia. Approximately 110 cases have been reported so far in subjects ≤18 years of age (male: 63%; female: 37%): intracranial surgery, meningo-encephalitis (most frequently tuberculous) or head injury were the most common underlying disorders. Volume and sodium repletion are the goals of treatment, and this can be performed using some combination of isotonic saline, hypertonic saline, and mineralocorticoids (fludrocortisone). It is worthy of a mention, however, that some authorities contend that cerebral salt wasting syndrome does not exist, since this diagnosis requires evidence of a reduced arterial blood volume, a concept but not a measurable variable.

Use of Intravenous Conivaptan in Neurosurgical Patients With Hyponatremia From Syndrome of Inappropriate Antidiuretic Hormone Secretion

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common cause of hyponatremia in hospitalized patients and is frequently associated with neurologic disorders and neurosurgical procedures. Traditional therapies such as fluid restriction, sodium repletion, and diuretics can help correct hyponatremia but do not address the underlying pathophysiology of excess arginine vasopressin secretion. Conivaptan is an arginine vasopressin receptor antagonist that has been shown to be both safe and effective in the treatment of euvolemic and hypervolemic hyponatremia. To analyze the use of conivaptan to treat SIADH in a mixed neurosurgical population. We conducted a retrospective review of 13 patients with neurosurgical disorders with SIADH that were treated with intravenous conivaptan at our institution between 2007 and 2009. The mean pretreatment serum sodium concentration was 125.8 ± 3.5 mEq/L. Conivaptan administration resulted in a rise in serum sodium to 132.5 ± 5.6 mEq/L at 12 hours (P < .01) and 134.1 ± 4.7 mEq/L at 24 hours posttreatment (P < .01). The mean time to an increase in serum sodium ≥ 6 mEq/L was 17.8 hours. There were no instances of rapid overcorrection. There were 3 cases of asymptomatic hyperkalemia, 3 cases of asymptomatic hypotension, and 1 case of elevated creatinine associated with conivaptan administration. These data provide further support that conivaptan can be safely used for the treatment of SIADH-induced hyponatremia in the neurosurgical arena.

Nucleus accumbens shell, but not core, tracks motivational value of salt

To appropriately respond to an affective stimulus, we must be able to track its value across changes in both the external and internal environment. The nucleus accumbens (NAc) is a critical component of reward circuitry, but recent work suggests that the NAc encodes aversion as well as reward. It remains unknown whether differential NAc activity reflects flexible changes in stimulus value when it is altered due to a change in physiological state. We measured the activity of individual NAc neurons when rats were given intraoral infusions of a hypertonic salt solution (0.45 M NaCl) across multiple sessions in which motivational state was manipulated. This normally nonpreferred taste was made rewarding via sodium depletion, which resulted in a strong motivation to seek out and consume salt. Recordings were made in three conditions: while sodium replete (REP), during acute sodium depletion (DEP), and following replenishment of salt to normal sodium balance (POST). We found that NAc neurons in the shell and core subregions responded differently across the three conditions. In the shell, we observed overall increases in NAc activity when the salt solution was nonpreferred (REP) but decreases when the salt solution was preferred (DEP). In the core, overall activity was significantly altered only after sodium balance was restored (POST). The results lend further support to the selective encoding of affective stimuli by the NAc and suggest that NAc shell is particularly involved in flexibly encoding stimulus value based on motivational state.

Sodium Depletion Increases Sympathetic Neurite Outgrowth and Expression of a Novel TMEM35 Gene-Derived Protein (TUF1) in the Rat Adrenal Zona Glomerulosa

The adrenal zona glomerulosa (ZG) secretes aldosterone to regulate sodium balance. Chronic sodium restriction increases aldosterone accompanied by ZG expansion. The ZG is innervated by sympathetic, vasoactive intestinal polypeptide (VIP) and neuropeptide tyrosine (NPY), and sensory, calcitonin gene-related peptide, nerves. It is unclear whether innervation is affected by ZG growth. Therefore, we measured neurite outgrowth in the ZG of adult male rats after dietary sodium manipulation. In response to 1 wk sodium restriction, VIP and NPY fibers elongated in parallel with expansion of the ZG, shown by aldosterone synthase (AS) expression, but calcitonin gene-related peptide fibers were not affected. Sodium repletion resulted in parallel regression in VIP and NPY fiber length and AS expression. These results show that sympathetic, but not sensory, innervation is coordinated with ZG growth. Mediators underlying changes in innervation are unknown; therefore, we characterized a novel gene TMEM35 [termed the unknown factor-1 (TUF1) due to its unknown function] that shows extensive overlap with AS in ZG. After sodium restriction, TUF1 expanded in parallel with the ZG. TUF1 bound the low-affinity neurotrophin receptor, p75NTR, which was expressed in NPY fibers and showed a response similar to TUF1 after sodium manipulation. TUF1- p75NTR binding was competitively displaced by nerve growth factor but not by TUF1 lacking the p75NTR binding motif. Moreover, TUF1 mRNA in rat ZG cells increased after angiotensin II exposure in vitro. Collectively, these findings suggest that TMEM35/TUF1 is a candidate for modulating neurite outgrowth in the ZG after sodium depletion.

The effects of dietary protein restriction on chorda tympani nerve taste responses and terminal field organization

Prenatal dietary sodium restriction produces profound developmental effects on rat functional taste responses and formation of neural circuits in the brainstem. Converging evidence indicates that the underlying mechanisms for these effects are related to a compromised nutritional state and not to direct stimulus-receptor interactions. We explored whether early malnourishment produces similar functional and structural effects to those seen following dietary sodium restriction by using a protein deficient, sodium replete diet. To determine if early dietary protein-restriction affects the development of the peripheral gustatory system, multi-fiber neurophysiological recordings were made from the chorda tympani nerve and anterograde track tracing of the chorda tympani nerve into the nucleus of the solitary tract (NTS) was accomplished in rats fed a protein-restricted or a control diet (6% and 20%, respectively). The dietary regimens began on embryonic day 7 and continued until rats were used for neurophysiological recordings (postnatal days (P) 35–50) or for chorda tympani terminal field labeling (P40–50). Responses to a concentration series of NaCl, sodium acetate, KCl, and to 0.50 M sucrose, 0.03 M quinine-HCl, and 0.01 N HCl revealed attenuated responses (30–60%) to sodium-specific stimuli in rats fed the 6% protein diet compared with those fed the 20% protein diet. Responses to all other stimuli were similar between groups. Terminal field volumes were nearly twofold larger in protein-restricted rats compared with controls, with the differences located primarily in the dorsal-caudal zone of the terminal field. These results are similar to the results seen previously in rats fed a sodium-restricted diet throughout pre- and postnatal development, suggesting that dietary sodium- and protein-restriction share similar mechanisms in altering gustatory development.

Scanning sports medicine

An Ultracyclist with Pulmonary Edema During the Bicycle Race Across America A recently published case report in the January 2007 issue of Medicine & Science in Sports & Exercise, the official journal of the ACSM, highlights the pitfalls of overly aggressive sodium intake during an endurance race at altitude. It is well known that multiday ultra-endurance athletic events tax the body’s ability to maintain sodium and water homeostasis. Much focus has been placed on the danger associated with excessive water intake without sodium repletion, namely hyponatremia. This case study presents the risk associated with aggressive sodium intake coupled with heavy exertion at a high altitude. The subject presented is an extremely fit 38-year-old male participant in the Bicycle Race Across America who developed severe pulmonary edema while cycling at an altitude of 2380 meters on the fourth day of his race. His daily sodium intake over the course of the race averaged between 1000 and 1100 mEq and his weight on the day of hospitalization was 2.7 kg greater than his prerace weight. The athlete responded appropriately to standard support for pulmonary edema while in the hospital and he made a full recovery. Later, he underwent testing for cardiopulmonary disease or susceptibility to high-altitude pulmonary edema. The results of the entire work-up were negative. The authors hypothesize that the excessive sodium intake led to an expanded extracellular volume, increased hydrostatic pressure, and decreased oncotic pressure. Racing at high altitudes, where a hypoxia-induced rise in pulmonary artery pressures already exists, may have exaggerated the effects of the changes in hydrostatic and oncotic pressures seen with extracellular volume expansion. This, coupled with ambient hypoxia, elevated cardiac output, and reduced renal perfusion associated with sustained highlevel exercise seems to lead to the development of acute pulmonary edema.