Arsenic trioxide (ATO), an inorganic arsenical, is a toxic environmental contaminant. It is also a widely used chemical with industrial and medicinal uses. Significant public health risk exists from its intentional or accidental exposure. The pulmonary pathology of acute high dose exposure is not well defined. We developed and characterized a murine model of a single inhaled exposure to ATO, which was evaluated 24 h post-exposure. ATO caused hypoxemia as demonstrated by arterial blood-gas measurements. ATO administration caused disruption of alveolar-capillary membrane as shown by increase in total protein and IgM in the bronchoalveolar lavage fluid (BALF) supernatant and an onset of pulmonary edema. BALF of ATO-exposed mice had increased HMGB1, a damage-associated molecular pattern (DAMP) molecule, and differential cell counts revealed increased neutrophils. BALF supernatant also showed an increase in protein levels of eotaxin/CCL-11 and MCP-3/CCL-7 and a reduction in IL-10, IL-19, IFN-γ, and IL-2. In the lung of ATO-exposed mice, increased protein levels of G-CSF, CXCL-5, and CCL-11 were noted. Increased mRNA levels of TNF-a, and CCL2 in ATO-challenged lungs further supported an inflammatory pathogenesis. Neutrophils were increased in the blood of ATO-exposed animals. Pulmonary function was also evaluated using flexiVent. Consistent with an acute lung injury phenotype, respiratory and lung elastance showed significant increase in ATO-exposed mice. PV loops showed a downward shift and a decrease in inspiratory capacity in the ATO mice. Flow-volume curves showed a decrease in FEV0.1 and FEF50. These results demonstrate that inhaled ATO leads to pulmonary damage and characteristic dysfunctions resembling ARDS in humans.

Serum sodium disorders are generally a marker of water balance in the body. Thus, hypernatremia is most often caused by an overall deficit of total body water. Other unique circumstances may lead to excess salt, without an impact on the body's total water volume. Hypernatremia is commonly acquired in both the hospital and community. As hypernatremia is associated with increased morbidity and mortality, treatment should be initiated promptly. In this review, we will discuss the pathophysiology and management of the main types of hypernatremia, which can be categorized as either a loss of water or gain of sodium that can be mediated by renal or extrarenal mechanisms.

Hypernatremia is an occasionally encountered electrolyte disorder, which may lead to fatal consequences under improper management. Hypernatremia is a disorder of the homeostatic status regarding body water and sodium contents. This imbalance is the basis for the diagnostic approach to hypernatremia. We summarize the eight diagnostic steps of the traditional approach and introduce new biomarkers: exclude pseudohypernatremia, confirm glucose-corrected sodium concentrations, determine the extracellular volume status, measure urine sodium levels, measure urine volume and osmolality, check ongoing urinary electrolyte free water clearance, determine arginine vasopressin/copeptin levels, and assess other electrolyte disorders. Moreover, we suggest six steps to manage hypernatremia by replacing water deficits, ongoing water losses, and insensible water losses: identify underlying causes, distinguish between acute and chronic hypernatremia, determine the amount and rate of water administration, select the type of replacement solution, adjust the treatment schedule, and consider additional therapy for diabetes insipidus. Physicians may apply some of these steps to all patients with hypernatremia, and can also adapt the regimens for specific causes or situations.

The key message from the 1958 Edelman study states that combinations of external gains or losses of sodium, potassium and water leading to an increase of the fraction (total body sodium plus total body potassium) over total body water will raise the serum sodium concentration ([Na]_S), while external gains or losses leading to a decrease in this fraction will lower [Na]_S. A variety of studies have supported this concept and current quantitative methods for correcting dysnatremias, including formulas calculating the volume of saline needed for a change in [Na]_S are based on it. Not accounting for external losses of sodium, potassium and water during treatment and faulty values for body water inserted in the formulas predicting the change in [Na]_S affect the accuracy of these formulas. Newly described factors potentially affecting the change in [Na]_S during treatment of dysnatremias include the following: (a) exchanges during development or correction of dysnatremias between osmotically inactive sodium stored in tissues and osmotically active sodium in solution in body fluids; (b) chemical binding of part of body water to macromolecules which would decrease the amount of body water available for osmotic exchanges; and (c) genetic influences on the determination of sodium concentration in body fluids. The effects of these newer developments on the methods of treatment of dysnatremias are not well-established and will need extensive studying. Currently, monitoring of serum sodium concentration remains a critical step during treatment of dysnatremias.

The population of elderly individuals is increasing worldwide. With aging, various hormonal and kidney changes occur, both affecting water homeostasis. Aging is a risk factor for chronic kidney disease (CKD) and many features of CKD are reproduced in the aging kidney. Dehydration and hyperosmolarity can be triggered by diminished thirst perception in this population. Elderly with dementia are especially susceptible to abnormalities of their electrolyte and body water homeostasis and should be (re-)assessed for polypharmacy. Hypo- and hypernatremia can be life threatening and should be diagnosed and treated promptly, following current practice guidelines. In severe cases of acute symptomatic hyponatremia, a rapid bolus of 100 to 150 ml of intravenous 3% hypertonic saline is appropriate to avert catastrophic outcomes; for asymptomatic hyponatremia, a very gradual correction is preferred. In summary, the body sodium (Na+) balance is regulated by a complex interplay of environmental and individual factors. In this review, we attempt to provide an overview on this topic, including dehydration, hyponatremia, hypernatremia, age-related kidney changes, water and sodium balance, and age-related changes in the vasopressin and renin-angiotensin-aldosterone system.

Hypernatremia is defined as a serum sodium level above 145 mmol/L. It is a frequently encountered electrolyte disturbance in the hospital setting, with an unappreciated high mortality. Understanding hypernatremia requires a comprehension of body fluid compartments, as well as concepts of the preservation of normal body water balance. The human body maintains a normal osmolality between 280 and 295 mOsm/kg via Arginine Vasopressin (AVP), thirst, and the renal response to AVP; dysfunction of all three of these factors can cause hypernatremia. We review new developments in the pathophysiology of hypernatremia, in addition to the differential diagnosis and management of this important electrolyte disorder.

Hypernatremia (serum sodium concentration >145 mEq/L) is a common electrolyte disorder with increased morbidity and mortality especially in the elderly and critically ill patients. The review presents the main pathogenetic mechanisms of hypernatremia, provides specific directions for the evaluation of patients with increased sodium levels and describes a detailed algorithm for the proper correction of hypernatremia. Furthermore, two representative cases of hypovolemic and hypervolemic hypernatremia are presented along with practical clues for their proper evaluation and treatment. Accurate diagnosis and appropriate treatment is crucial since undercorrection or overcorrection of hypernatremia are both associated with poor patients' prognosis.

The development of many electrolyte disturbances in the ICU can be prevented by attention to the use of intravenous fluids and nutrition. Hyponatremia is a relative contraindication to the use of hypotonic intravenous fluids and hypernatremia calls for the administration of water. Formulae have been devised to guide the therapy of severe hyponatremia and hypernatremia. All formulae regard the patient as a closed system, and none takes into account ongoing fluid losses that are highly variable between patients. Thus, therapy of severe hyponatremia and hypernatremia must be closely monitored with serial electrolyte measurements. The significance of hypocalcemia in the critically ill is controversial. Hypokalemia, hypophosphatemia, and hypomagnesemia should be corrected.

To assess early clinical signs and their prognostic value in elderly patients with hypernatremia.

Prospective, case control study of 150 patients with hypernatremia matched to 300 controls.

Multicenter study including seven short- and long-term geriatric care facilities.

Clinical assessment of hydration status at bedside, such as abnormal skin turgor or dry oral mucosa.

30-day mortality rate and clinical indicators (assessed at the peak of natremia) associated with mortality.

Patients and controls were comparable in terms of drugs and underlying diseases, except for history of dementia, which was more frequent in patients than in controls. Patients were significantly more likely than controls to have low blood pressure, tachycardia, dry oral mucosa, abnormal skin turgor, and recent change of consciousness. Only three clinical findings were found in at least 60% of patients with hypernatremia: orthostatic blood pressure and abnormal subclavicular and forearm skin turgor. The latter two signs were significantly more frequent in patients with hypernatremia. Four other signs (tachycardia, abnormal subclavicular skin turgor, dry oral mucosa, and recent change of consciousness) had a specificity of greater than 79%. Using logistic regression, four signs were significantly and independently associated with hypernatremia: abnormal subclavicular and thigh skin turgor, dry oral mucosa, and recent change of consciousness. The mortality rate was 41.5% and was significantly higher in patients with hypernatremia. The status of consciousness when hypernatremia was diagnosed was the single prognostic indicator associated with mortality (odds ratio=2.3, 95% confidence interval=1.01-5.2).

Most of the classical signs of dehydration are irregularly present in patients with hypernatremia. Caregivers should carefully screen any variations in consciousness, because they may reveal severe hypernatremia.

Burns and deaths due to burns to remain an important public health and social problem in India. Most of the victims, who survive the initial 24h after burns, succumb to infection of the burnt area and its complications. Burns cause devitalization of tissues, leaving extensive raw areas, which usually remain moist due to the outflow of serous exudate. This exposed, moist area along with the dead and devitalized tissue provides the optimum environment favoring colonization and proliferation of numerous microorganisms, which is further enhanced by the depression of the immune response. All these factors, i.e., disruption of the skin barrier, a large cutaneous bacterial load, the possibility of the normal bacterial flora turning into opportunistic pathogens and the severe depression of the immune system, contribute towards sepsis in a burns victim, which usually is life threatening. Despite various advances in infection control measures, early detection of microorganisms and newer, broader spectrum antibiotics, management of burn septicemia still remains a challenge. Pulmonary, cardiac and other complications also contribute to the delayed deaths following severe burn.

To evaluate whether a reset osmostat and salt and water retention may be features of the course of some patients with hyponatremia, we present the long-term course of 6 selected patients. Three patients had spinal cord injury, 3 had marked psychiatric problems, and 3 had alcoholism. Five developed severe hyponatremia superimposed on chronic hyponatremia consequent to a reset osmostat. In 5 patients marked salt and water retention of unclear etiology occurred during therapy on 11 occasions. In 4 of these 11 episodes hypernatremia developed. Knowledge of a patient's past history and the possibility of developing salt and water overload should influence therapy.

From April 1993 to January 2000, 105 patients in the burn intensive care unit (BICU) that developed septicaemia in the course of their treatment were studied retrospectively to investigate as to why only 36 septicaemic patients (34%) developed hypernatremia (serum sodium >150mmol/l). Septicaemic burn patients who developed hypernatremia were found to have a higher incidence of inhalation injury and a larger burn area (TBSA) signifying greater free water losses in the face of increasing fluid requirements. Patients who developed hypernatremia showed a characteristic pattern of septicaemia: early onset, multiple episodes, polymicrobial, need for multiple antibiotics, longer duration and a higher mortality, indicating a more severe degree of sepsis. The level of incapacitation either from the burn itself, mechanical ventilation or from impaired mental status leading to an inadequate free water intake was more in septicaemic patients who developed hypernatremia. Increased urinary free water losses and solute diuresis from hyperglycemia were significant factors in the development of hypernatremia. Patients who were treated with early wound excisions were less prone to develop hypernatremia when compared to those who did not undergo early wound excision. The close association between the onset of hypernatremia and the onset of septicaemia noted in this study suggests the use of hypernatremia as a marker for septicaemia in burn patients. Hypernatremia in a septicaemic burn patient is multi-factorial and a thorough understanding of the underlying factors will help prevent the onset and progress of hypernatremia.