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Hyperglycemic crisis and hyponatremia

Hyperglycemic crisis and hyponatremia

Vascular Blood pressure monitoring devices changes caused by elevated hylonatremia levels of cytokines hyponagremia chemokines Blood pressure monitoring devices to inflammatory status associated with DKA were proposed Gut health and allergies the authors of the PECARN study as the main mechanism for the development of cerebral edema. Normal ageing, especially after the sixth decade, is associated with a decline in renin production. Arney GK, Pearson E, Sutherland AB. TI: conceptualization. This has been shown to decrease the incidence of DKA at the onset of diabetes 30 ,

Hyperglycemic crisis and hyponatremia -

However, in diabetic patients hypernatremia and hypokalemia in the absence of hyponatremia or hyperosmolality are rarely associated with ODS. The mechanism by which these electrolyte disorders may cause ODS in the diabetic state is not yet known[ 25 , 26 ].

In fact, there is evidence that hyperglycemic patients with hypertonicity are symptomatic only if hypernatremia is present[ 5 , 27 ]. On the contrary, neurological symptoms may be absent in the context of severe gradually developing hyperglycemia[ 27 , 28 ]. This could be attributed to the capacity of the brain tissue to restore intracellular water by accumulating electrolytes and the so-called idiogenic osmoles.

Furthermore, the brain cells are relatively permeable to glucose even in the absence of insulin[ 28 , 29 ]. Therefore, hyperglycemia by itself does not create severe hypertonicity in central nervous system CNS [ 28 ]. On the other hand, hypernatremia induces severe cellular dehydration in CNS cells.

This state is associated with a rather slow compensatory accumulation of brain osmolar content[ 28 ]. The development of hypernatremia is associated with endocrine dysfunction. There is some evidence in animals and man that hypernatremia and hyperosmolarity are associated with impairment of both insulin-mediated glucose metabolism and glucagon-dependent glucose release[ 30 - 33 ].

Thus, hypernatremia and hyperosmolarity should be considered as contributing factors to the occurrence of hyperglycemia in critically ill patients[ 34 ]. Moreover, hypernatremia is implicated in the profound inhibition of gonadotrophin release in postmenopausal diabetic women with HHS.

Although the underlying mechanisms remain unknown, it appears that hypernatremia induces a decrease in gonadotrophin-releasing hormone expression in GT neurons[ 35 ].

Rhabdomyolysis, though uncommon, has been described in the diabetic state[ 36 ]. It appears that high serum sodium and glucose levels represent the most important determinants for the occurrence of this complication[ 37 ]. The increased secretion of epinephrine due to insulin-induced hypoglycemia may also play a contributory role[ 40 ].

The major setting in which insulin administration leads to hypokalemia is during the treatment of severe hyperglycemia.

It is thought that hyperosmolality and insulin deficiency are primarily responsible for the relative rise in the serum potassium concentration in this setting.

As mentioned, hyperglycemia increases serum osmolality resulting in movement of water out of cells. In addition, since diabetics are frequently on diuretics, diuretic-associated hypokalemia as well as hypomagnesemia and hypophosphatemia should be taken into account in this setting.

Hypokalemia is associated with impaired insulin secretion and decreased peripheral glucose utilization resulting in carbohydrate intolerance and hyperglycemia[ 47 ]. The incidence of hyperkalemia is higher in diabetic patients than in the general population[ 48 , 49 ].

Examples of shift hyperkalemia in DM include acidosis for each 0. These include angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, renin inhibitors, beta blockers and potassium-sparing diuretics. This syndrome is characterized by mild to moderate renal insufficiency and patients typically present with asymptomatic hyperkalemia.

The development of overt hyperkalemia is most common in patients with other risk factors that further impair the efficiency of potassium excretion, such as renal insufficiency, volume depletion, or the use of medications that interfere with potassium handling see above.

Of note, dapagliflozin a SGLT2 inhibitor may be protective from the development of hyperkalemia in patients with moderate renal impairment due to osmotic diuresis[ 17 ].

However, the administration of SGLT2 inhibitors in hypovolemic patients may cause elevated serum creatinine levels and decreases in glomerular filtration rate due to deterioration of intravascular volume contraction. Indeed, worsening renal function and hyperkalemia may occur in patients on canagliflozin, particularly those predisposed to hyperkalemia due to impaired renal function, medications or other medical conditions[ 51 ].

Hyporeninemic hypoaldosteronism is more frequently observed in diabetic and elderly patients as well as in those with chronic renal impairment. Normal ageing, especially after the sixth decade, is associated with a decline in renin production.

Clinicians must also be alert that hyperkalemia in patients with type 1 DM may be due to concurrent adrenal insufficiency in the setting of autoimmune polyglandular syndrome[ 55 ]. Hypomagnesemia is a frequent electrolyte disorder in diabetic patients[ 56 ].

Osmotic diuresis accompanied by inappropriate magnesiuria was the prominent underlying mechanism of hypomagnesemia in these diabetic patients[ 57 ]. Except for glucosuria, several other possible explanations for hypomagnesemia in DM have been reported.

These include poor dietary intake, glomerular hyperfiltration, altered insulin metabolism, diuretic administration and recurrent metabolic acidosis[ 56 ]. The increased secretion of epinephrine due to insulin-induced hypoglycemia may also play a role.

It should be noted that hypoalbuminemia is associated with spurious hypomagnesemia. The most clinically significant consequences of hypomagnesemia are ascribed to alterations in the function of excitable membranes in nerve, muscle, and the cardiac conducting system.

Hypomagnesemia has been implicated in various long-term complications of DM, such as hypertension, increased carotid wall thickness, coronary artery disease, dyslipidemia, diabetic retinopathy, neuropathy, ischemic stroke, and foot ulcerations[ 56 ].

Hypomagnesemia has also been linked to diabetic nephropathy from microalbuminuria to advanced renal disease [ 64 - 66 ]. It has been proposed that hypomagnesemia is a predictor of end-stage renal disease in patients with diabetic nephropathy[ 66 ]. In addition, magnesium deficit is associated with carbohydrate intolerance and insulin resistance, thus inducing or worsening existing DM[ 67 , 68 ].

Patients with DM have an increased risk for development of acute renal failure due to volume depletion, sepsis, rhabdomyolysis and drugs e. In this setting severe hyperphosphatemia may occur when phosphorus cannot be excreted by the malfunctioning kidney either with or without increased cell catabolism, thus resulting in hypocalcemia.

Advanced chronic renal insufficiency may be associated with hypocalcemia due to accompanying hyperphosphatemia and low levels of vitamin D.

Patients with nephrotic syndrome may exhibit hypocalcemia, even if the glomerular filtration rate is well preserved. This is attributed to the loss of hydroxyvitamin D 3 and its binding protein in the urine. Hypomagnesemia is another potential cause of hypocalcemia in diabetics.

Vitamin D deficiency and furosemide administration may also play a role in the occurrence of hypocalcemia[ 70 ]. There is evidence that diabetic patients are relatively hypoparathyroid[ 71 ].

In fact, a mild shift downwards in the set-point for PTH secretion in patients with insulin-dependent DM as well as a diminished parathyroid gland responsiveness to hypocalcemia in uremic diabetic patients have been reported[ 72 , 73 ].

Hypoalbuminemia is associated with pseudohypocalcemia defined as a reduction of total serum calcium concentration in the presence of normal ionized serum calcium levels.

In hypoalbuminemic states, one of the commonly used formulas to correct total calcium levels is by adding 0. Given that the accuracy of this method is poor particularly among critically ill and geriatric patients , the biologically active ionized calcium concentration should be measured when possible[ 1 , 74 ].

Both values are about three-fold higher than that anticipated in the general population[ 75 ]. Hyperparathyroidism is related to long-term insulin resistance and relative insulin insufficiency, leading to overt DM or deterioration of glycemic control of established DM[ 75 , 76 ].

It is thought that an elevated intracellular free calcium concentration by decreasing normal insulin-stimulated glucose transport increases the requirement for insulin, resulting in hyperparathyroidism-mediated insulin resistance[ 75 ].

Diabetic patients should be evaluated for hypercalcemia given that untreated hyperparathyroidism is linked to hypertension[ 75 , 77 ]. The detection of high serum calcium levels in a patient with type 1 DM should raise the suspicion that autoimmune hyperparathyroidism associated with anti-calcium-sensing receptor autoantibodies may be present[ 78 ].

Dehydration might represent the most important causative factor for the occurrence of hypercalcemia in this case. A decreased bone formation due to metabolic acidosis and an increased bone mineral dissolution and resorption due to severe insulin deficiency and metabolic acidosis may also play a role[ 80 ].

Hyperglycemia-mediated inhibition of bone mineralization, insulin growth factor-1 deficiency, hypophosphatemia and immobilization are also included among the potential contributory factors of hypercalcemia in DKA[ 79 , 81 , 82 ]. Also, diabetic patients on thiazide diuretics are more prone to exhibit hypercalcemia.

Diabetic patients have underlying conditions that predispose to the development of hypophosphatemia. These include primary hyperthyroidism, vitamin D deficiency, malabsorption, and the use of diuretics thiazides and furosemide [ 83 ]. It is known that increased insulin levels promote the transport of both glucose and phosphate into the skeletal muscle and liver cells.

However, in normal subjects the administration of insulin leads only to a slight decrement of serum phosphate levels.

The risk of severe hypophosphatemia is increased in cases of underlying phosphate depletion[ 62 , 84 ]. Decompensated DM with ketoacidosisis associated with excessive phosphate loss due to osmotic diuresis.

Despite phosphate depletion, the serum phosphate concentration at presentation is usually normal or even high because both insulin deficiency and metabolic acidosis cause a shift of phosphate out of cells[ 85 ]. Administration of insulin and fluids, and correction of ketoacidosis may reveal phosphate deficiency and cause a sharp decrease in plasma phosphate concentration due to intracellular shift[ 83 ].

In a study of 69 patient with DKA, the incidence of hyperphosphatemia was The mean serum phosphate concentration fell from 9. The routine administration of phosphate during treatment of DKA and HHS is not recommended since randomized trials failed to show any clinical benefit from phosphate administration[ 42 , 83 , 86 , 87 ].

What is more, correction of hypophosphatemia may have adverse effects, such as hypocalcemia and hypomagnesemia[ 42 , 83 , 88 ]. Careful phosphate replacement is required in patients with severe hypophosphatemia of less than 1. Electrolyte abnormalities are common in diabetic patients and may be associated with increased morbidity and mortality.

These disturbances are particularly common in decompensated DM, in the elderly as well as in the presence of renal impairment. Patients with DM may receive complex drug regimens some of which may be associated with electrolyte disorders. Discontinuation of these medications, when possible, as well as strict control of glycemia are of paramount importance to prevent electrolyte abnormalities in diabetic patients.

The successful management of these disorders can best be accomplished by elucidating the underlying pathophysiologic mechanisms.

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Liamis G, Liberopoulos E, Barkas F, Elisaf M. Diabetes mellitus and electrolyte disorders. World J Clin Cases ; 2 10 : [PMID: DOI: Corresponding Author of This Article. George Liamis, MD, PhD, Assistant Professor of Internal Medicine, Department of Internal Medicine, School of Medicine, University of Ioannina, Stavrou Niarchou Avenue, Ioannina, Greece.

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Copyright © Baishideng Publishing Group Inc. All rights reserved. World J Clin Cases. Oct 16, ; 2 10 : Published online Oct 16, doi: George Liamis , Evangelos Liberopoulos , Fotios Barkas , Moses Elisaf. George Liamis, Evangelos Liberopoulos, Fotios Barkas, Moses Elisaf, Department of Internal Medicine, School of Medicine, University of Ioannina, Stavrou Niarchou Avenue, Ioannina, Greece.

Author contributions : Liamis G, Liberopoulos E, Barkas F and Elisaf M contributed to this paper. Correspondence to : George Liamis, MD, PhD, Assistant Professor of Internal Medicine, Department of Internal Medicine, School of Medicine, University of Ioannina, Stavrou Niarchou Avenue, Ioannina, Greece.

Received: December 25, Revised: July 24, Accepted: September 23, Published online: October 16, Key Words: Glucose , Osmotic diuresis , Hyponatremia , Hyperkalemia , Hypomagnesemia. Citation: Liamis G, Liberopoulos E, Barkas F, Elisaf M. Table 1 Principal causes of electrolyte disorders in diabetic patients.

Sodium disorders 1 Hyponatremia Pseudohyponatremia marked hyperlipidemia Hyperglycemia hypertonicity -induced movement of water out of the cells dilutional hyponatremia Osmotic diuresis-induced hypovolemic hyponatremia Drug-induced hyponatremia: hypoglycemic agents chlorpropamide, tolbutamide, insulin or other medications e.

Liamis G , Milionis HJ, Elisaf M. A review of drug-induced hypocalcemia. J Bone Miner Metab. Liamis G , Kalogirou M, Saugos V, Elisaf M. Therapeutic approach in patients with dysnatraemias. Nephrol Dial Transplant. Liamis G , Rodenburg EM, Hofman A, Zietse R, Stricker BH, Hoorn EJ.

Electrolyte disorders in community subjects: prevalence and risk factors. Am J Med. In hyperglycemia, hypertonicity results from solute glucose gain and loss of water in excess of sodium plus potassium through osmotic diuresis.

Patients with stage 5 chronic kidney disease CKD and hyperglycemia have minimal or no osmotic diuresis; patients with preserved renal function and diabetic ketoacidosis DKA or hyperosmolar hyperglycemic state HHS have often large osmotic diuresis.

Hypertonicity from glucose gain is reversed with normalization of serum glucose [Glu] ; hypertonicity due to osmotic diuresis requires infusion of hypotonic solutions. Prediction of the serum sodium after [Glu] normalization the corrected [Na] estimates the part of hypertonicity caused by osmotic diuresis.

Theoretical methods calculating the corrected [Na] and clinical reports allowing its calculation were reviewed. Corrected [Na] was computed separately in reports of DKA, HHS and hyperglycemia in CKD stage 5.

The theoretical prediction of [Na] increase by 1. Mean corrected [Na] was In patients with preserved renal function, mean corrected [Na] was within the eunatremic range However, in DKA corrected [Na] was in the hypernatremic range in several reports and rose during treatment with adverse neurological consequences in other reports.

The corrected [Na], computed as [Na] increase by 1. However, the corrected [Na] may change during treatment because of ongoing fluid losses and should be monitored during treatment. Imbalances that develop in patients with severe hyperglycemia and preserved renal function include extracellular gain of solute glucose and deficits of water, sodium, potassium, and other ions resulting from glycosuria.

These imbalances, which cause extracellular and intracellular volume deficits, changes in the concentrations of key serum ions, and hypertonicity, constitute major treatment targets 1. This report addresses the management of hyperglycemic hypertonicity.

Hypertonicity is seen routinely in severe hyperglycemia 1 — 5 , causes potentially life-threatening neurological manifestations 6 , 7 , and represents an important component of the treatment 1 , 2.

In experimental studies, tonicity of a fluid can be measured directly by rapid photographic recordings of changes in the volume of cells, usually red blood cells, suspended in the fluid of interest 8.

In clinical practice, tonicity is evaluated by surrogate biochemical measurements, including serum osmolality and sodium concentration [Na] 8. In the absence of solutes with extracellular distribution other than sodium salts e.

In hyperglycemia, glucose accumulation in the extracellular compartment contributes to tonicity Ton , which is expressed by the formula 9 :.

Formula 1 provides accurate information on tonicity in hyperglycemia, except when high levels of plasma solids lower plasma water content e. However, this formula should not be used to guide the composition of the replacement solution. Hypertonicity in hyperglycemia results from gain of extracellular solute glucose and osmotic diuresis 2 , 5.

Correction of hyperglycemia results in extracellular solute loss 11 and decrease in tonicity The tonicity of the replacement solutions should correct the component of hypertonicity resulting from osmotic diuresis 2 , 5.

The tonicity of replacement solutions should be based on the projected value of [Na] after normalization of [Glu] 2 , 6 , 8.

The corrected [Na] is calculated using a predicted value of the change in [Na] Δ[Na] that results directly from the required change in [Glu] Δ[Glu] and is applied in the evaluation of the component of hyperglycemic hypertonicity that results from osmotic diuresis.

The value of the coefficient used to calculate the corrected [Na] is a point of dispute This perspective article reviews the sources of various estimates of the coefficient for the corrected [Na] and clinical studies providing evidence for the appropriate coefficient.

Then, it computes the corrected [Na] in reports of various categories of hyperglycemic crises, and based on these last reports, provides a frame for the clinical application of the corrected [Na].

This section addresses the modeling of the effect on [Na] from change in [Glu] not accompanied by changes in external balance of body water or monovalent cations, i. Applying this principle and considering that the amounts of sodium in the extracellular compartment and effective solute in the intracellular compartment remain constant during development of hyperglycemia, Katz calculated that [Na] changes by 1.

Goldberg proposed using the Katz coefficient to predict the value of [Na] after correction of hyperglycemia Subsequently, Al-Kudsi et al. provided the following formula to calculate this corrected [Na] 16 :. The Al-Kudsi formula predicts the value of [Na] after correction of [Glu] to 5.

The corrected [Na] at any desired final value of [Glu] can be calculated by substituting this desired [Glu] for 5. The Katz report created new insights into the change in tonicity produced by glucose gain. As a matter of fact, the increase in total body effective solute baseline solute plus glucose gain causes equal rises in both intracellular and extracellular fluid tonicities.

The glucose-induced gain in extracellular solute causes water exit from the cells 19 to bring about hypertonic hyponatremia Katz's coefficient computes tonicity increase ΔTon of 2.

Several guidelines for managing hyperglycemia 21 — 24 and other reports 25 — 29 have adopted the Katz coefficient for calculating the corrected [Na].

Alternate guidelines for treating hyperglycemia 30 , 31 and hyponatremia 32 , and various other reports 33 — 35 advocate other coefficients. The variation of these coefficients resulted from both theoretical calculations and clinical studies.

This section addresses the theoretical calculations. Note: In the text and Table 1 , the subscripts 1 and 2 denote respectively baseline euglycemia and hyperglycemia. Table 1. Tonicity-related and body fluid variables in a closed system of hyperglycemia. Total glucose gain during development of hyperglycemia is the product of ECFV 1 and [Glu] A.

Table 1 shows general formulas used by Katz for computation of tonicity-related and volume-related parameters. Total intracellular and extracellular solutes in this Table are the total solutes determining tonicity Solutes with body water distribution, e.

For all examples the baseline values were 5. For the same volume ratio α 1 , the same degree of hyperglycemia results in the same hypertonicity values regardless of the size of extracellular volume.

ECFV 1 values are 16 and 32 L and glucose loads are 1, 16 × and 3, 32 × mmol, respectively. For comparable degrees of hyperglycemia, hypertonicity is higher in hypervolemia and lower in hypovolemia compared to euvolemia. Euvolemic values are shown in the previous example.

b Differences in sodium concentration between plasma and interstitial compartment due to Gibbs-Donnan equilibrium between these two sub-compartments of the ECFV 17 ; c Exit of potassium from cells and changes in intracellular solute during development of hyperglycemia Finally, both definition and methods of measurement of ECFV encounter difficulties 43 , The difference between these corrected [Na] values has minimal clinical significance.

Hyperglycemia in patients with advanced renal failure allows study of the theoretical predictions in a closed system because it can be treated with insulin infusion and with no or minimal changes in the external balance of sodium, potassium and water 45 , Mean ± standard deviation values at presentation and end of observation, respectively, were as follows: [Glu] Another study analyzed the relationship between [Glu] and [Na] by linear regression in patients on dialysis who had at least three measurements of [Glu] and [Na] and a difference between the lowest and highest value of [Glu] exceeding Hyperglycemic episodes in patients with preserved renal function represent a different entity.

The next section addresses these patients. Severe hyperglycemia in patients with preserved renal function causes deficits in body sodium, potassium, and water, which are the key determinants of [Na] at euglycemia Balance abnormalities specific to hyperglycemia develop from water gain in the gastrointestinal tract and losses of water, sodium and potassium from the urinary tract.

Thirst is caused by hyperglycemic hypertonicity and hypovolemia from urinary losses. Hyperglycemic hypertonicity caused thirst in animal experiments Polydipsia is a prominent clinical manifestation of hyperglycemic crises 7 , 52 , Water intake from hyperglycemia led to hyponatremia after correction with insulin of approximately one-third of the hyperglycemic episodes in dialysis patients A major rise in tonicity in hyperglycemia results from osmotic diuresis, in which water loss is relatively greater than loss of sodium plus potassium 5 , 17 , Thus, in hyperglycemic crises occurring in patients with preserved renal function, who represent an open system, [Na] receives influences from three pathophysiologic processes: rise in [Glu] and water gain cause [Na] decreases, while osmotic diuresis causes [Na] increase.

In these patients, quantitating the isolated effect of glucose gain is imperative because this effect is predictable with a reasonable degree of certainty, as shown in the previous section, and more importantly, it will disappear with correction of hyperglycemia without requiring additional measures.

Prediction of the quantitative effects of water intake and particularly of osmotic diuresis, which is the dominant effect on tonicity in severe hyperglycemic episodes 2 , 3 , is difficult because the magnitude of these processes varies greatly 2 , The effects of osmotic diuresis on [Na] require correction by fluid infusion.

One report calculated the effects of osmotic diuresis on tonicity-related values in a hypothetical subject with extreme hyperglycemia [Glu] of This finding suggests that the corrected [Na] by the Al-Kudsi formula provides a reasonable prediction of the part of hypertonicity that is due to osmotic diuresis.

Accounting for changes in external balances of water, sodium, and potassium during development and treatment of hyperglycemia is necessary for any evaluation of the corrected [Na] in patients with renal function.

There is a paucity of studies in this area. These findings were used in the development of several guidelines 30 — Assuming baseline values of 5. According to these calculations, tonicity, after rising appropriately with [Glu] rising from 5. The guidelines for hyperglycemic crises address diabetic ketoacidosis DKA and hyperosmolar hyperglycemic state HHS 1 , 21 — The diagnostic features of DKA include low arterial blood pH and serum bicarbonate, presence of ketone bodies in serum and urine, a wide serum anion gap, and variable tonicity 1.

However, euglycemic DKA has become more frequent after the introduction of sodium glucose cotransporter 2 SGLT-2 inhibitors in the treatment of diabetes mellitus Hypertonicity may cause coma in hyperglycemic syndromes 60 , At equal levels of hyperglycemic hypertonicity, elevated [Na] indicates severe water deficit 64 , The corrected [Na] illustrates the difference in water deficit between high [Na] and high [Glu] in this case.

Table 2 shows presenting values for [Glu], [Na], tonicity, and corrected [Na] in reports of DKA 66 — , HHS 3 , 9 , 13 , 75 — 78 , , , , — , and hyperglycemia in chronic kidney disease CKD stage V 12 , 16 , 47 — 49 , , , — , which was included in Table 2 as the control group because it causes limited or no water and electrolyte losses through osmotic diuresis.

All but three of the cases in this last group were on maintenance dialysis. To show the range of the tonicity-related values, Table 2 includes studies as well as case reports. Reports of combined DKA and HHS were included in the DKA part of the table.

Studies reporting median, instead of mean, tonicity-related values were not included in this table. The reason for including these cases was explained above.

Table 2. Presenting serum glucose, sodium, tonicity, and corrected sodium levels in reported hyperglycemic crises. In Table 2 , there exists considerable overlap of [Glu], [Na] tonicity, and corrected [Na] ranges in the three categories of hyperglycemia.

DKA combined with HHS occurred in many instances. The term Diabetic Hyperosmolar Ketoacidosis DHKA was proposed for DKA combined with HHS Patients on dialysis who presented with hyperglycemia and elevated corrected [Na] have usually lost hypotonic fluids through hemodialysis , or peritoneal dialysis — , , with high glucose concentration in the dialysate.

The second important finding in Table 2 is in the mean corrected [Na] values. Thus, although many patients have water deficits in excess of sodium and potassium deficits, an equal or even larger number of patients do not have excessive water deficits at presentation with DKA.

This finding has important consequences in the choice of the tonicity of replacement solutions. Mean corrected [Na] was in the eunatremic range in hyperglycemia of patients with CKD stage 5. Preventing cerebral edema is a key concern during treatment of hyperglycemic crises.

Tonicity-related parameters have received attention in the studies of the pathogenesis of this complication. These values do not differ substantially from the mean values of all DKA cases in Table 2. However, factors related to tonicity statistically associated with brain edema during treatment of DKA include decrease in tonicity, large early infusion volumes, very high [Glu] at presentation, rapid decline in [Glu], very low [Na], and administration of large doses of insulin , , The change in corrected [Na] during treatment of DKA was the best discriminator for the development of severe coma in one study Deterioration of neurological manifestations associated with substantial rises of the corrected [Na] has been reported during treatment of both DKA 2 , and HHS , , Other reported factors associated with cerebral edema in DKA include the degree of acidosis 96 , , , , high levels of blood urea at presentation , , and vasogenic factors One study found no effect of the rate of replacement fluid infusion The PECARN study found no significant differences in neurological manifestations during and following treatment of DKA between using 0.

Vascular endothelial changes caused by elevated blood levels of cytokines and chemokines secondary to inflammatory status associated with DKA were proposed by the authors of the PECARN study as the main mechanism for the development of cerebral edema. High value of corrected [Na] at presentation with DKA is associated with increased incidence and severity of acute kidney injury AKI , Weighed mean values at presentation with DKA and AKI were AKI occurs frequently in HHS 3 , , , , , , Attention to tonicity plays a role in prevention of severe neurological manifestations during treatment of hyperglycemic emergencies.

Decrease in tonicity from extracellular solute loss leads to osmotic entry of fluid into cells and could contribute to the development of cerebral edema For this reason, one report proposed a very slow decrease in tonicity during the early stages of treatment The optimal rate of decline in tonicity, however, has not been clarified.

The change in tonicity due exclusively to correction of hyperglycemia has two components, a fall in [Glu] and a rise in [Na]. Guidelines propose hourly rates of 2. The corrected [Na] predicts the relation between effective body solute and total body water after decrease of [Glu] to its desired level 2 , 17 and should be used as a guide for the composition of replacement solutions in the same fashion as actual [Na] values are used to guide fluid management of dysnatremias 7 , — Evidence presented earlier supports the use of the Al-Kudsi formula for calculation of the corrected [Na].

Two limitations of the corrected [Na] should be addressed during treatment: First, the corrected [Na] using the Al-Kudsi formula is not accurate in some conditions, mainly in advanced extracellular volume disturbances. Second, and more importantly, the corrected [Na] reflects the relation between effective body solute and body water at the moment of blood sampling 2 , 17 , Correction of the extracellular volume deficit improves renal function and in the face of persistent hyperglycemia leads to large volume osmotic diuresis, which causes further water deficit and rises in the corrected [Na] 2.

We propose the following scheme for use of the corrected [Na] during treatment of hyperglycemic crises: The initial measurement of serum values should include osmolality in addition to basic metabolic panel.

In the absence of an exogenous solute e. In the second case, falsely low [Na] values are reported when this measurement is performed in an autoanalyzer that requires dilution of the samples measured If there is a large osmol gap, [Na] should be measured again in an apparatus that does not require dilution of the measured specimen, e.

The tonicity of replacement solutions should be based on repeated calculations of the corrected [Na]. If the corrected [Na] at presentation is in the eunatremic range, infusion of isotonic saline should be started at a rate dictated by clinical manifestations of hypovolemia.

Prevention of either decline or rise in the corrected [Na] is critical. Patients with corrected [Na] values within the normal range of [Na], like the average patient with DKA Table 2 , do not have relatively larger deficit of water compared to monovalent cations.

In these patients, use of isotonic solutions as initial treatment of DKA and slow decline of [Glu], as proposed in the guidelines 1 , leads to rapid correction of severe extracellular volume deficits and prevents sharp changes in the corrected [Na]. In subjects with initial corrected [Na] in the eunatremic range, tonicity should decline at a low rate.

Maintenance of the corrected [Na] at the same level and decrease in [Glu] at the rate proposed in the guidelines 2. In the rare instance of low presenting corrected [Na], or for treatment of cerebral edema, hypertonic saline infusion may be used During treatment, urine volume should be monitored and [Glu], [Na], serum potassium concentration, and other relevant parameters should be measured frequently, initially every 1—2 h.

The corrected [Na] should be calculated after each measurement of [Glu] and [Na] and should guide changes in the tonicity of the infusate. Development of large osmotic diuresis may lead to increases in the corrected [Na] and the need for hypotonic infusions later in the course of treatment.

A corrected [Na] in the hypernatremic range at presentation with hyperglycemia indicates excessive water deficit that must be corrected. Initially, infusion of isotonic fluids will correct rapidly volume deficits and will also decrease the level of hypertonicity.

However, the subsequent development of large volume osmotic diuresis may lead to rise in the corrected [Na].

Monitoring urine volume, frequent measurement of the relevant serum biochemical values, and repeated calculation of the corrected [Na] after each measurement of [Glu] and [Na] is imperative.

The corrected [Na] should not rise further; however, deciding whether it should remain at the same level at least early during the decrease in [Glu] or it should decrease at a slow rate e. Infusion of hypotonic solutions will eventually be needed regardless of whether the early phase of treatment aims at maintaining or decreasing the corrected [Na].

Addition of potassium salts to the infused saline should be guided by repeated measurements of the serum potassium concentration.

In deciding the concentration of sodium in the replacement solutions, it is important to take into account the concentration of potassium salts in the infusate 2.

The corrected [Na] calculated by the Al-Kudsi formula should guide the tonicity of replacement solutions. This use should be tempered by the knowledge that rarely encountered extreme volume disturbances can cause [Na] changes substantially different from those predicted by the corrected [Na] and, more importantly, that the corrected [Na] can vary greatly during treatment depending on changes in the external balances of water, sodium and potassium.

For these reasons, frequent measurements of [Glu] and [Na], repeated calculation of the corrected [Na] after each measurement, and changes in the tonicity of replacement solutions based on the corrected [Na] are critical steps in the management of tonicity issues in hyperglycemia.

Publicly available datasets were analyzed in this study. This data came from tables of publications cited in the text. TI: conceptualization. TI, KG, GB, CA, and AT: literature review. TI, GB, SL, and AT: methodology. SL, CA, and AT: visualization.

TI and AT: writing-original draft preparation. KG, GB, SL, EA, and CA: writing-review and editing. All authors contributed to the article and approved the submitted version. GB was supported by a Burrows Wellcome Fund Career Award for Medical Scientists and NIH grant RO1 DK The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The reviewer DM declared a past co-authorship with several of the authors TI, AT, and CA to the handling editor. The authors acknowledge Dialysis Clinic Inc. for supporting this work by covering publication expenses [DCI C].

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Hypertonicity: Clinical entities, manifestations and treatment. World J Nephrol. Rohrscheib M, Rondon-Berrios H, Argyropoulos C, Glew RH, Murata GH, Tzamaloukas AH. Indices of serum tonicity in clinical practice. Am J Med Sci. McCurdy DK. Hyperosmolar hyperglycemic nonketotic diabetic coma.

Med Clin North Am. Goldman MH, Kashani M. Spurious hyponatremia in diabetic ketoacidosis with massive lipid elevations. PubMed Abstract Google Scholar. Tomkins AM, Dormandy TL. Osmolal pattern during recovery from diabetic coma. Tzamaloukas AH, Levinstone AR, Gardner KD Jr.

Hyperglycemia in advanced renal failure: sodium and water metabolism. Baldrighi M, Sainaghi PP, Bellan M, Bartoli E, Castello LM. Hyperglycemic hyperosmolar state: a pragmatic approach to properly manage sodium derangements. Curr Diabetes Rev. Katz MA.

Hyperglycemia-induced hyponatremia: calculation of the expected serum sodium depression. Goldberg M. Al-Kudsi RR, Daugirdas JT, Ing TS, Kheirbek AO, Popli JE, Hano JE, et al. Extreme hyperglycemia in dialysis patients. Clin Nephrol. Tzamaloukas AH, Khitan Z, Glew RH, Roumelioti M-A, Rondon-Berrios H, Elisaf MS, et al.

Serum sodium concentration and tonicity in hyperglycemic crises: major influences and treatment implications. J Am Heart Assoc. Welt LG. Clinical Disorders of Hydration and Acid-Base Balance.

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Kitabchi AE, Umpierrez GE, Murphy MB, Barrett EJ, Kreisberg RA, Malone JI, et al. Management of hyperglycemic crises in patients with diabetes. Chiasson JL, Aris-Jilwan N, Bélanger R, Bertrand S, Beauregard H, Ekoé JM, et al. Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state.

Diabetes Canada Clinical Practice Guidelines Expert Committee, Goguen J, Gilbert J. Hyperglycemic emergencies in adults. Can J Diabetes. Wolfsdorf JI, Glaser N, Agus M, Fritsch M, Hanas R, Rewers A, et al. ISPAD Clinical Practice Consensus Guidelines Diabetic ketoacidosis and the hyperglycemic hyperosmolar state.

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Tzamaloukas AH, Ing TS, Siamopoulos KC, Raj DS, Elisaf MS, Rohrscheib M, et al. Pathophysiology and management of fluid and electrolyte disturbances in patients on chronic dialysis with severe hyperglycemia.

Semin Dial. Sun Y, Roumelioti ME, Ganta K, Glew RH, Gibb J, Vigil D, et al. Dialysis-associated hyperglycemia: manifestations and treatment. Tzamaloukas AH, Rohrscheib M, Ing TS, Siamopoulos KC, Elisaf MF, Spalding CT.

Serum tonicity, extracellular volume and clinical manifestations in symptomatic dialysis-associated hyperglycemia treated only with insulin. Int J Artif Organs. Tzamaloukas AH, Ing TS, Siamopoulos KC, Rohrscheib M, Elisaf MS, Raj DSC, et al. Body fluid abnormalities in severe hyperglycemia in patients on chronic dialysis: review of published reports.

J Diabetes Complications. Penne EL, Thijssen S, Raimann JG, Levin NW, Kotanko P. Add or change institution. Download PDF Full Text Cite This Citation Popli S , Leehey DJ , Daugirdas JT, et al.

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Diabetic Blood pressure monitoring devices frequently develop a constellation of electrolyte disorders. These disturbances are particularly common hyoonatremia decompensated diabetics, especially in the context of diabetic ketoacidosis or nonketotic hyperglycemic hyperosmolar syndrome. Hypetglycemic patients Hyperglycemic crisis and hyponatremia markedly potassium- magnesium- and phosphate-depleted. Hyprglycemic mellitus DM is linked to both hypo- and hyper-natremia reflecting the coexistence of hyperglycemia-related mechanisms, which tend to change serum sodium to opposite directions. The most important causal factor of chronic hyperkalemia in diabetic individuals is the syndrome of hyporeninemic hypoaldosteronism. Impaired renal function, potassium-sparing drugs, hypertonicity and insulin deficiency are also involved in the development of hyperkalemia. This article provides an overview of the electrolyte disturbances occurring in DM and describes the underlying mechanisms.

Hyperglycemic crisis and hyponatremia -

See Kitabchi et al. Phosphate concentration decreases with insulin therapy. Prospective randomized studies have failed to show any beneficial effect of phosphate replacement on the clinical outcome in DKA 32 , and overzealous phosphate therapy can cause severe hypocalcemia with no evidence of tetany 17 , No studies are available on the use of phosphate in the treatment of HHS.

Continuous monitoring using a flowsheet Fig. Commonly, patients recovering from DKA develop hyperchloremia caused by the use of excessive saline for fluid and electrolyte replacement and transient non-anion gap metabolic acidosis as chloride from intravenous fluids replaces ketoanions lost as sodium and potassium salts during osmotic diuresis.

These biochemical abnormalities are transient and are not clinically significant except in cases of acute renal failure or extreme oliguria. Cerebral edema is a rare but frequently fatal complication of DKA, occurring in 0.

It is most common in children with newly diagnosed diabetes, but it has been reported in children with known diabetes and in young people in their twenties 25 , Fatal cases of cerebral edema have also been reported with HHS.

Clinically, cerebral edema is characterized by a deterioration in the level of consciousness, with lethargy, decrease in arousal, and headache. Neurological deterioration may be rapid, with seizures, incontinence, pupillary changes, bradycardia, and respiratory arrest. These symptoms progress as brain stem herniation occurs.

The progression may be so rapid that papilledema is not found. Although the mechanism of cerebral edema is not known, it likely results from osmotically driven movement of water into the central nervous system when plasma osmolality declines too rapidly with the treatment of DKA or HHS.

There is a lack of information on the morbidity associated with cerebral edema in adult patients; therefore, any recommendations for adult patients are clinical judgements, rather than scientific evidence. Hypoxemia and, rarely, noncardiogenic pulmonary edema may complicate the treatment of DKA.

Hypoxemia is attributed to a reduction in colloid osmotic pressure that results in increased lung water content and decreased lung compliance.

Patients with DKA who have a widened alveolo-arteriolar oxygen gradient noted on initial blood gas measurement or with pulmonary rales on physical examination appear to be at higher risk for the development of pulmonary edema. Many cases of DKA and HHS can be prevented by better access to medical care, proper education, and effective communication with a health care provider during an intercurrent illness.

The observation that stopping insulin for economic reasons is a common precipitant of DKA in urban African-Americans 35 , 36 is disturbing and underscores the need for our health care delivery systems to address this problem, which is costly and clinically serious.

Sick-day management should be reviewed periodically with all patients. It should include specific information on 1 when to contact the health care provider, 2 blood glucose goals and the use of supplemental short-acting insulin during illness, 3 means to suppress fever and treat infection, and 4 initiation of an easily digestible liquid diet containing carbohydrates and salt.

Most importantly, the patient should be advised to never discontinue insulin and to seek professional advice early in the course of the illness.

Adequate supervision and help from staff or family may prevent many of the admissions for HHS due to dehydration among elderly individuals who are unable to recognize or treat this evolving condition.

Better education of care givers as well as patients regarding signs and symptoms of new-onset diabetes; conditions, procedures, and medications that worsen diabetes control; and the use of glucose monitoring could potentially decrease the incidence and severity of HHS. The annual incidence rate for DKA from population-based studies ranges from 4.

Significant resources are spent on the cost of hospitalization. Many of these hospitalizations could be avoided by devoting adequate resources to apply the measures described above.

Because repeated admissions for DKA are estimated to drain approximately one of every two health care dollars spent on adult patients with type 1 diabetes, resources need to be redirected toward prevention by funding better access to care and educational programs tailored to individual needs, including ethnic and personal health care beliefs.

In addition, resources should be directed toward the education of primary care providers and school personnel so that they can identify signs and symptoms of uncontrolled diabetes and new-onset diabetes can be diagnosed at an earlier time.

This has been shown to decrease the incidence of DKA at the onset of diabetes 30 , Protocol for the management of adult patients with DKA. Normal ranges vary by lab; check local lab normal ranges for all electrolytes.

Obtain chest X-ray and cultures as needed. IM, intramuscular; IV, intravenous; SC subcutaneous. Protocol for the management of adult patients with HHS. This protocol is for patients admitted with mental status change or severe dehydration who require admission to an intensive care unit.

For less severe cases, see text for management guidelines. IV, intravenous; SC subcutaneous. From Kitabchi et al. See text for details. Data are from Ennis et al. The highest ranking A is assigned when there is supportive evidence from well-conducted, generalizable, randomized controlled trials that are adequately powered, including evidence from a meta-analysis that incorporated quality ratings in the analysis.

An intermediate ranking B is given to supportive evidence from well-conducted cohort studies, registries, or case-control studies. A lower rank C is assigned to evidence from uncontrolled or poorly controlled studies or when there is conflicting evidence with the weight of the evidence supporting the recommendation.

Expert consensus E is indicated, as appropriate. For a more detailed description of this grading system, refer to Diabetes Care 24 Suppl. The recommendations in this paper are based on the evidence reviewed in the following publication: Management of hyperglycemic crises in patients with diabetes Technical Review.

Diabetes Care —, The initial draft of this position statement was prepared by Abbas E. Kitabchi, PhD, MD; Guillermo E.

Umpierrez, MD; Mary Beth Murphy, RN, MS, CDE, MBA; Eugene J. Barrett, MD, PhD; Robert A. Kreisberg, MD; John I. Malone, MD; and Barry M. Wall, MD.

The paper was peer-reviewed, modified, and approved by the Professional Practice Committee and the Executive Committee, October Revised Sign In or Create an Account. Search Dropdown Menu. header search search input Search input auto suggest. filter your search All Content All Journals Diabetes Care.

Advanced Search. User Tools Dropdown. Sign In. Skip Nav Destination Close navigation menu Article navigation. Previous Article. Article Navigation. Position Statements January 01 Hyperglycemic Crises in Diabetes American Diabetes Association American Diabetes Association.

This Site. Google Scholar. Get Permissions. toolbar search Search Dropdown Menu. toolbar search search input Search input auto suggest. Figure 1—. View large Download slide. Figure 2—. Figure 3—. Figure 4—. Table 1— Diagnostic criteria for DKA and HHS. View Large. Table 3— Summary of major recommendations.

Therefore, to avoid the occurrence of cerebral edema, follow the recommendations in the position statement regarding a gradual correction of glucose and osmolality as well as the judicious use of isotonic or hypotonic saline, depending on serum sodium and the hemodynamic status of the patient.

McGarry JD, Woeltje KF, Kuwajima M, Foster DW: Regulation of ketogenesis and the renaissance of carnitine palmitoyl transferase. Diabetes Metab Rev. DeFronzo RA, Matsuda M, Barrett E: Diabetic ketoacidosis: a combined metabolic-nephrologic approach to therapy.

Diabetes Rev. Atchley DW, Loeb RF, Richards DW, Benedict EM, Driscoll ME: A detailed study of electrolyte balances following withdrawal and reestablishment of insulin therapy. J Clin Invest. Halperin ML, Cheema-Dhadli S: Renal and hepatic aspects of ketoacidosis: a quantitative analysis based on energy turnover.

Malone ML, Gennis V, Goodwin JS: Characteristics of diabetic ketoacidosis in older versus younger adults. J Am Geriatr Soc. Matz R: Hyperosmolar nonacidotic diabetes HNAD. In Diabetes Mellitus: Theory and Practice. Morris LE, Kitabchi AE: Coma in the diabetic.

In Diabetes Mellitus: Problems in Management. Kreisberg RA: Diabetic ketoacidosis: new concepts and trends in pathogenesis and treatment. Ann Int Med. Klekamp J, Churchwell KB: Diabetic ketoacidosis in children: initial clinical assessment and treatment.

Pediatric Annals. Glaser NS, Kupperman N, Yee CK, Schwartz DL, Styne DM: Variation in the management of pediatric diabetic ketoacidosis by specialty training. Arch Pediatr Adolescent Med. Kitabchi AE, Umpierrez GE, Murphy MB, Barrett EJ, Kreisberg RA, Malone JI, Wall BM: Management of hyperglycemic crises in patients with diabetes mellitus Technical Review.

Diabetes Care. Beigelman PM: Severe diabetic ketoacidosis diabetic coma : episodes in patients: experience of three years. Polonsky WH, Anderson BJ, Lohrer PA, Aponte JE, Jacobson AM, Cole CF: Insulin omission in women with IDDM.

Kitabchi AE, Fisher JN, Murphy MB, Rumbak MJ: Diabetic ketoacidosis and the hyperglycemic hyperosmolar nonketotic state. Ennis ED, Stahl EJVB, Kreisberg RA: The hyperosmolar hyperglycemic syndrome.

Marshall SM, Walker M, Alberti KGMM: Diabetic ketoacidosis and hyperglycaemic non-ketotic coma. In International Textbook of Diabetes Mellitus. Carroll P, Matz R: Uncontrolled diabetes mellitus in adults: experience in treating diabetic ketoacidosis and hyperosmolar coma with low-dose insulin and uniform treatment regimen.

Ennis ED, Stahl EJ, Kreisberg RA: Diabetic ketoacidosis. Hillman K: Fluid resuscitation in diabetic emergencies: a reappraisal. Intensive Care Med. Fein IA, Rackow EC, Sprung CL, Grodman R: Relation of colloid osmotic pressure to arterial hypoxemia and cerebral edema during crystalloid volume loading of patients with diabetic ketoacidosis.

Ann Intern Med. Matz R: Hypothermia in diabetic acidosis. Kitabchi AE, Sacks HS, Young RT, Morris L: Diabetic ketoacidosis: reappraisal of therapeutic approach.

Ann Rev Med. Mahoney CP, Vleck BW, DelAguila M: Risk factors for developing brain herniation during diabetic ketoacidosis.

Pediatr Neurology. Finberg L: Why do patients with diabetic ketoacidosis have cerebral swelling, and why does treatment sometimes make it worse? Pediatr Adolescent Med. Duck SC, Wyatt DT: Factors associated with brain herniation in the treatment of diabetic ketoacidosis.

J Pediatr. Then, it computes the corrected [Na] in reports of various categories of hyperglycemic crises, and based on these last reports, provides a frame for the clinical application of the corrected [Na]. This section addresses the modeling of the effect on [Na] from change in [Glu] not accompanied by changes in external balance of body water or monovalent cations, i.

Applying this principle and considering that the amounts of sodium in the extracellular compartment and effective solute in the intracellular compartment remain constant during development of hyperglycemia, Katz calculated that [Na] changes by 1.

Goldberg proposed using the Katz coefficient to predict the value of [Na] after correction of hyperglycemia Subsequently, Al-Kudsi et al. provided the following formula to calculate this corrected [Na] 16 :. The Al-Kudsi formula predicts the value of [Na] after correction of [Glu] to 5.

The corrected [Na] at any desired final value of [Glu] can be calculated by substituting this desired [Glu] for 5.

The Katz report created new insights into the change in tonicity produced by glucose gain. As a matter of fact, the increase in total body effective solute baseline solute plus glucose gain causes equal rises in both intracellular and extracellular fluid tonicities. The glucose-induced gain in extracellular solute causes water exit from the cells 19 to bring about hypertonic hyponatremia Katz's coefficient computes tonicity increase ΔTon of 2.

Several guidelines for managing hyperglycemia 21 — 24 and other reports 25 — 29 have adopted the Katz coefficient for calculating the corrected [Na]. Alternate guidelines for treating hyperglycemia 30 , 31 and hyponatremia 32 , and various other reports 33 — 35 advocate other coefficients.

The variation of these coefficients resulted from both theoretical calculations and clinical studies. This section addresses the theoretical calculations. Note: In the text and Table 1 , the subscripts 1 and 2 denote respectively baseline euglycemia and hyperglycemia.

Table 1. Tonicity-related and body fluid variables in a closed system of hyperglycemia. Total glucose gain during development of hyperglycemia is the product of ECFV 1 and [Glu] A. Table 1 shows general formulas used by Katz for computation of tonicity-related and volume-related parameters. Total intracellular and extracellular solutes in this Table are the total solutes determining tonicity Solutes with body water distribution, e.

For all examples the baseline values were 5. For the same volume ratio α 1 , the same degree of hyperglycemia results in the same hypertonicity values regardless of the size of extracellular volume. ECFV 1 values are 16 and 32 L and glucose loads are 1, 16 × and 3, 32 × mmol, respectively.

For comparable degrees of hyperglycemia, hypertonicity is higher in hypervolemia and lower in hypovolemia compared to euvolemia. Euvolemic values are shown in the previous example.

b Differences in sodium concentration between plasma and interstitial compartment due to Gibbs-Donnan equilibrium between these two sub-compartments of the ECFV 17 ; c Exit of potassium from cells and changes in intracellular solute during development of hyperglycemia Finally, both definition and methods of measurement of ECFV encounter difficulties 43 , The difference between these corrected [Na] values has minimal clinical significance.

Hyperglycemia in patients with advanced renal failure allows study of the theoretical predictions in a closed system because it can be treated with insulin infusion and with no or minimal changes in the external balance of sodium, potassium and water 45 , Mean ± standard deviation values at presentation and end of observation, respectively, were as follows: [Glu] Another study analyzed the relationship between [Glu] and [Na] by linear regression in patients on dialysis who had at least three measurements of [Glu] and [Na] and a difference between the lowest and highest value of [Glu] exceeding Hyperglycemic episodes in patients with preserved renal function represent a different entity.

The next section addresses these patients. Severe hyperglycemia in patients with preserved renal function causes deficits in body sodium, potassium, and water, which are the key determinants of [Na] at euglycemia Balance abnormalities specific to hyperglycemia develop from water gain in the gastrointestinal tract and losses of water, sodium and potassium from the urinary tract.

Thirst is caused by hyperglycemic hypertonicity and hypovolemia from urinary losses. Hyperglycemic hypertonicity caused thirst in animal experiments Polydipsia is a prominent clinical manifestation of hyperglycemic crises 7 , 52 , Water intake from hyperglycemia led to hyponatremia after correction with insulin of approximately one-third of the hyperglycemic episodes in dialysis patients A major rise in tonicity in hyperglycemia results from osmotic diuresis, in which water loss is relatively greater than loss of sodium plus potassium 5 , 17 , Thus, in hyperglycemic crises occurring in patients with preserved renal function, who represent an open system, [Na] receives influences from three pathophysiologic processes: rise in [Glu] and water gain cause [Na] decreases, while osmotic diuresis causes [Na] increase.

In these patients, quantitating the isolated effect of glucose gain is imperative because this effect is predictable with a reasonable degree of certainty, as shown in the previous section, and more importantly, it will disappear with correction of hyperglycemia without requiring additional measures.

Prediction of the quantitative effects of water intake and particularly of osmotic diuresis, which is the dominant effect on tonicity in severe hyperglycemic episodes 2 , 3 , is difficult because the magnitude of these processes varies greatly 2 , The effects of osmotic diuresis on [Na] require correction by fluid infusion.

One report calculated the effects of osmotic diuresis on tonicity-related values in a hypothetical subject with extreme hyperglycemia [Glu] of This finding suggests that the corrected [Na] by the Al-Kudsi formula provides a reasonable prediction of the part of hypertonicity that is due to osmotic diuresis.

Accounting for changes in external balances of water, sodium, and potassium during development and treatment of hyperglycemia is necessary for any evaluation of the corrected [Na] in patients with renal function.

There is a paucity of studies in this area. These findings were used in the development of several guidelines 30 — Assuming baseline values of 5. According to these calculations, tonicity, after rising appropriately with [Glu] rising from 5.

The guidelines for hyperglycemic crises address diabetic ketoacidosis DKA and hyperosmolar hyperglycemic state HHS 1 , 21 — The diagnostic features of DKA include low arterial blood pH and serum bicarbonate, presence of ketone bodies in serum and urine, a wide serum anion gap, and variable tonicity 1.

However, euglycemic DKA has become more frequent after the introduction of sodium glucose cotransporter 2 SGLT-2 inhibitors in the treatment of diabetes mellitus Hypertonicity may cause coma in hyperglycemic syndromes 60 , At equal levels of hyperglycemic hypertonicity, elevated [Na] indicates severe water deficit 64 , The corrected [Na] illustrates the difference in water deficit between high [Na] and high [Glu] in this case.

Table 2 shows presenting values for [Glu], [Na], tonicity, and corrected [Na] in reports of DKA 66 — , HHS 3 , 9 , 13 , 75 — 78 , , , , — , and hyperglycemia in chronic kidney disease CKD stage V 12 , 16 , 47 — 49 , , , — , which was included in Table 2 as the control group because it causes limited or no water and electrolyte losses through osmotic diuresis.

All but three of the cases in this last group were on maintenance dialysis. To show the range of the tonicity-related values, Table 2 includes studies as well as case reports. Reports of combined DKA and HHS were included in the DKA part of the table.

Studies reporting median, instead of mean, tonicity-related values were not included in this table. The reason for including these cases was explained above.

Table 2. Presenting serum glucose, sodium, tonicity, and corrected sodium levels in reported hyperglycemic crises. In Table 2 , there exists considerable overlap of [Glu], [Na] tonicity, and corrected [Na] ranges in the three categories of hyperglycemia.

DKA combined with HHS occurred in many instances. The term Diabetic Hyperosmolar Ketoacidosis DHKA was proposed for DKA combined with HHS Patients on dialysis who presented with hyperglycemia and elevated corrected [Na] have usually lost hypotonic fluids through hemodialysis , or peritoneal dialysis — , , with high glucose concentration in the dialysate.

The second important finding in Table 2 is in the mean corrected [Na] values. Thus, although many patients have water deficits in excess of sodium and potassium deficits, an equal or even larger number of patients do not have excessive water deficits at presentation with DKA.

This finding has important consequences in the choice of the tonicity of replacement solutions. Mean corrected [Na] was in the eunatremic range in hyperglycemia of patients with CKD stage 5. Preventing cerebral edema is a key concern during treatment of hyperglycemic crises.

Tonicity-related parameters have received attention in the studies of the pathogenesis of this complication. These values do not differ substantially from the mean values of all DKA cases in Table 2.

However, factors related to tonicity statistically associated with brain edema during treatment of DKA include decrease in tonicity, large early infusion volumes, very high [Glu] at presentation, rapid decline in [Glu], very low [Na], and administration of large doses of insulin , , The change in corrected [Na] during treatment of DKA was the best discriminator for the development of severe coma in one study Deterioration of neurological manifestations associated with substantial rises of the corrected [Na] has been reported during treatment of both DKA 2 , and HHS , , Other reported factors associated with cerebral edema in DKA include the degree of acidosis 96 , , , , high levels of blood urea at presentation , , and vasogenic factors One study found no effect of the rate of replacement fluid infusion The PECARN study found no significant differences in neurological manifestations during and following treatment of DKA between using 0.

Vascular endothelial changes caused by elevated blood levels of cytokines and chemokines secondary to inflammatory status associated with DKA were proposed by the authors of the PECARN study as the main mechanism for the development of cerebral edema.

High value of corrected [Na] at presentation with DKA is associated with increased incidence and severity of acute kidney injury AKI , Weighed mean values at presentation with DKA and AKI were AKI occurs frequently in HHS 3 , , , , , , Attention to tonicity plays a role in prevention of severe neurological manifestations during treatment of hyperglycemic emergencies.

Decrease in tonicity from extracellular solute loss leads to osmotic entry of fluid into cells and could contribute to the development of cerebral edema For this reason, one report proposed a very slow decrease in tonicity during the early stages of treatment The optimal rate of decline in tonicity, however, has not been clarified.

The change in tonicity due exclusively to correction of hyperglycemia has two components, a fall in [Glu] and a rise in [Na]. Guidelines propose hourly rates of 2. The corrected [Na] predicts the relation between effective body solute and total body water after decrease of [Glu] to its desired level 2 , 17 and should be used as a guide for the composition of replacement solutions in the same fashion as actual [Na] values are used to guide fluid management of dysnatremias 7 , — Evidence presented earlier supports the use of the Al-Kudsi formula for calculation of the corrected [Na].

Two limitations of the corrected [Na] should be addressed during treatment: First, the corrected [Na] using the Al-Kudsi formula is not accurate in some conditions, mainly in advanced extracellular volume disturbances. Second, and more importantly, the corrected [Na] reflects the relation between effective body solute and body water at the moment of blood sampling 2 , 17 , Correction of the extracellular volume deficit improves renal function and in the face of persistent hyperglycemia leads to large volume osmotic diuresis, which causes further water deficit and rises in the corrected [Na] 2.

We propose the following scheme for use of the corrected [Na] during treatment of hyperglycemic crises: The initial measurement of serum values should include osmolality in addition to basic metabolic panel.

In the absence of an exogenous solute e. In the second case, falsely low [Na] values are reported when this measurement is performed in an autoanalyzer that requires dilution of the samples measured If there is a large osmol gap, [Na] should be measured again in an apparatus that does not require dilution of the measured specimen, e.

The tonicity of replacement solutions should be based on repeated calculations of the corrected [Na]. If the corrected [Na] at presentation is in the eunatremic range, infusion of isotonic saline should be started at a rate dictated by clinical manifestations of hypovolemia.

Prevention of either decline or rise in the corrected [Na] is critical. Patients with corrected [Na] values within the normal range of [Na], like the average patient with DKA Table 2 , do not have relatively larger deficit of water compared to monovalent cations.

In these patients, use of isotonic solutions as initial treatment of DKA and slow decline of [Glu], as proposed in the guidelines 1 , leads to rapid correction of severe extracellular volume deficits and prevents sharp changes in the corrected [Na].

In subjects with initial corrected [Na] in the eunatremic range, tonicity should decline at a low rate. Maintenance of the corrected [Na] at the same level and decrease in [Glu] at the rate proposed in the guidelines 2. In the rare instance of low presenting corrected [Na], or for treatment of cerebral edema, hypertonic saline infusion may be used During treatment, urine volume should be monitored and [Glu], [Na], serum potassium concentration, and other relevant parameters should be measured frequently, initially every 1—2 h.

The corrected [Na] should be calculated after each measurement of [Glu] and [Na] and should guide changes in the tonicity of the infusate. Development of large osmotic diuresis may lead to increases in the corrected [Na] and the need for hypotonic infusions later in the course of treatment.

A corrected [Na] in the hypernatremic range at presentation with hyperglycemia indicates excessive water deficit that must be corrected. Initially, infusion of isotonic fluids will correct rapidly volume deficits and will also decrease the level of hypertonicity.

However, the subsequent development of large volume osmotic diuresis may lead to rise in the corrected [Na]. Monitoring urine volume, frequent measurement of the relevant serum biochemical values, and repeated calculation of the corrected [Na] after each measurement of [Glu] and [Na] is imperative.

The corrected [Na] should not rise further; however, deciding whether it should remain at the same level at least early during the decrease in [Glu] or it should decrease at a slow rate e. Infusion of hypotonic solutions will eventually be needed regardless of whether the early phase of treatment aims at maintaining or decreasing the corrected [Na].

Addition of potassium salts to the infused saline should be guided by repeated measurements of the serum potassium concentration. In deciding the concentration of sodium in the replacement solutions, it is important to take into account the concentration of potassium salts in the infusate 2.

The corrected [Na] calculated by the Al-Kudsi formula should guide the tonicity of replacement solutions. This use should be tempered by the knowledge that rarely encountered extreme volume disturbances can cause [Na] changes substantially different from those predicted by the corrected [Na] and, more importantly, that the corrected [Na] can vary greatly during treatment depending on changes in the external balances of water, sodium and potassium.

For these reasons, frequent measurements of [Glu] and [Na], repeated calculation of the corrected [Na] after each measurement, and changes in the tonicity of replacement solutions based on the corrected [Na] are critical steps in the management of tonicity issues in hyperglycemia.

Publicly available datasets were analyzed in this study. This data came from tables of publications cited in the text. TI: conceptualization. TI, KG, GB, CA, and AT: literature review.

TI, GB, SL, and AT: methodology. SL, CA, and AT: visualization. TI and AT: writing-original draft preparation. KG, GB, SL, EA, and CA: writing-review and editing.

All authors contributed to the article and approved the submitted version. GB was supported by a Burrows Wellcome Fund Career Award for Medical Scientists and NIH grant RO1 DK The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The reviewer DM declared a past co-authorship with several of the authors TI, AT, and CA to the handling editor. The authors acknowledge Dialysis Clinic Inc. for supporting this work by covering publication expenses [DCI C].

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Hyperglycemic crisis and hyponatremia Body mass index Departments of Hyperglycemif, Veterans Administration Hospital, Hines, Ill, Cigarette smoke Loyola Hyponatremka Stritch School Blood pressure monitoring devices Medicine, Maywood, Ane. As opposed to most of Hyerglycemic previously described patients with hyperglycemic, nonketotic, hyperosmolar coma, our patients were hyponatremic. The lack of symptoms in our patients may be related to the absence of cerebral cellular dehydration. Aggressive treatment of hyperglycemia in such patients is unnecessary. Attention to the serum sodium level as well as to the serum glucose concentration will allow recognition of this clinical entity. Hyperglycemic crisis and hyponatremia

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