Fluid Therapy

The Management of Circulatory Shock

December 27, 2013 Cardiology, Critical Care, Infectious Diseases, Pharmacology, Pharmacotherapy, Physiology and Pathophysiology, Therapeutics 1 comment , ,

CaduceusShock is the clinical expression of circulatory failure that results in inadequate cellular oxygen utilization. Shock is a common condition in critical care, affecting about one third of patients in the intensive care unit.

The Diagnosis of Circulatory Shock

The fundamental defect in shock is reduced perfusion of vital tissues. Once perfusion declines and O2 delivery to cells is inadequate for aerobic metabolism, cells shift to anaerobic metabolism with increased production of CO2 and accumulation of lactic acid. Cellular function declines, and if shock persists, irreversible cell damage and death occur.

A diagnosis of shock is based on clinical, hemodynamic, and biochemical signs, which can broadly be summarized into three components. See below.

1. Systemic arterial hypotension is usually present, but the magnitude of the hypotension may be only moderate, especially in patients with chronic hypertension. Typically, in adults, the systolic arterial pressure is less than 90 mm Hg or the mean arterial pressure is less than 70 mm Hg, with associated tachycardia. In addition, BP is not always low in the early stages of shock (although hypotension eventually occurs if shock is not reversed). Similarly, not all patients with “low” BP have shock. The degree and consequences of hypotension vary with the adequacy of physiologic compensation and the patient’s underlying diseases. Thus, a modest degree of hypotension that is well tolerated by a young, relatively healthy person might result in severe cerebral, cardiac, or renal dysfunction in an older person with significant arteriosclerosis.

2. There are clinical signs of tissue hypoperfusion, which are apparent through the three “windows” of the body: cutaneous (skin that is cold and clammy, with vasoconstriction and cynaosis, findings that are most evident in low-flow states), renal (urine output of ,0.5 ml per kilogram of body weight per hour), and neurologic (altered mental state, which typically includes obtundation, disorientation, and confusion).

3. Hyperlactatemia is typically present, indicating abnormal cellular oxygen metabolism. The normal blood lactate level is approximately 1 mmol per liter, but the level is increased (>1.5 mmol per liter) in acute circulatory failure.


The Pathophysiology of Circulatory Shock

Once the diagnosis of shock has been made, the causing of circulatory shock must be cleared. Shock results from four potential, and not necessarily exclusive, pathophysiological mechanisms:

1. Hypovolemia (from internal or external fluid loss);

2. Cardiogenic factors (e.g., acute myocardial infarction, end-stage cardiomyopathy, advanced valvular heart disease, myocarditis, or cardiac arrhythmias);

3. Obstruction (e.g., pulmonary embolism, cardiac tamponade, or tension pneumothorax);

4. Distributive factors (e.g., severe sepsis or anaphylaxis from the release of inflammatory mediators).

According to these four potential mechanisms, circulatory shock can be categoried into four subtypes: hypovolemic shock, cardiogenic shock, obstructive shock, and distributive shock. Attention must be paid that these four subtypes are not completely independent, while they have relative interrelationship.

The first three mechanisms are characterized by low cardiac output and, hence, inadequate oxygen transport. Among these three types of circulatory shock, obstructive is seen when there is an obstruction to blood flow to a region of tissue. The last one mechanism is characterized by deficit of circulation in the periphery, with decreased systemic vascular resistance and altered oxygen extraction. Distributive shock is seen when there is inappropriate vasodilation, which leads to changes in blood flow distribution between tissues. Typically, in such cases cardiac output is high, although it may be low as a result of associated myocardial depression. But in other situations, blood pools in venous capacitance beds and cardiac output falls. Again, attention must be paid that these four subtypes are not completely independent, they could turn up in the same patient simultaneously.

Let’s talk more about the pathophysiology of shock.

During shock, both the inflammatory and clotting cascades may be triggered in areas of hypoperfusion. Hypoxic vascular endothelial cells activate WBCs, which bind to the endothelium and release directly damaging substances (eg, reactive O2 species, proteolytic enzymes) and inflammatory mediators (eg, cytokines, leukotrienes, tumor necrosis factor [TNF]). Some of these mediators bind to cell surface receptors and activate nuclear factor kappa B (NFκB), which leads to production of additional cytokines and nitric oxide (NO), a potent vasodilator.

In septic shock, vasodilation of capacitance vessels leads to pooling of blood and hypotension because of “relative” hypovolemia (ie, too much volume to be filled by the existing amount of blood). Attention that circulating blood volume is normal. In some cases, cardiac output (and DO2) is high, but increased blood flow through arteriovenous shunts bypasses capillary beds; this bypass plus uncoupled cellular O2 transport cause cellular hypoperfusion (shown by decreased O2 consumption [normal or increased Svo2]), which means localized vasodilation may shunt blood past the capillary exchange beds, causing focal hypoperfusion despite normal cardiac output and BP. Additionally, excess NO is converted to peroxynitrite, a free radical that damages mitochondria and decreases ATP production. In other situations, blood pools in venous capacitance beds and cardiac output falls (increase in the capacity of the vascular bed preclude adequate venous return).

Blood flow to microvessels including capillaries is reduced even though large-vessel blood flow is preserved in settings of septic shock. Mechanical microvascular obstruction may, at least in part, account for such limiting of substrate delivery. Leukocytes and platelets adhere to the endothelium, and the clotting system is activated with fibrin deposition.

Multiple mediators, along with endothelial cell dysfunction, markedly increase microvascular permeability, allowing fluid and sometimes plasma proteins to escape into the interstitial space. In the GI tract, increased permeability possibly allows translocation of the enteric bacteria from the lumen, potentially leading to sepsis or metastatic infection.

Neutrophil apoptosis may be inhibited, enhancing the release of inflammatory mediators. In other cells, apoptosis may be augmented, increasing cell death and thus worsening organ function.

Figure 1. Initial Assessment of Shock States.

Circulatory Shock

 


The Results of Shock

Compensation:

Initially, when O2 delivery (DO2) is decreased, tissues compensate by extracting a greater percentage of delivered O2. Low arterial pressure triggers an adrenergic response with sympathetic-mediated vasoconstriction and often increased heart rate. Initially, vasoconstriction is selective, shunting blood to the heart and brain and away from the splanchnic circulation. Circulating β-adrenergic amines (epinephrine, norepinephrine) also increase cardiac contractility and trigger release of corticosteroids from the adrenal gland, renin from the kidneys, and glucose from the liver. Increased glucose may overwhelm ailing mitochondria, causing further lactate production.

Reperfusion:

Reperfusion of ischemic cells can cause further injury. As substrate is reintroduced, neutrophil activity may increase, increasing production of damaging superoxide and hydroxyl radicals. After blood flow is restored, inflammatory mediators may be circulated to other organs.

Multiple organ dysfunction syndrome (MODS):

The combination of direct and reperfusion injury may cause MODS—the progressive dysfunction of ≥ 2 organs consequent to life-threatening illness or injury. MODS can follow any type of shock but is most common when infection is involved; organ failure is one of the defining features of septic shock (see Sepsis and Septic Shock). MODS also occurs in > 10% of patients with severe traumatic injury and is the primary cause of death in those surviving >24 h.

Any organ system can be affected, but the most frequent target organ is the lung, in which increased membrane permeability leads to flooding of alveoli and further inflammation. Progressive hypoxia may be increasingly resistant to supplemental O2 therapy. This condition is termed acute lung injury or, if severe, acute respiratory distress syndrome (ARDS—see Acute Hypoxemic Respiratory Failure (AHRF, ARDS)).

The kidneys are injured when renal perfusion is critically reduced, leading to acute tubular necrosis and renal insufficiency manifested by oliguria and progressive rise in serum creatinine.

In the heart, reduced coronary perfusion and increased mediators (including TNF and IL-1) may depress contractility, worsen myocardial compliance, and down-regulate β-receptors. These factors decrease cardiac output, further worsening both myocardial and systemic perfusion and causing a vicious circle often culminating in death. Arrhythmias may occur.

In the GI tract, ileus and submucosal hemorrhage can develop. Liver hypoperfusion can cause focal or extensive hepatocellular necrosis, transaminase and bilirubin elevation, and decreased production of clotting factors.


The Management of Circulatory Shock

Early, for the initial management to the patient who is in shock, adequate hemodynamic support is crucial to prevent worsening organ dysfunction and failure. Resuscitation should be started even while investigation of the cause is ongoing.

Once identified, the cause must be corrected rapidly (e.g., control of bleeding, percutaneous coronary intervention for coronary syndromes, thrombolysis or embolectomy for massive pulmonary embolism, and administration of antibiotics and source control for septic shock).

Some catheters should be inserted for monitoring of vital signs such as arterial blood pressure, blood sampling, and for the infusion of fluids and vasoactive agents and to guide fluid therapy, unless the condition is rapidly reversed.

Therapeutic Goals for Circulatory Shock

The goals of initial management of shock, regardless of cause, is same. The primary goal of resuscitation should be not only to restore blood pressure but also to provide adequate cellular metabolism, for which the correction of arterial hypotension is prerequisite. Generally we should restore the mean systemic arterial pressure to 65 to 70 mm Hg, but the level should be adjusted to restore tissue perfusion, assessed on the basis of mental status, skin appearance, and urine output.

Second, we should maintain adequate cardiac output and oxygen delivery to the tissues, which is essential. Although cardiac output is one of the three principal determinants of oxygen delivery, the optimal cardiac output is difficult to define due to many reasons (e.g., cardiac output needed will vary among patients and in the same patient over time). Other two parameters determining oxygen delivery are vascular integrity and oxygen content (hemoglobin and arterial oxygen saturation [Sao2]) of the blood. Measurements of mixed venous oxygen saturation (Svo2) may be helpful in assessing the adequacy of the balance between oxygen demand and supply. For more information about the predicting significance of Svo2 for adequacy of oxygen delivery please visit http://clinicaltrials.gov/ct2/show/NCT00510835?term=NCT00510835&rank=1 and http://clinicaltrials.gov/ct2/show/NCT00975793?term=nct00975793&rank=1.

In addition, Scvo2 could be the surrogate to Svo2, but it only reflects the oxygen saturation of the venous blood from the upper half of the body. Under normal circumstances, Scvo2 is slightly less than Svo2, but in critically ill patients it is often greater. Generally, during circulatory shock, due to the decrease of Do2, peripheral tissues have to extract more oxygen from blood to maintenance adequate oxygen as much as possible, which results in a decrease in Svo2 or Scvo2. Some studies showed that a treatment algorithm targeting an Scvo2 of at least 70% during the first 6 hours was associated with decreased rates of death.

First, the underlying cause(s) of shock should be corrected. And then there is the VIP rule.

First, ventilate (oxygen administration); second, infuse (fluid resuscitation); and third, pump (administration of vasoactive agent).

Ventilatory Support (V)

The administration of oxygen should be started immediately to increase oxygen delivery and prevent pulmonary hypertension. Pulse oximetry is often unreliable as a result of peripheral vasoconstriction, and precise determination of oxygen requirements will often require blood gas monitoring.

To provide ventilatory support, endotracheal intubation should become the standard of care since other modalities such as mask has a limitation because of the possibility of rapid technical failure due to respiratory and cardiac arrest.

In addition, invasive mechanical ventilation has the benefits of reducing the oxygen demand of respiratory muscles and decreasing intrathoracic pressure.

Fluid Resuscitation (I)

Fluid therapy to improve microvascular blood flow and increase cardiac output is an essential part of the treatment of any form of shock. Even patients with cardiogenic shock may benefit from fluids, since acute edema can result in a decrease in the effective intravascular volume. But, fluid administration should be closely monitored, since too much fluid carries the risk of edema with its unwanted consequences. Almost all circulatory shock states require large-volume IV fluid replacement, as does severe intravascular volume depletion (eg, due to diarrhea or heatstroke). Intravascular volume deficiency is acutely compensated for by vasoconstriction, followed over hours by migration of fluid from the extravascular compartment to the intravascular compartment, maintaining circulating volume at the expense of total body water. However, this compensation is overwhelmed after major losses.

Route and Rate of Fluid Administration

Standard, large (eg, 14- to 16-gauge) peripheral IV catheters are adequate for most fluid resuscitation. With an infusion pump, they typically allow infusion of 1 L of crystalloid in 10 to 15 min and 1 unit of packed RBCs in 20 min. For patients at risk of exsanguination, a large (eg, 8.5 French) central venous catheter provides more rapid infusion rates; a pressure infusion device can infuse 1 unit of packed RBCs in < 5 min.

Patients in shock typically require and tolerate infusion at the maximum rate. Adults are given 1 L of crystalloid (20 mL/kg in children) or, in hemorrhagic shock, 5 to 10 mL/kg of colloid or packed RBCs, and the patient is reassessed. An exception is a patient with cardiogenic shock who typically does not require large volume infusion.

Patients with intravascular volume depletion without shock can receive infusion at a controlled rate, typically 500 mL/h. Children should have their fluid deficit calculated (see Practical Example) and replacement given over 24 h (half in the first 8 h).

End Point and Monitoring

The actual end point of fluid therapy in shock is to optimize tissue perfusion, which however, is not measure directly. The end points include clinical indicators of end-organ perfusion and measurements of preload.

Adequate end-organ perfusion is best indicated by urine output of >0.5 to 1 mL/kg/h. Heart rate, mental status, and capillary refill may be affected by the underlying disease process and are less reliable markers. Because of compensatory vasoconstriction, mean arterial pressure is only a rough guideline; organ hypoperfusion may be present despite apparently normal values.

An elevated arterial blood lactate level reflects hypoperfusion; but levels do not decline for several hours after successful resuscitation. The trend of the base deficit can help indicate whether resuscitation is adequate.

CVP is the mean pressure in the superior vena cava, reflecting right ventricular end-diastolic pressure or preload which may be useful in guiding fluid resuscitation for critical ill patients. A sick or injured patient with a CVP < 3 mm Hg is presumed to be volume depleted and may be given fluids with relative safety.

When the CVP is within the normal range, volume depletion cannot be excluded, and the response to 100- to 200-mL fluid boluses should be assessed; a modest increase in CVP in response to fluid generally indicates hypovolemia. An increase of > 3 to 5 mm Hg in response to a 100-mL fluid bolus suggests limited cardiac reserve. A CVP > 12 to 15 mm Hg casts doubt on hypovolemia as the sole etiology of hypoperfusion, and fluid administration risks fluid overload. Stimulation of the patient and any other change in therapy should be avoided during the test. Fluid test can be repeated as required but must be stopped rapidly in case of non-response in order to avoid fluid overload.

Vasoactive Agents (P)

Vasopressors

If hypotension is severe or if it persists despite fluid administration, the use of vasopressors is indicted. It is acceptable practice to administer a vasopressor temporarily while fluid resuscitation is ongoing, with the aim of discontinuing it, if possible, after hypovolemia has been corrected. Adrenergic agonists are the first-line vasopressors. However, we must be aware of their benefits and harmful effects.

For example, β-adrenergic stimulation can increase blood flow but also increases the risk of myocardial ischemia as a result of increased heart rate and contractility, which limits the use of pure β-adrenergic agents in patients with severe bradycardia. At the other extreme, α-adrenergic stimulation will increase vascular tone and blood pressure but can also decrease cardiac output and impair tissue blood flow, especially in the hepatosplanchnic region, which makes the pure α-adrenergic agents rarely indicated.

Norepinephrine is the first choice of vasopressor since it has predominantly α-adrenergic properties to maintain blood pressure, meanwhile its modest β-adrenergic effects help to maintain cardiac output. Administration generally results in a clinically significant increase in mean arterial pressure, with little change in heart rate or cardiac output. The usually dose is 0.1 to 2.0 μg per kilogram of body weight per minute.

Controlled trials of dopamine have failed to show a protective effect on renal function. Also the routine use of dopamine to improve or maintain renal function is no longer recommended. More, in a recent randomized, controlled, double-blind trial, dopamine had no advantage over norepinephrine as the first-line vasopressor agent; and it induced more arrhythmias and was associated with and increased 28-day rate of death among patients with cardiogenic shock. Administration of dopamine, as compared with norepinephrine, may also be associated with higher rates of death among patients with septic shock. In conclusion, we no longer recommend dopamine for the treatment of patients with shock.

Epinephrine, which is a stronger agent, has predominantly β-adrenergic effects at low dose, with α-adrenergic effects becoming more clinically significant at higher doses. However, epinephrine administration can be associated with an increased rate of arrhythmia and a decrease in splanchnic blood flow and can increase blood lactate level, probably by increasing cellular metabolism. Prospective, randomized studies have not shown any beneficial effects of epinephrine over norepinephrine in septic shock. We reserve epinephrine as a second-line agent for severe cases.

Vasopressin deficiency can develop in patients with very hyperkinetic form of distributive shock, and the administration of low-dose vasopressin may result in substantial increases in arterial pressure. This rationale has been proved by VASST trial, with conclusion that additional low-dose vasopressin to norepinephrine in patients with septic shock was safe and may have been associated with a survival benefit for patients with forms of shock that were not severe and for those who also received glucocorticoids. Vasopressin should not be used at doses higher than 0.04 U per minute and should be administered only in patients with a high level of cardiac output.

Inotropic Agents

We consider dobutamine to be the intropic agent of choice for increasing cardiac output, regardless of whether norepinephrine is also being given. With predominantly β-adrenergic properties, dobutamine is less likely to induce tachycardia than isoproterenol. An initial dose of just a few micrograms per kilogram per minute may substantially increase cardiac output. Intravenous doses in excess of 20 μg per kilogram per minute usually provide little additional benefit.

Phosphodiesterase type III inhibitors, such as milrinone and enximone, combine inotropic and vasodilating properties. They might be useful, such as reinforcing the effects of dobutamine, but phosphodiesterase type III inhibitors may have unacceptable adverse effects in patients with hypotension, and the long half-lives of these agents (4 to 6 hours) prevent minute-to-minute adjustment. Hence, intermittent, short-term infusions of small doses of phosphodiesterase III inhibitors may be preferable to a continuous infusion in shock states.

Levosimendan acts primarily by binding to cardiac troponin C and increasing the calcium sensitivity of myocytes, but it also acts as a vasodilator by opening ATP-sensitive potassium channels in vascular smooth muscle. However, this agent has a half-life of several days, which limits the practicality of its use in acute shock states.

Vasodilators

By reducing ventricular afterload, vasodilating agents may increase cardiac output without increasing myocardial demand for oxygen. However, the major limitation of these drugs is the risk of decreasing arterial pressure to a level that compromises tissue perfusion.

The Management of Hyperglycemic Crises in Diabetes

November 11, 2013 Critical Care, Diabetes, Pharmacotherapy, Therapeutics No comments , , , ,

Diabetic ketoacidosis (DKA) and the hyperosmolar hyperglycemic state (HHS) are the two most serious acute metabolic complications of diabetes. The triad of uncontrolled hyperglycemia, metabolic acidosis (SAG elevated metabolic acidosis), and increased total body ketone concentration characterizes DKA. HHS is characterized by severe hyperglycemia, hyperosmolality, and dehydration in the absence of significant ketoacidosis.

Pathogenesis

DKA

In DKA, hyperglycemia develops as a result of three processes: increased gluconeogenesis, accelerated glycogenolysis, and imaired glucose utilization by peripheral tissues.

The mechanisms of these three processes include: reduced effective insulin concentrations and increased concentrations of counterregulatory hormones (catecholamines, cortisol, glucagon, and growth hormone) lead to hyperglycemia and ketosis.

The combination of insulin deficiency and increased counterregulatory hormones in DKA lead to the release of free fatty acids into the circulation from adipose tissue (lipolysis) and to unrestrained hepatic fatty acid oxidation in the liver to ketone bodies (β-hydroxybutyrate and acetoacetate), with resulting ketonemia and metabolic acidosis.

HHS

The pathogenesis of HHS is not as well understood as that of DKA, but a greater degree of dehydration (due to osmotic diuresis) and differences in insulin availability distinguish it from DKA. Although relative insulin deficiency is clearly present in HHS, endogenous insulin secretion (reflected by C-peptide levels) appears to be greater than in DKA, where it is negligible. Insulin levels in HHS are inadequate to facilitate glucose utilization by insulin-sensitive tissues but adequate to prevent lipolysis and subsequent ketogenesis.

Figure 1. Pathogenesis of DKA and HHS

Precipitating Factors

The most common precipitating factor in the developmemt of DKA and HHS is infection. Other precipitating factors include discontinuation of or inadequate insulin therapy, pancreatitis, myocardial infarction, cerebrovascular accident, and drugs.

However, an increasing number of DKA cases without precipitating cause have been reported in patients with diabetes.

On admission, leukocytosis with cell counts in the 10,000-15,000 mm3 range is the rule in DKA and may not be indicative of an infectious process. However, leukocytosis with cell counts >25,000 mm3 may designate infection and require further evaluation.

Diagnosis

The key diagnostic feature in DKA is the elevation in circulating total blood ketone concentration and hyperglycemia. If available, measurement of β-hydroxybutyrate may be useful for diagnosis. For hyperglycemia, however, a wide range of plasma glucose can be present on admission.

While HHS is characterized by severe hyperglycemia, hyperosmolality, and dehydration in the absence of significant ketoacidosis. Studies on serum osmolality and mental alteration have established a positive linear relationship between osmolality and mental obtundation. The occurrence of stupor or coma in a diabetic patient in the absence of definitive elevation of effective osmolality (≥320 mOsm/kg) demands immediate consideration of other causes of mental status change.

PS: The effective osmolality can be calculated as: [sodium ion (mEq/L) × 2 + glucose (mg/dL)/18]. For example, a given serum sodium ion concentration of 100 mEq/L, with a serum glucose concentration of 750 mg/dL, the effective osmolality should be [100 × 2 + 750/18] = 241.67 mOsm/kg. Note that the BUN/urea concentration is not taken into account becaue it is freely permeable and its accumulation dose not induce major changes in intracellular volume or osmotic gradient across the cell membrane.

Diagnostic Criteria for DKA and HHS

Treatment

Fluid and Electrolyte Correction

Successful treatment of DKA and HHS requires correction of dehydration, hyperglycemia, and electrolyte imbalances; identification of comorbid precipitating events; and above all, frequent patient monitoring. Generally, the treatment strategies include fluid therapy (necessary), insulin therapy (necessary), potassium correction (necessary), pH correction (if necessary), and phosphate correction (if necessary).

Initial fluid therapy for both DKA and HHS is fluid replacement with 0.9% NaCl infused at a rate of 15-20 ml · kg body wt-1 · h-1 or  1-1.5 l during the first hour. Thereafter if the corrected serum sodium is low, 0.9% NaCl should be administered at a rate of 250-500 ml/h. Conversely, if the corrected serum after the fluid replacement of the initial first hour is normal or elevated, 0.45% NaCl infused at a rate of 250-500 ml/h is the strategy. Subsequent choice for fluid replacement depends on hemodynamics, the state of hydration, serum electrolyte levels, and urinary output.

Once the plasma glucose is ~ 200 mg/dL (DKA) or ~ 300 mg/dL (HHS), the fluid replacement should be changed to 5% dextrose with 0.45% NaCl at the drip rate of 150-250 ml/hr.

Despite total-body potassium depletion, mild-to-moderate hyperkalemia is common in patients with hyperglycemic crises. Insuilin therapy, correction of acidosis (alkali replacement enhance the risk of increased potassium waste), and volume expansion decrease serum potassium concentration. To prevent hypokalemia, potassium replacement is initiated after serum levels fall below the upper level of normal for the particular laboratory (5.0-5.2 mEq/L). The treatment goal of potassium replacement is to maintain srum potassium levels within the normal range of 4-5 mEq/L. Generally, 20-30 mEq potassium in each liter of infusion fluid is sufficient to get this goal. Rarely, DKA patients may present with significant hypokalemia. In such cases, potassium replacement should begin with fluid therapy (note that in such cases insulin therapy should be delayed until serum potassium restores to >3.3 mEq/Ll).

Despite whole-body phosphate deficits in DKA, serum phosphate is often normal or increased at presentation. Phosphate concentration decreases with inslulin therapy. However, prospective randomized studies have failed to show any beneficial effect of phosphate replacement on the clinical outcome in DKA, and overzealous phosphate therapy can cause severe hypocalcemia. But, to avoid potential cardiac and skeletal muscle weakness and respiratory depression due to hypophosphatemia, careful phosphate replacement may sometimes be indicated in patients with cardiac dysfunction and in those with serum phosphate concentration <1.0 mg/dL. When needed, 20-30 mEq/L potassium phosphate can be added to replacement fluids. For HHS, no studies are available on the use of phosphate.

The maximal rate of phosphate replacement generally regarded as safe to treat severe hypophosphatemia is 4.5 mmol/h.

Insulin Therapy

Low-dose regular insulin by intravenous infusion have demonstrated it effectiveness and benefit in the treatment of both DKA and HHS. Regular insulin should be given to patients with DKA or HHS on admission, but, for patients with significant hypokalemia on admission, insulin treatment should be delayed until patassium concentration is restored to >3.3 mEq/L. Regular insulin should be administered intravenously at a continuous dose of 0.1 U/kg/hr, with a prior IV bolus dose of 0.1 U/kg. If serum glucose dose not fall by at leaset 10% in the first hour, we should give 0.14 U/kg as IV bolus, then continue previous Rx.

Once the plasma glucose is ~ 200 mg/dL (DKA) or ~ 300 mg/dL (HHS), the rate of intravenously continuous regular insulin should be decreased to 0.02-0.05 U/kg/hr. Thereafter, the rate of insulin administration or the concentration of dextrose may need to be adjusted to maintain glucose values between 150 and 200 mg/dL in DKA or 250 and 300 mg/dL in HHS until they are resolved.

Transition to subcutaneous insulin. Once DKA or HHS is resolved, subcutaneous insulin theray can be started and continuous intravenous insulin should be allow a overlap of 1-2 h before discontinuation due to prevention recurrence of hyperglycemia or ketoacidosis during the transition period from IV insulin to SC insulin. Patients with known diabetes may be given insulin at the dosage they were receiving before the onset of DKA so long as it was controlling glucose properly. In insulin-naïve patients, a multidose insulin regimen should be started at a dose of 0.5-0.8 units · kg-1 · day-1.

Acid-Base Disorders

Prospective randomized study failed to show either beneficial or deleterious changes in morbidity or mortality with bicarbonate therapy in DKA patients with an admission arterial pH between 6.9 and 7.1. Nine small studies in a total of 434 patients with diabetic ketoacidosis (217 treated with bicarbonate and 178 without alkali therapy) support the notion that bicarbonate therapy for DKA offers no advantage in improving cardiac or neurologic functions or in the rate of recovery of hyperglycemia and ketoacidosis. However, due to the reason that severe acidosis may lead to a numerous adverse vascular effects, it is recommended that adult patients with a pH <6.9 should receive 100 mmol sodium bicarbonate in 400mml sterile water (an isotonic solution) with 20 mEq KCl (due to that alkali therapy enhance the risk of increased potassium wasting) administered at a rate of 200 ml/h for 2 hours until the venous pH is >7.0. If the pH is still <7.0 after this is infused, it is recommended repeating infusion every 2 h unitl pH reaches >7.0.

Recovery criteria

Criteria for resolution of ketoacidosis include a blood glucose <200 mg/dL and two of the following criteria: a serum bicarbonate level ≥15 mEq/L, a venous pH >7.3, and a calculated anion gap ≤12 mEq/L (DKA belongs to elevated anion gap metabolic acidosis).

Criteria for resolution of HHS is associated with normal osmolality and regain of normal mental status.