Hyperchloremic Acidosis is a common problem. It is usually an iatrogenic problem. Unfortunately, the majority of doctors who cause a patient to have Hyperchloremic Acidosis (HCA) are either unaware of the problem or ambivalent to it. For the most part, HCA is caused by the intravenous administration of isotonic saline solution (NS – “normal saline – NaCl 0.9%). This problem has been known about for more than 100 years and led Alexis Hartmann, a pediatrician from St Louis, to construct a balanced intravenous fluids, that he called “Lactated Ringers” solution. Ironically, in clinical practice, HCA is induced as part of the local hospital “protocol” for management of Diabetic Ketoacidosis. Inevitably, as the ketones fall, the Chloride rises, and the acidosis persists.
HCA is the only cause of “normal” anion gap metabolic acidosis and is almost always caused, . In the tutorial I explain that HCA is caused by a reduction in the Na-Cl strong ion difference (SID). The acidosis associated with NaCl 0.9% is more complex that merely a rise in plasma Chloride. Other serum electrolytes, Albumin and Hemoglobin are diluted – and this has an alkalinizing effect. Other resuscitation fluids have different impacts on acid base. Hyperchloremia is also a feature of Renal Tubular Acidosis (RTA), various other nephropathies, the administration of acetazolamide and other drugs, and following surgical transplantation of the ureters into the small bowel, If renal function is normal, and the Chloride level is lower than 125mmol/L, then the patient’s kidneys will resolve the problem over 36 to 48 hours. If the Chloride is very high, acidosis will persist, particularly in patients with poor renal function, and Sodium Bicarbonate infusions may be warranted.
This tutorial looks at the twin problems of Alcohol related and Starvation Ketoacidosis. These diagnoses are frequently missed by clinicians because 1. they attribute the metabolic acidosis to another cause e.g. lactate or acute kidney injury or 2. they do not routinely measure blood ketones. It is my view that, in any patient presenting with a plasma bicarbonate below 20mmol or mEq/L or a base deficit of -5 or greater, it is mandatory to measure blood ketones (beta-hydroxybutyrate).
I present two cases, the first is a patient who is admitted with abdominal pain and a likely upper GI bleed, with a history of an eating disorder, who has metabolic acidosis. The second patient is an alcoholicwho recently stopped both eating and consuming alcohol. She also has a metabolic acidosis. I discuss the biochemistry of alcohol metabolism and explain why alcoholics are at risk for ketoacidosis. I also explain why this is part of a paradigm of metabolic failure that, without significant attention to detail, may result in therapy that precipitates a variety of withdrawal syndromes: these include acute Wernicke’s Encephalopathy, Alcohol Withdrawal Syndrome, and acute aquaresis and Osmotic Demyelination. Alcoholic ketoacidosis almost always follows cessation of alcohol intake – and one is unlikely to make this diagnosis in a patient who, for example, presents drunk to the ED (this results in a host of other metabolic anomalies, for example hypoglycemia despite high plasma lactate).
Starvation ketoacidosis is seen in patients who are chronically malnourished or fasted for prolonged periods for surgery, in whom the pancreatic Islet cells have either atrophied or are hibernating. Careful attention must be applied to feeding and refeeding: it is imperative that the patient does not lose further lean body mass. On the other hand refeeding syndrome may result in rhabdomyolysis and death. I guarantee you’ll learn something.
Traditionally rules of thumb regarding the changes in PaCO2 and Bicarbonate in acid base balance have utilized mmHg. Unfortunately, in large tracts of the world, particularly in Europe, blood gases are reported in the SI unit kPa. This tutorial is for those people. I cover various acid base abnormalities – pH vs PaCO2, acute and chronic respiratory acidosis, respiratory alkalosis, metabolic acidosis and alkalosis and go through the various acid base rules of thumb using kPa, with examples. I guarantee you’ll learn something.
Rules:
Rule 1 H+ vs pH: a 1nmol/L increase in [H+} results in a 0.01 fall in pH
Rule 2 PaCO2 in Apnea: In apnea the PaCO2 rises by 1.5kPa in the first minute and by 0.5kPa per minute thereafter (this reduces progressively over time to 0.2-3kPa)
Rule 3 PaCO2 vs pH: For every 1kPa increase in the PaCO2 the pH falls by 0.06
Rule 4 PaCO2 vs HCO3 in Acute Respiratory Failure: For every 1kPa increase in the PaCO2, the HCO3 rises by 1mmol/L
Rule 5 PaCO2 vs HCO3 in Chronic Respiratory Failure: For every 1kPa increase in the PaCO2, the HCO3 rises by 3mmol/L and the Chloride falls by an equal value.
Rule 6 PaCO2 vs HCO3 in Acute Respiratory Alkalosis: For every 1kPa increase in the PaCO2, the HCO3 falls by 2mmol/L
Rule 7 PaCO2 versus Base Deficit in Acute Metabolic Acidosis: For every 1mmol/L increase in the Base Deficit (-BE e.g. from -1 to -2), the PaCO2 falls by 0.13kPa e.g. if the BD is -10 the PaCO2 will fall by 1.3kPa from 5.3 to 4
Rule 8 PaCO2 vs HCO3 in Chronic Metabolic Alkalosis (in ICU): For every 1mmol/L increase in the Base Excess (or HCO3) the PaCO2 increase by 0.13kPa e.g. if the BE is +10 then the PaCO2 will increase from 5.3 to 6.6
This tutorial looks at the problem of ketoacidosis and, in particular, focuses on diabetic ketoacidosis. Ketones are produced from free fatty acids in the liver, converted to acetyl coenzyme A and oxidatively metabolized for energy production or packaged in the form of acetoacetate or beta hydroxybutyrate and exported to the tissues. This occurs continuously in the body. Control over metabolism is provided by insulin. When insulin levels are high glucose is utilized primarily for energy production and fatty acid metabolism is curtailed. When insulin levels are low fatty acids become the primary source of energy. In situations of very low carbohydrate intake ketones may be measurable in the blood and we call this ketosis. When plasma ketones exceed 3 millimoles per liter this results in a strong ion effect and ketoacidosis. This is generally only seen in states of metabolic failure such as type 1 diabetes starvation and alcoholism.
The ketones acetoacetate and beta hydroxybutyrate are strong anions and cause metabolic acidosis when they accumulate. This manifests as a fall in the bicarbonate and an increase in the base deficit. Classically there is a widened anion gap metabolic acidosis with full respiratory compensation. Nevertheless the extent of the acidosis is rarely explained by ketones alone. Lactic acidosis is frequently present as is acidosis caused by the accumulation of metabolic junk products. Iatrogenic metabolic acidosis may ensue caused by the administration of hyperchloremic (0.9% NaCl + KCl) saline solutions.
Diabetic ketoacidosis is characterized by loss of control of blood glucose, loss of control of blood lipids and hypercatabolism of proteins. Failure to suppress gluconeogenesis within the liver depletes the tricarboxylic acid cycle reserves and results in uncontrolled ketone production. Patients become hyperglycemic glycosuric, keto acidotic, initially hyponatremic, later hypernatremic, and hyperkalemic. The treatment is to fluid resuscitate the patient, administer insulin by intravenous infusion, replenish glycogen stores and provide glucose for intracellular substrate and prevent further ketone production. Extra care must be taken to avoid hypoglycemia and hypokalemia. @ccmtutorials
This is an opinion piece – a rant if you like about the perceptions and understanding of most healthcare professionals regarding the status of Lactate and Lactic Acidosis. It seems to me that everyone has an opinion on Lactic Acidosis, in my own opinion – they are often misinformed. The bottom line is that the body manufactures and processes vast quantities of Lactate each day and that accumulation of Lactate in the blood – Lactic Acidosis – is a sign of acute illness and multifactorial in origin. The Lactate is not the problem. The Lactate will eventually be processed by the liver and kidneys. You need to identify the underlying problem and control the source. Moreover, as Lactate is a signalling molecule and part of a multi-system process for energy transmission (the “Lactate Shuttle”), particularly when there is a lot of white blood cell activity, a raised lactate late in critical illness is frequently a sign of tissue healing, rather than acute inflammation. The biggest problem that I encounter, on a daily basis is the binary belief that hyperlactatemia means global oxygen debt. Certainly it is associated with hypovolemia (which can be identified by capillary refill time and mixed venous oxygen saturation) but more often it is associated with increased catecholamines associated with the stress response. If you are playing lactate-fluid “whack a mole” – each blood sample leads to a fluid bolus, your patient will become fluid overloaded very quickly. The latter is strongly associated with worse outcomes in critical illness.
I make the following points in this tutorial.
Most clinicians overestimate their knowledge of lactate and consider it a waste product of aerobic metabolism. Lactate is likely the end product of glycolysis and a major fuel source for the body. Lactate is always an Arrhenius acid in the body. Lactate is not a good endpoint of resuscitation (“clearance”). Using Lactate “clearance” as an endpoint usually results in excessive fluid resuscitation. High Lactate and Low Glucose is an Ominous Sign. Nobody can be really sure what is in a bag of Hartmann’s Solution (Ringers Lactate). D-Lactate is likely more harmful than you think. There is no specific treatment for Lactic Acidosis.
Lactic acidosis is one of the best biomarkers of acute critical illness, its presence should alert the clinician to a major stress response, where medical and surgical and iatrogenic sources should be considered.
The magnitude and duration of hyperlactatemia (in the acute phase) is predictive of patient prognosis in critical illness. A sustained high lactate reflects a prolonged stress response. The lactate is not the cause or the problem. It is merely a biomarker.
If I were to pick one topic over which I have sweated tear during the past 2 decades, it is lactic acidosis. The problem is that every time I try to explain lactic acidosis, many of those around me become hostile, as if I was committing some atrocity against their religion. And that is because, for the past 100 years, every high school, science, nursing and medical student has been taught that lactate is a waste product that is only made in anerobic conditions. This is 100% ABSOLUTELY completely verifiably WRONG. Lactate, or lactic acid is produced all the time, continuously, in all tissues and is likely the major endpoint of glycolysis. Once produced, it is then either used for oxidative phosphorylation, shuttled to other tissues as a partially metabolized energy source (e.g. the heart and the brain – they love lactate) or metabolized in the liver, principally (the “Cori Cylcle”) – where gluconeogenesis takes place leading to subsequent glycogen storage, fat production or oxidative phosphorylation. As such, glucose is a universal substrate and lactate is a universal fuel.
Lactic acidosis occurs when the production of lactate exceeds the capacity of the liver to clear it. As we produce at least 1250mmol of lactate per day and it is barely measurable in the blood, hepatic clearance capacity is vast. Hyperadrenergic states promote the production of lactate, increase blood glucose and reduce hepatosplanchnic blood flow. The consequence is sometimes called “stress hyperlactatemia” or “aerobic glycolysis.” This is the form of hyperlactatemic seen in sepsis, for example. As such it is an acute phase reactant biomarker – lactate concentration mirrors adrenaline/epinephrine, and should be seen in the same light as CRP, IL-6 and Procalcitonin.
Hyperlactatemia results in metabolic acidosis as a consequence of water dissociation. The strong ion difference (SID) falls. The surplus “hydrogen ions” are mopped up by bicarbonate resulting in a modest fall in pH, but a mEq/L for mEq/L fall in bicarbonate and base excess. Lacate, like Chloride and Ketones, always functions as an acid surrogate and chronic hyperlactatemia is compensated for, usually, by increasing urinary Chloride loss, manifest as hypochloremia.
The terms “Type A” and “Type B” lactic acidosis were introduced by Huckabee in 1961. I believe that these monikers are still useful today. “Type A” represents lactic acidosis associated with blood loss and hypovolemia, intense systemic and splanchnic vasoconstriction, high ejection fraction, low stroke volume and cardiac output and low mixed venous oxygen saturation. Production of lactate increases (and this is multifactorial – not just anerobic), and production falls – due to hepatic hypoperfusion. The treatment is resuscitation, preferably with blood products.
For lactic acidosis, what is not Type A must be Type B – and this represents medley causes (toxic – alcohols), metabolic (end stage liver disease), inflammatory (sepsis), drug induced (metformin and particularly intravenous or inhaled catecholamines).
The term “Clearance” has been used to describe the removal of lactate from the circulation. It is a pharmacological rather than biochemical term, and that has led to some abuse in clinical practice: the belief that “Clearance” can be hurried along with aggressive fluid resuscitation. However, like any particle that is metabolized by the liver, clearance of lactate is determined by the quantity delivered, hepatic blood flow and hepatic clearance capacity. If there is a sustained surge in lactate production, then it may take a while for the liver to clear the surplus from the system while simultaneously dealing with the continued production of lactate by the tissues. In critical illness, we like to see the plasma lactate level falling, but 10-20% is sufficient to be reassuring. A rising lactate is ominous and may indicated inadequate source control or a secondary problem, such as bowel ischemia.
Lactic acidosis may or may not be a marker of tissue perfusion. It is a poor endpoint of resuscitation – and if used as such (the “drive by saline assault”), the result is fluid overload, mutiiorgan dysfunction and prolonged ICU stay.
Sodium Lactate Solutions do not cause lactic acidosis, as they are fully balanced. Most formulations contain a racemic mixture of L-Lactate (which is what the body produces) and D-Lactate (produced by fermentation by bacteria). Blood gas machines do not measure D-Lactate.
You may think that this whole ionization and pKa stuff is of little relevance to you as a clinician working in ED, Anesthesiology or ICU, but you are mistaken. The pH of blood (whether or not the [H+] exceeds the [OH-] has major impact on the pharmacokinetics of certain drugs. Moreover, some drugs rely on a differential between extracellular and intracellular pH to be effective.
This tutorial looks at the pharmacology of three types of drugs impacted by pH. These drugs are local anesthetics, opioids and the benzodiazepine – midazolam. All of these agents are weak bases whose degree of ionization varies with pH.
Speed of onset is related to the pKa – the lower the pKa of weak bases the more rapid the onset of action
Duration of action is related to protein binding – particularly albumin (there are other proteins). Albumin depletion is common in critical illness, leading to higher bioavailability and shorter duration of action.
Potency is related to lipid solubility. Fentanyl is highly potent because of this.
This tutorial is supplementary to the acid base course. The material is ESSENTIAL for trainees and practitioners in Anesthesiology and Dentistry. @ccmtutorials http://www.ccmtutorials.org
To truly understand acid base chemistry, it is imperative that you have a grasp of ionization theory. Although this might appear a little nerdy, it is quite straightforward and will also provide you with a basis for understanding the basic pharmacology of local anesthetics and opioids. Particles that disintegrate into component parts that carry charge are known as ions. If that charge is positive they are cations and if it is negative they are anions. Measurement of charge is known as valency, Most electrolytes in the body are univalent – Na, Cl, K, HCO3 – and their valency is quantifiably identical to their molarity (i.e. 140 mmol/L of Na+ = 1mEq/L). Some, however, are divalent – Calcium and Magnesium and Phosphorous. Ionized particles are a major component of acid base chemistry. They may be derived from mineral salts – Na, Cl, K, PO4, Mg, Ca or organic molecules – Lactate, Ketones, Metabolic Junk Products – manufactured in the body. Weak anionic acids are also manufactured – Bicarbonate and Albumin.
The relative quantities of different particles is governed by MASS CONSERVATION. Regardless of the source and quantity of anions and cations ELECTRICAL NEUTRALITY must always hold. Where there is imbalance between anions and cations the electrochemical void is filled by hydrogen or hydroxyl (derived from water dissociation) and acid base abnormalities ensue.
What makes ionized particles “strong” or “weak” acids or bases is determined by the pKa – the Ion Dissociation constant. This is the pH at which the particle is 50% dissociated or associated. As all electrochemical activity in the body occurs withing the physiological range of pH – 6.8 to about 7.65 – whether a ionic particle’s pKa is below or above, essentially 7.4, determines whether it is an acid or a base. For example – Lactic Acid has a pKa of 3.1 – at that point is is 50% associated (LA-H) and 50% dissociated (La-). At the environmental pH falls, for example towards 1, for example in the stomach, the chemical associates more (Lactic Acid). As the pH rises towards 7.4 it dissociates more (Lactate). At all physiologic ranges of pH Lactate is fully dissociated. Likewise, chemicals that have a pKa above the physiologic range pH (i.e greater than 7.6) are bases – and they become more associated at higher pH ranges. Sodium Hydroxide has a pKa of greater than12, which means that at pH 12 it is 50% associated, at pH 15 it is close to 100% associated. At physiologic range pH it is fully dissociated. Particles that are fully dissociated at all physiologic ranges of pH – cations such as Na+, K+, Mg2+ and Ca2+ and anions such as Cl-, Lactate- and Beta-Hydroxybutyrate, are known as STRONG IONS – they never bind to other ions (to create salts), hydroxyl or hydrogen in the body. Particles that are partially dissociated, whose pKa is closer to 7.4 – Bicarbonate, Albumin, Phosphate, Hemoglobin, are WEAK ACIDS and as they pick up more hydrogen ions at lower pH levels, they act as buffers.
Metabolic acid base balance is governed by the relative charge distribution (mEq/L) of STRONG IONS – known as the STRONG ION DIFFERENCE (SID) and the availability of weak acid buffers (ATOT). If the SID reduces, there is excess anion and metabolic acidosis. If the SID increases, there is excess cation or deficient anion and metabolic alkalosis.
This is Tutorial 2 in the Series on Acid Base: The FIzz of CO2.
Carbon Dioxide is a gas that is produced by the mitochodria and passes through the cell membrane into the extracellular fluid and blood. There it dissolves, attaches to hemoglobin or, under the influence of carbonic anhydrase, hydrates with water to generate carbonic acid – which rapidly dissociates to release hydrogen (bound to hemoglobin) and bicarbonate. Carbon Dioxide obeys Dalton’s law and Henry’s law. The latter determines that the PCO2 is directly proportionate to the CO2 content. Carbon Dioxide becomes more soluble in the blood as temperature falls. Hence measuring gaseous CO2 requires the blood gas machine to be set at 37 degrees.
The body produces, at rest, 200ml per minute of CO2. The body excretes 200ml per minute of CO2. As metabolism increases, respiratory excretion of CO2 increases. This results in a PaCO2 of 40mmHg or 5.1kPa. There is a 3-4mmHg or 0.5kPa difference between the PaCO2 and the etCO2. Because the body exists, usually, is steady state, the etCO2 can be used to estimate the PaCO2 (most of the time). In apnea, the PaCO2 rises rapidly – it doubles in 8 minutes.
When PaCO2 rises, [HCO3-] rises also – and in a very predictable way. So, when a patient develops acute respiratory failure, or underventilates (for example under anesthesia), pH falls, predictably, the PaCO2 rises, predictably and the Bicarbonate rises, predictably. This is acute respiratory acidosis – and in this tutorial I will explain how and why this occurs.
It is imperative to understand that CO2 and [HCO3-] are different versions of the same thing in the body and the rise in bicarbonate in respiratory disorders is not some form of “compensation” it is physiology. Indeed in chronic respiratory failure, the increase in respiratory acids (Chronic respiratory acidosis) is counterbalanced by a fall in the plasma Chloride levels. Acute respiratory alkalosis is associated with pain, anxiety, agitation or over ventilation and is associated with a modest fall in Bicarbonate.
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