This discussion came about following a discussion with my colleague, Dr Bairbre McNicholas. It focuses principally on the problem of hyponatremia in elderly patients and undernourished alcoholics. I explain why the lack of dietary salt and protein intake massively inhibits water excretion resulting in hypotonic hyponatremia, often with fluid overload. The traditional approach to managing hyponatremia – fluid restriction – frequently fails because it is a problem of solute “underload” rather than water overload. Commencing iv fluids may precipitate a rapid and potentially dangerous diuresis – hence the most effective therapy for these patients is the FEED them.
Patients who present with symptomatic hyponatremia (usually the Na+ is lower than 120mmol/L) should be treated with hypertonic saline (HTS) and then fluid restricted. The goal of HTS therapy is to reverse the symptoms and raise the plasma Na+ by 5mmol per liter. What then? It depends on the circumstance – acute or chronic, high risk or low risk. This tutorial addresses the issue of rate of correction of plasma sodium, explains why you need to modify that rate in high risk patients (very low sodium, alcoholics, the malnourished, those with liver disease and profound hypokalemia). The reason why you need to be careful is because of concerns regarding the development of Central Pontine Myelinolysis – usually known now as Osmotic Demyelination Syndrome.
I wish to acknowledge the help of my colleagues Dr Bairbre McNicholas, Dr Peter Moran, Prof. John Bates, Dr Leo Kevin and Ms Aoife Boyle for clarifying my thoughts on this topic.
Click on this link for the 2014 European Guidelines (and a good review of the topic).
This tutorial is about the Syndrome of Inappropriate Diuresis. SIAD also known as SIADH is a form of hypotonic hyponatremia associated with iso- or hypervolemia, high urinary osmolality and high urinary sodium. Traditionally this is associated with high levels of circulating vasopressin (antidiuretic hormone – ADH), that may be associated with sepsis, acute critical illness, pneumonia or mechanical ventilation. However, SIAD is also associated with a variety of brain injuries, drugs (SSRIs and anticonvulsants) and a variety of cancers.
Treatment of symptomatic SIAD is with hypertonic saline (150ml of 3% over 20 minutes). Chronic or asymptomatic SIAD is treated with fluid restriction (determined by the Furst equation uNa + uK/pNa – if the result is less than1 the patient is suitable for fluid restriction).
Alternative inexpensive therapies include Urea (30 to 60mg per day), salt tablets plus frusemide or demeclocycline.
Vaptan agents, the block the V2 receptors, appear to be effective for long term therapy. Tolvaptan is available commercially but quite expensive for the majority of patients.
Cerebral salt wasting is associated with subarachnoid hemorrhage. It shares the same blood and urinary profile as SIAD(H) but is associated with hypovolemia. The disorder is self limiting and is treated with isotonic fluids.
This is the second tutorial in the series on Hyponatremia. I initially discuss why it is important to evaluate volume status in the setting of a low plasma sodium – patients may be isovolemic, hypovolemic or hypovolemic. The overall treatment is different in each case. Regardless, if a patient presents with symptomatic hyponatremia, then the treatment is 3% hypertonic saline solution – targeted at raising the plasma sodium or osmolality level or both and relieving symptoms. During the remainder of the tutorial I explore several clinical scenarios where patients present with acute symptomatic hyponatremia and work the problem of each seeking the definitive diagnosis.
This is the first tutorial in a short series on hyponatremia. About 15% of our critical care patients has a problem with dysnatremia — high or low sodium levels in plasma. Hyponatremia, with symptoms, is a medical emergency as it can result in cerebral edema and irreversible brain injury.
In this tutorial I first present two case of hyponatremia – one that needs to be treated emergently and one that does not, despite both having the same plasma sodium levels. I then proceed to discuss the physiology of sodium and why it is a key component of body osmolality. The main part of the tutorial is developing a decision tree for working the hyponatremic problem. The key question is whether this is hypotonic or non hypotonic hyponatremia. If it is non hypotonic you need to look for other sources of unmeasured osmoles (usually alcohols). Hypotonic hyponatremia may be associated with myriad problems – but your main concern is whether or not this is being caused by kidney injury or blockade or normal renal pathways (e.g. diuretics). Ultimately I provide an algorithm for how to make a firm diagnosis of the cause of hyponatremia. @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.
This is Tutorial 4 in the Acid Base Series – on the topic of Metabolic Acidosis. The tutorial is based on a single blood gas – a random sample that was handed to me in the ICU recently. Blood Gas Used in This Tutorial: pH 7.19 PaCO2 32mmHg (4.1kPa) HCO3- 13.1 BE – 16.5 AG 20 Na+ 126 K+ 3.1 Cl- 96 Lactate- 7.2 Ketones- 0.6mmol/L Albumin 21g/L Creatinine 3.3mg/dl (293mmol/l)
Metabolic Acidosis is characterized by an increase in the relative ratio of strong anions to strong cations in the plasma. The PaCO2 and the Bicarbonate fall in a predictable manner. It is possible to compute the effectiveness of respiratory compensation for metabolic acidosis by using the Winters equation.
To understand the mechanism of metabolic acidosis – caused by accumulation of mineral (Chloride) and organic (Lactate, Ketones, Metabolic Junk Products) anions – one needs to apply the law of Electrical Neutrality. All of the positive charges must equal all of the negative charges. As Bicarbonate is consumed in the process of buffering metabolic acidosis, the change in the Bicarbonate level (downwards) can be used to quantify the degree of acidosis. This is important because the pH may be within the normal range due to respiratory compensation. Be aware that the HCO3- quantum that is displayed on a blood gas is derived from the pH and PCO2 by the Henderson Hasselbalch equation.
Unfortunately, because respiratory abnormalities may complicate the diagnosis of metabolic acidosis, and pH and PCO2 are altered by changes in temperature, the precision of a single reading of PCO2 and HCO3- may be poor. Consequently, the Standard Base Excess was developed to excise the respiratory component from the change in bicarbonate. Again it is a derived variable and may be imprecise. Nevertheless, BE (or 1-BE the Base Deficit BD) is a terrific scanning tool to identify the presence of a metabolic acidosis (BD) or alkalosis (BE). It is defined as the amount of strong cation (BD) or strong anion (BE) required to bring the pH back to 7.4 when the temperature is 37 degrees Celcius and the the PaCO2 is 40mmHg or 5.3kPa.
The Base Deficit does not indicate the source of the acidosis, but it can be recalculated to remove the impact of the [Na+], the [Cl-], the body water and the serum Albumin (and the Lactate) to determine the Base Deficit Gap – indicative of the quantity of Unmeasured Anions (UMA, Ketones, if not measured, and Renal Acids (metabolic junk products – MJP).
Traditionally clinicians use the Anion Gap to determine whether a patient has a Hyperchloremic Acidosis (no gap) from a UMA acidosis. I find this quite a dated concept. If the [Cl-] exceeds 105 and the plasma Sodium is normal, the patient has a Hypercloremic acidosis. We can easily measure Ketones and Lactate. The AG is imprecise and should be adjusted for the Albumin level, which tends to hover around 25g per liter in critically ill patients (narrowing the Gap and alkalinizing the patient). I do think if you are calculating the AG that you must include the K+ on the Cation side, the Lactate on the Anion side and adjust the Albumin.
The Strong Ion Gap is a more advanced, more precise and more cumbersome version of the AG. Regardless of the approach, one eventually ends up with a quantify of unidentifiable anions (SIG) that may be of medley origin (metabolism, poisoning etc). It is my opinion that it is useful to tease out all of the different acidifying and alkalinizing processes (the Fencl approach) to determine what is going on with the patient. All of these calculations can be done in seconds with smartphone apps and spreadsheets.
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.
ORtoICU 