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
I often wonder if the obsession amongst physicians regarding the prevention of Osmotic Demyelination Syndrome (ODS or Central Pontine Myelinolysis – CPM) results in adverse patient outcomes – for example a greater incidence of iatrogenic complications, prolonged length of stay etc.
In this discussion, I look at the history of ODS/CPM, how it became identified with rapid correction of hyponatremia and what patients are at particular risk of this disorder. In the second part of the discussion I address the re-ignited controversy about Sodium/Osmolality correction subsequent to the publication of a major study in NEJM Evidence in 2023.
Ultimately each clinician must make up their own minds on the evidence that is available. It appears to me that there is little or no risk of ODS/CPM in patients with acute hyponatremia, symptomatic or not, and those with a plasma sodium of greater than 120mmol/L. Patients with Sodium levels below 105mmol/L, alcoholics or cirrhotics and malnourished patient appear to be at very high risk. Finally attention should be paid not only to the speed of correction, but where the plasma sodium levels ends up. In many studies – ODS/CMP is a late diagnosis and patients, at the time of diagnosis are hypernatremic (greater than 145mmol/l) – although the rise in Sodium/Osmolality may appear slow over days or weeks.
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 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 tutorial is about weaning from mechanical ventilation. This is not an easy topic because every professional in the ICU has their own weaning method and their own opinions regarding how best to wean and liberate patients. The literature is unhelpful. Some patients, for example those who have been intubated for a brief period of time, can be awoken and the tube removed after a couple of spontaneous breaths. Other patients require careful multidisciplinary activity over weeks to months to liberate. This tutorial focuses on the in-between group patient who have been intubated for a week or so, who require both clinical and mechanical assessment of their ability to wean and liberate from the ventilator.
Generally the first intervention in weaning is to change the patient over to a spontaneous breathing mode – pressure support or volume support and ensure that alveolar ventilation is adequate to maintain CO2 clearance.
Then a number of clinical and mechanical assessments can be made: is the patient awake, do they have a cough, are they triggering adequately, what is their rapid shallow breathing index (RSBI)? One can estimate muscle strength by performing an occlusion test – either a partial occlusion (P0.1) or a longer occlusion (NIF). Once the patient is assessed as being a candidate for weaning, then one can perform a spontaneous breathing trial (SBT) that is either supported (PS, VS, ATC) or unsupported (T-piece, C-circuit, Trach mask, Swedish Nose).
If the SBT is successful after 90 minutes – extubate the patient. SBTs may fail due to worsening hypoxemia, hypercarbia or hypocarbia, respiratory distress (increase RSBI or use of accessory muscles) or cardiovascular instability (hypotension, hypertension, tachycardia, bradycardia, arrhythmias) or falling levels of consciousness, agitation or acute delirium.
Is there anything more frustrating in the ICU when you decide to start weaning a patient – they look like they’re assisting the ventilator. You switch them over to a “spontaneous” mode and then……nothing…..no breaths….eventually the backup starts.
This tutorial is about triggering of mechanical ventilation. I will revisit how patients trigger the ventilator, the different systems used and introduce I-Sync – a new method of triggering.
Finally I will discuss the problem of Auto-PEEP and explain why, in the setting of Auto-PEEP, there is no point fiddling with the flow by or negative pressure.
The patient is turning purple in the bed, alarms are going off, he is desaturating: he is “fighting the ventilator.” Although a widely used description I believe that it is misused to redefine the problem away from an issue of ventilator operator competency and reframe it as a patient problem. It is not. Most of the time that patient have negative interactions with the ventilator it is a problem of triggering, flow or expiratory cycling. The treatment is not deep sedation and controlled ventilation. The treatment requires skill and nuance, and does not always work. This tutorial looks at inspiration and reasons why it may go wrong.
The most frequently seen patient ventilator dysynchrony is scooping of the pressure waveform, usually associated with flow limited volume controlled ventilation. This can be resolved by increasing the peak flow or changing to pressure control.
In general the ambition to establish a patient on spontaneous assisted ventilation is laudable, but oftentimes we have no idea about what is going on underneath the pressure, flow and volume waveforms. In this tutorial I try and correct the narrative about patient-ventilator interaction when using pressure support. I suggest that volume support in some situations may be a superior approach. I point out that the tidal volume in pressure support has little to do with patient effort and more to do with lung compliance.
I finish the tutorial with a discussion about the inspiratory rise time and explain why you must be careful when using older ventilators.
ORtoICU 