Welcome to PICU Doc On Call, A Podcast Dedicated to Current and Aspiring Intensivists.

I'm Pradip Kamat coming to you from Children’s Healthcare of Atlanta/Emory University School of Medicine

and I'm Rahul Damania from Cleveland Clinic Children’s Hospital. We are two Pediatric ICU physicians passionate about all things MED-ED in the PICU. PICU Doc on Call focuses on interesting PICU cases & management in the acute care pediatric setting so let’s get into our episode:

In today's episode, we discuss about a 12-year-old male with lethargy after ingestion.

Here's the case presented by Rahul:

A 12-year-old male is found unresponsive at home. He was previously well and has no relevant past medical history. The mother states that he was recently in an argument with his sister and thought he was going into his room to “have some space.” The mother noticed the patient was in his room for about 1 hour. After coming into the room she noticed him drooling, minimally responsive, and cold to the touch. The patient was noted to be moaning in pain pointing to his abdomen and breathing fast. Dark red vomitus was surrounding the patient. The mother called 911 as she was concerned about his neurological state. With 911 on the way, the mother noticed a set of empty vitamins next to the patient. She noted that these were the iron pills the patient’s sister was on for anemia. EMS arrives for acute stabilization, and the patient is brought to the ED. En route, serum glucose was normal. The patient presents to the ED with hypothermia, tachycardia, tachypnea, and hypertension. His GCS is 8, he has poor peripheral perfusion and a diffusely tender abdomen. He continues to have hematemesis and is intubated for airway protection along with declining neurological status. After resuscitation, he presents to the Pediatric ICU. Upon intubation, an arterial blood gas is drawn. His pH is 7.22/34/110/-6 — serum HCO3 is 16, and his AG is elevated.

To summarize key elements from this case, this patient has:

• Lethargy and unresponsiveness after acute ingestion.
• His hematemesis is most likely related to his acute ingestion.
• And finally, he has an anion gap metabolic acidosis, as evidenced by his low pH and low HCO3.
• All of these salient factors bring up the concern for acute iron ingestion! In today’s episode, we will not only go through acute management pearls for iron poisoning, but also go back to the fundamentals, and cover ACID BASE disorders.
• We will break this episode down into giving a broad overview of acid base, build a stepwise approach, and apply our knowledge with integrated cases.

We will use a physiologic approach to cover this topic!

• Pradip, can you give us a quick overview of some general principles when it comes to tackling this high-yield critical care topic?
• Absolutely, internal acid base homeostasis is paramount for maintaining life. Moreover, we know that accurate and timely interpretation of an acid–base disorder can be lifesaving.
• When we conceptualize acid base today, we will focus on pH, HCO3, and CO2.
• As we go into each disorder keep in mind to always correlate your interpretation of blood gasses to the clinical status of the patient.
• Going back to basic chemistry, can you comment on the relationship between CO2 and HCO3?
• Yes, now this is a throwback. However, we have to review the Henderson–Hasselbalch equation. The equation has constants & logs involved, however in general this equation shows that the pH is determined by the ratio of the serum bicarbonate (HCO3) concentration and the PCO2, not by the value of either one alone. In general, an acid–base disorder is called “respiratory” when it is caused by a primary abnormality in respiratory function (i.e., a change in the PaCO2) and “metabolic” when the primary change is attributed to a variation in the bicarbonate concentration.
• Now that we have some fundamentals down, let’s move into definitions. Can you define acidemia and alkalemia and comment on how the sampling sites may vary these definitions?
• Acidemia is defined as an arterial pH below 7.35.
• Alkalemia is defined as an arterial pH above 7.45.
• Thus, normal pH range for an arterial blood gas is 7.35 to 7.45.
• Bicarbonate (HCO3) concentration, 21 to 27 mEq/L; and for PCO2, 35 to 45 mmHg.
• What about the venous side?
• Normal values for peripheral venous blood gases differ from those of arterial blood due to the uptake and buffering of metabolically produced CO2 in the capillary circulation and the addition of organic acids produced by the tissue bed drained by the vein.
• The range for peripheral venous pH is approximately 0.03 to 0.04 pH units lower than in arterial blood, the HCO3 concentration is approximately 2 to 3 mEq/L higher, and the PCO2 is approximately 3 to 8 mmHg (0.4 to 1.1 kPa) higher.

These subtleties are important physiological considerations as you trend blood gasses. For example, if you have a venous blood gas of 7.32, on the arterial side, it may be correlated to 7.35. Similarly on the venous side if you have a CO2 of 48, on the arterial side, this value may be about 5 mmHg lower, so around 43.

Rahul, we mentioned that prior to chasing gasses, it is important to assess the patient’s clinical state. Can you comment on this a bit further?

Yes, so the key here is that various signs and symptoms often provide clues regarding the underlying acid–base disorder; these include the patient’s vital signs (which may indicate shock or sepsis), neurologic state, pulmonary status (respiratory rate and presence or absence of Kussmaul respiration), and gastrointestinal symptoms (vomiting and diarrhea). We saw some of these in our case. We should also take into account any medications that affect acid–base balance in our assessment of acute acid-base changes. Relevant medications include laxatives, diuretics, topiramate, etc. Also, watch for specific ingestions such as methanol for example which can cause blindness.

As we dive into the various disorders, can you frame an approach to acid base blood gas interpretation?

Here are 3 steps:

Establish the primary acid base abnormality — are we dealing with an acidemia or alkalemia.Establish what value correlates with the primary acid base disorder:

CO2 HCO3

For example, when you diagnose an acidemia, a metabolic acidosis is characterized by a low serum HCO3. Also, it is important to note for each 10 mmHg pCO2, pH falls by 0.08 units.

Assess for compensation:

• For example, in a metabolic alkalosis, your lungs will compensate by increasing your CO2 via hypoventilation.
• Please note that renal compensation may take 24-48 hours after your initial respiratory acidosis/alkalosis.

Yes, I think this point of compensation is important to note especially when assessing for mixed disorders. If we take for example an acute respiratory acidosis, the normal compensatory response to acute respiratory acidosis is an increase in the serum HCO3 concentration by approximately 1 mEq/L for every 10 mmHg elevation in the PCO2. When the respiratory acidosis persists for more than three to five days, the HCO3 increases by approximately 3.5 to 5 mEq/L for every 10 mmHg elevation in the PCO2.

Important to note, with the exception of chronic respiratory alkalosis and mild to moderate respiratory acidosis compensatory responses do not usually return the arterial pH to normal.

Yes, in fact, in contrast with older data, data from more recent studies indicate that the pH in chronic respiratory acidosis may be normal and, in individual cases, higher than generally recognized (pH >7.40).

Let’s revisit our index case to review the acid base disturbance. Do you mind refreshing our memory on his initial ABG?

• pH 7.22/34/110/-6 — serum HCO3 was 16 meQ/L.

Rahul, take us through the step-wise approach:

1. Acidemia as evidenced by a low pH of 7.22
2. What supports an acidemia is a low bicarbonate so we can say it is metabolic
3. And in the case of a metabolic acidosis it is important for us to assess the degree of compensation using winter’s formula.

What is Winter’s formula?

• PaCO2 = 1.5 × [HCO3−] + 8±2 mm Hg
• In this case, our expected CO2 given our Bicarb is 16 would be 30-34, and our patient’s was 34, so this is a true metabolic acidosis.

The patient had an anion gap metabolic acidosis, can you tell us a bit more about what is the anion gap?

• Disorders that produce metabolic acidosis by increasing organic acid generation like in the case of ingestion or cases with increased accumulation of phosphoric and sulfuric acid such as severe chronic kidney disease can usually result in an increased serum anion gap.
• The anion gap can conceptually be understood as Na + All unmeasured cations  =  Cl + HCO3 + All unmeasured anions. In general it the is positives minus negatives, and clinically we simplify this as. Na - (Cl + HCO3), normal is 8-12. If the anion gap is elevated, we recognize that this is some organic acid that is creating a gap between positives and negatives.

Now Rahul, let's say we have a patient with hypoalbuminemia, would this affect the anion gap?

• Yes, it definitely can in healthy individuals, the major unmeasured anion responsible for the existence of a serum anion gap is albumin.
• This circulating protein has a significant net negative charge in the physiologic pH range. As a result, the expected baseline value for the anion gap must be adjusted downward in patients with hypoalbuminemia.
• Thus, Corrected serum anion gap  =  (Serum anion gap measured) + (2.5  x  [4.5 - Observed serum albumin])
• It is also important to note: In addition to hypoalbuminemia, marked hyperkalemia may affect the interpretation of the anion gap.

With a metabolic acidosis, think about two things, calculate anion gap & the Winter’s formula for compensation.

Clinically, what would be a good differential to keep in mind for an elevated anion gap metabolic acidosis?

• Traditionally the Mnemonic was taught as mud piles, however, I wanted to add a little bit of a flare, and that is considering "CAT MUDPILES":
• Carbon monoxide and Cyanide
• Aminoglycosides
• Theophylline
• Methanol
• Uremia
• Diabetic ketoacidosis
• Paracetamol/Acetaminophen, Paraldhyde
• Iron, Isoniazid, Inborn errors of metabolism
• Lactic acidosis
• Ethanol (due to lactic acidosis), Ethylene glycol
• Salicylates

Lactic acidosis is frequently encountered in the pediatric intensive care setting. It is one of our most common causes of an elevated anion gap metabolic acidosis and in general indicates poor oxygen delivery, mitochondrial paralysis, or increased oxygen consumption. Please review our podcast entitled oxygen delivery to review this foundational PICU concept.

• As an advanced integration, can you comment on the delta anion gap/delta HCO3 ratio in patients with elevated anion gap metabolic acidosis?
• The most common causes of acute, high AG acidosis in the PICU are are lactic acidosis and ketoacidosis. The degree to which the AG rises in relation to the fall in bicarbonate (HCO3) varies with the cause of the metabolic acidosis. When the AG increases in magnitude as a result of metabolic acidosis, that increase should be compared with the magnitude of the fall in HCO3.
• This represents the delta AG/delta HCO3 ratio, where delta AG is the patient's value of the AG minus the normal AG, and delta HCO3 is the normal serum HCO3 (ie, 24 mEq/L) minus the patient's serum HCO3
• In our patient, he had a delta AG of 9 divided by a delta HCO3 of 8. The normal value is between 1 & 1.6.
• What if you have a low delta AG/delta bicarbonate ratio?
• A lower value (in which the delta AG is less than expected from the delta HCO3) can be seen in a number of settings:
• In ketoacidosis, D-lactic acidosis, or toluene intoxication, the accumulating organic acid anions can be excreted by the kidney as sodium and/or potassium salts. As a result, in these disorders, the delta AG/delta HCO3 ratio is often below 1, and the serum AG may be normal.
• A higher value of the ratio above 1.6, usually reflects a mixed acid-base disorder in which a high AG acidosis coexists with a process that elevates the serum HCO3.
• As we pivot back to our case, he had an elevated anion gap metabolic acidosis 2/2 to acute iron poisoning, after the A B C tenants, what are our next steps in management?
• Severe symptoms and an anion gap MA are indications for iron chelation using (IV) deferoxamine. You would definitely want to consult with a medical toxicologist and/or regional poison control center.
• At times in acute iron overdose, you may note radio-opaque pills visible on a plain radiograph of the abdomen. This may also be a sign of severe poisoning.

Important to note, because iron does not bind to activated charcoal, GI decontamination for acute iron poisoning consists of whole-bowel irrigation (WBI) and, rarely, orogastric lavage via upper endoscopy. The severity of disease can be guided based on plain abdominal radiographs. In most patients, the risk of gastric lavage following iron overdose outweighs the limited benefit.

• To wrap up our discussion on metabolic acidosis, what are some common causes of non-anion gap metabolic acidosis?
• In the big picture, NAGMA usually results from a loss of bicarbonate or an isolated reduction in renal acid excretion.
• The most common NAGMA we see in the PICU:
• Diarrhea or NG losses
• Proximal (type 2) RTA or even Type 1 & Type 4 RTA where there is impaired renal acid excretion.
• We also frequently encounter hyperchloremia and a NAGMA with resuscitation of 0.9% normal saline as it provides a chloride load; adult studies show that infusing more than 3-4L can cause acidosis.
• Frequently as a fellow when we see a metabolic acidosis, we reflexively think about administering bicarbonate. Can you shed some clinical pearls on this management decision?
• I think in a pinch it is appropriate to consider, especially if blood pH is <7.1 or, in some patients, <7.2 & clinically the patient is deteriorating.
• Although intravenous bicarbonate may be helpful if administered to children with severe acute metabolic acidosis, the therapeutic focus should be on slowing the rate of acid generation (ie correcting the cause of acidosis).
• In general, shooting for a goal of pH >7.2 and/or serum bicarbonate concentration >16 mEq/L should be considered. We frequently dose Bicarbonate as 1-4 meQ/kg keeping in mind that your typical vial has 50 meQ of bicarbonate.
• As mixed disorders are important to also recognize let's conclude this episode by revisiting some compensation formulas.
• To review:
• Acute respiratory acidosis (less than a day) the serum HCO3 concentration increases by approximately 1 mEq/L for every 10 mmHg elevation in the PCO2 from normal.
• Chronic respiratory acidosis (usually three to five days) serum HCO3 increases by about 4 mEq/L for every 10 mmHg elevation in PCO2 in patients with chronic respiratory acidosis.
• Acute respiratory alkalosis, the serum HCO3 concentration reduces by 2 mEq/L for every 10 mmHg decline in the PCO2 from normal. In chronic, HCO3 will fall by 4 mEq/L.
• What about for a metabolic alkalosis?
• The respiratory compensation to metabolic alkalosis should raise the PCO2 by approximately 0.7 mmHg for every 1 mEq/L elevation in the serum HCO3 concentration.
• A very-easy-to-use relationship: PCO2  =  HCO3 + 10. Studies have shown that high CO2 levels are probably generated by respiratory muscle weakness associated with marked hypokalemia and potassium depletion, which almost invariably develop in these patients. This is classically seen in a baby with It may also help to obtain urine electrolytes such as urinary cl in metabolic alkalosis. We will visit an approach to urinary chloride interpretation in future episodes!

We talked about a wide breadth of topics today! Let's summarize…

Key objective takeaways:

1. Trend blood gasses based on similar sampling sites, remember for a peripheral venous sample, the range for pH is approximately 0.03 to 0.04 pH units lower than in arterial blood.
2. Have a step-wise approach for acid base disorders — we covered 1. establish alkalemia vs acidemia; 2. which value CO2 or HCO3 supports your primary disorder; 3. assess compensation
3. In metabolic acidosis, you'll have a low pH and a low bicarb, make sure that you do an Anion gap calculation, as well as Winter's formula.

This concludes our episode on the approach to acid base disorders. We hope you found value in our short, case-based podcast. We welcome you to share your feedback, subscribe & place a review on our podcast! Please visit our website picudoconcall.org which showcases our episodes as well as our Doc on Call management cards. PICU Doc on Call is co-hosted by myself Dr. Pradip Kamat and Dr. Rahul Damania. Stay tuned for our next episode! Thank you!

• More information can be found
• Berend K, de Vries AP, Gans RO. Physiological approach to the assessment of acid-base disturbances. N Engl J Med. 2014 Oct 9;371(15):1434-45. doi: 10.1056/NEJMra1003327. Erratum in: N Engl J Med. 2014 Nov 13;371(20):1948. PMID: 25295502.
• Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed, McGraw-Hill, New York 2001. p.328.
• Malatesha G, Singh NK, Bharija A, et al. Comparison of arterial and venous pH, bicarbonate, PCO2 and PO2 in initial emergency department assessment. Emerg Med J 2007; 24:569.