The Importance of Serum Sodium in the Brain

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

I'm Pradip Kamat and I'm Rahul Damania. We are coming to you from Children's Healthcare of Atlanta - Emory University School of Medicine.

Here's the case:

A 6-year-old child with a known h/o craniopharyngioma who has been endocrinologically intact with exception of needing thyroid replacement was admitted to the PICU prior to craniotomy to proceed with further tumor resection as well as the removal of a secondary cyst impacting his brainstem. The patient is receiving Keppra for seizures and per mother, he has recently been significantly more sleepy at school.

On POD Op day 5: the PICU the bedside nurse notices increased urine output (6cc/kg/hr to as high as 10cc/kg/hr). Initially, there was an increase in Na to 157mEq/L within 48-72 hours the serum Na dropped to 128mEq/L

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

• Increase UOP
• Rapidly increasing Na initially followed by a drop
• All of which brings up a concern for Na abnormality post craniotomy

In today’s episode, we will be breaking down all things Sodium & the Brain. We will discuss diagnostic & management frameworks related to three pathologies:

1. Central Diabetes Insipidus
2. Syndrome of inappropriate Anti-Diuretic Hormone or SIADH
3. Cerebral Salt Wasting

These diagnoses can certainly be seen individually inpatients or as a spectrum of diseases — as we go through each of these diagnoses, pay particular attention to patient characteristics and lab abnormalities. Namely, serum sodium, serum osm, and urine osm.

To build the fundamentals, lets first start with classic nephrology saying: Serum Na represents Hydration

This takes us into a brief review of normal physiology — talking about three important hormones:

1. ADH
2. Aldosterone
3. Atrial Natriuretic Peptide (ANP)

Let’s go through a quick multiple-choice question.

A patient is recently started on DDAVP for pan-hypopituitarism. The medication acts similarly to a hormone that is physiologically synthesized in which of the following from which are in the body?

A. Paraventricular Nucleus of the Hypothalamus

B. Supraoptic Nucleus of the Hypothalamus

C. Anterior Pituitary

D. Vascular Endothelium

The correct answer here is B the Supraoptic Nucleus of the Hypothalamus. Remember that ADH is synthesized in the hypothalamus and released from the posterior pituitary.

What are the physiologic actions of ADH?

ADH Increases H2O permeability by directing the insertion of aquaporin 2 (AQP2) H2O channels in the luminal membrane of the principal cells. Thus, as we will see with Central Diabetes insipidus, in the absence of ADH, the principal cells are virtually impermeable to water.

Let's talk about our next hormone, aldosterone. What are the important physiologic considerations?

• Aldosterone is secreted from the adrenal cortex as a byproduct of the RAAS.
• Aldosterone increases Na+ reabsorption by the renal distal tubule, thereby increasing extracellular fluid (ECF) volume, blood volume, and arterial pressure.
• It also helps in secreting K and H. This physiology is applied directly at the bedside when we have patients in the ICU who have a contraction alkalosis secondary to diuretics. The increase in aldosterone as these patients lose free water from their Lasix administration results in hypokalemia and metabolic alkalosis.

Alright, what about the third hormone, ANP?

• Atrial natriuretic peptide (ANP) is released from the atria in response to an increase in blood volume and atrial pressure.
• ANP causes relaxation of vascular smooth muscle, dilation of arterioles, and decreased TPR.
• causes increased excretion of Na+ and water by the kidney, which reduces blood volume and attempts to bring arterial pressure down to normal.

As ANP causes natriuresis, diuresis, and inhibition of renin, you can consider this hormone as having a complementary & opposite effect to ADH and aldosterone.

Alright, now that we have the basics, let's talk about our index case presentation, central diabetes insipidus, can you illustrate the key diagnostic features of this disease?

• Central diabetes insipidus (CDI) is an important cause of hypernatremia in the intensive care setting and can be seen in primary brain lesions, traumatic brain injury, or as a harbinger of brain death.
• CDI results from inadequate ADH secretion. Children in the intensive care setting typically present with abrupt polyuria and free water diuresis.

What are common triggers for CDI?

• Traumatic brain injury, brain tumors, pituitary surgery (i.e. postoperative craniopharyngioma resection), central nervous system infections, and cerebral hemorrhages or infarcts.
• CDI occurs most commonly in the setting of brain death.

 Because patients with CDI can conserve sodium appropriately, they typically do not manifest signs of volume depletion unless the diagnosis is delayed. Thus CDI is a cause of euvolemic hypernatremia.

Absolutely, actually, in CDI the urine osmolality is typically less than the plasma osmolality. These patients have about >4 mL/kg/hr of urine output.

What is the management of CDI?

• CDI includes the correction of free water deficit and the administration of the ADH synthetic analog desmopressin acetate (dDAVP). In a critically-ill patient, a vasopressin infusion may be needed for the rapid increase in UOP and serum Na. An advantage of vasopressin is the “quick on-off effect”
• Desmopressin can be administered subcutaneously, intranasally, or intravenously. The dosing varies by the route of administration and can be thought of as the 1-10-100 rule.
• IV 1mcg
• IN 10mcg (one puff = 10mcg)
• PO 100mcg
• In critically ill patients, edema and peripheral vasoconstriction may preclude effective subcutaneous administration therefore intravenous administration of dDAVP or a continuous vasopressin infusion may be required.

Alright, so you gave the patient with presumed CDI a dose of DDAVP. What will you expect?

• Patients with central diabetes insipidus will typically have a reduction in urinary output and a greater than 50% increase in urine osmolality in response to the first dose of dDAVP.
• At times we are measuring their urine output in mL/kg/hr so if a patient is on a continuous vasopressin infusion for DI, titrating to a UOP of 1-2 mL/kg/hr can be appropriate.

Rahul why do you think in our patient with high UOP and a high serum Na, the serum Na suddenly dropped in 48 hours?

There are two possibilities. Either patient has received DDAVP or more likely patient is having a Triphasic Response as many patients undergoing pituitary surgery do (DI within 2-4 days, followed by SIADH for 2-5 days, and a return to DI), which sometimes can be difficult to treat.

Most patients with CP already have pituitary hormone deficiencies at the time of diagnosis, which is more common in children than adults. Approximately 70% of children had growth hormone (GH) deficiency, followed by gonadotropin deficiency (51.7%), central diabetes insipidus (CDI, 28.6%), and thyroid-stimulating hormone (TSH) deficiency (21.9%), and adrenocorticotrophic hormone (ACTH) deficiency (12.5%).

The course of postoperative CDI can be transient, permanent, or a component of the triphasic pattern.

Pradip, can you highlight the triphasic response a bit more?

• In the first phase of the triphasic pattern, there is an acute increase in hypo-osmolar urine output within 24–48 h following surgery due to antidiuretic hormone (ADH) deficiency resulting from traumatic edema of the neurons, axonal shock due to impairment of vascular supply, and/or pituitary stalk transection.
• The patients have a tendency toward hypernatremic dehydration during this phase, which lasts approximately 1–7 days. At this phase, appropriate fluid replacement is required to prevent water loss and hypernatremic dehydration.
• However, low-dose diamino D-arginine vasopressin (desmopressin; dDAVP) can be used to decrease fluid intake/output. dDAVP replacement dose should be titrated with caution because its long half-life during this phase may complicate the subsequent hyponatremic phase of the triphasic response.

Let’s transition to the other extreme, and that is SIADH — syndrome of too much ADH. What are some common etiologies?

• SIADH can occur due to a variety of illnesses, but most often occurs due to central nervous system disorders, pulmonary disorders, and medications. As this episode is all things brain and salt related, common CNS diagnosis that can lead to SIADH are:
• Meningitis, encephalitis
• Neoplasms
• Post-pituitary surgery
• Hydrocephalus
• Head Trauma

We will be reviewing specific electrolyte disorders in future episodes however please remember that hyponatremia like SIADH typically develops when a relative excess of free water is accompanied by an underlying condition that impairs the kidney’s ability to excrete free water. In SIADH, ADH secretion occurs independently of serum osmolality and intravascular volume status.

Interestingly, SIADH is essentially a diagnosis of exclusion. Before SIADH can be diagnosed, diseases causing decreased effective circulating volume, renal impairment, adrenal insufficiency, and hypothyroidism must be excluded.

Clinically, what will we see?

• The hallmarks of SIADH are:
• mild volume expansion with low to normal plasma concentrations of creatinine, urea, uric acid, and potassium
• impaired free water excretion with normal sodium excretion which reflects sodium intake
• hyponatremia which is relatively unresponsive to sodium administration in the absence of fluid restriction.

If left uncorrected, SIADH can lead to severe hyponatremia (plasma Na <120 mEq/L) - leading to seizures.

To close out this topic, how would you approach the management of SIADH?

• SIADH is usually of short duration and resolves with treatment of the underlying disorder and discontinuation of the offending medication.
• Additionally, fluid restriction is the cornerstone of therapy for SIADH.
• However, fluid restriction results in slow correction of hyponatremia and is frequently impractical in infants who receive most of their nutrition as liquids.

Finally, let’s talk about Cerebral salt wasting. How can we compare and contrast CSW and SIADH?

• In the setting of CNS injury or following a neurosurgical procedure, hyponatremia is usually attributed to SIADH, a condition whose hallmark is euvolemia to mild hypervolemia, with the cornerstone of management being fluid restriction.
• More recently it has become apparent that an increasing number of neurosurgical patients with hyponatremia can have CSW a condition whose hallmark is renal sodium loss leading to extracellular volume depletion.

So to summarize patients with CSW and SIADH can both be hypoNa in the setting of brain injury however patients with CSW are hypovolemic relative to patients with SIADH who have a euvolemic hypoNa.

What is the pathogenesis of CSW?

• The pathogenesis of CSW is not completely understood, but it appears to be due to the release of natriuretic peptides, such as an atrial natriuretic peptide. As we reviewed in our physiology discussion, ANP helps us with three things:
• hemodynamic effects leading to an increased GFR
• inhibition of the renin
• Inhibition of the secretion and action of ADH
• And, just to summarize, the key distinguishing feature between CSW and SIADH is extracellular volume depletion. You can establish this assessment via serial monitoring of UOP, clinical exam, and CVPs.

Pradip, any other clinical pearl regarding CSW?

• Yes, so when you provide NS infusion to a patient, let's say with SIADH — it should be adequate prophylaxis to prevent hypoNa (i.e. a sodium <130 meQ/L)
• However, If clinically significant hyponatremia develops inpatient with a CNS disorder receiving only normal saline, then the diagnosis of CSW should be strongly considered.

How do we manage these patients?

• The hallmark pearl is to expand their intravascular space.
• This can be achieved by normal saline, followed by sufficient quantities of normal saline and 3% NaCl to main fluid balance and normal serum sodium. There have been studies that have advocated the administration of fludrocortisone as aldosterone production is relatively decreased in CSW.

Ok, Rahul, do you mind summarizing today’s episode?

This concludes our episode on All Things Sodium & the Brain in the PICU. 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!

• References:
• Bereket A: Postoperative and Long-Term Endocrinologic Complications of Craniopharyngioma. Horm Res Paediatr 2020;93:497-509. doi: 10.1159/000515347
• Prete A, Corsello SM, Salvatori R. Current best practice in the management of patients after pituitary surgery. Therapeutic Advances in Endocrinology and Metabolism. March 2017:33-48. doi:10.1177/2042018816687240