Consult Rounds: the Heart Failure, hyponatremia and no clues on physical exam???-- Detective Nephron style

The Heart Failure That Left No Clues on Physical Exam

Patient: Severe heart failure

Exam: Shockingly normal
Question: Where did the signs go?

CLUE #1: The Missing Congestion

• No crackles

• No JVD

• No edema

What may be happening?
Chronic HF adapts. Lymphatics drain. Veins stretch. Congestion hides.

CLUE #2: The Resting Alibi

• Looks fine in bed

• Symptoms only with exertion

What really is happening?
The exam interrogates patients at rest—CHF commits its crimes on exertion.

CLUE #3: Masked by Modern Therapy

• Diuretics

• ARNI / MRA

• SGLT2 inhibitors

What is possible?
Congestion is controlled. The disease is not.

CLUE #4: The Low-Output Plot Twist

• Poor perfusion

• Fatigue, weakness

• No obvious volume overload

This is Low-output HF leaves few visible footprints.

CLUE #5: Body Habitus Interference

• Obesity

• Thick chest wall

Strange: Classic signs are present—but physically undetectable.

What a nephrologist can do to get FORENSIC EVIDENCE 

What solves the case when the exam fails:

• Echocardiography -- looking also at IVC

• BNP / NT-proBNP

• Lung ultrasound (B-lines > crackles)

• Hemodynamics when needed ( RHC)

Severe heart failure with a silent physical exam

Verdict: The bedside exam detects overt congestion, not chronic compensation or low-output physiology. Use POCUS wisely!

Concept Map- Hyponatremia, a more modern approach

Created using biorender.com 
Content edited: Dr Rondon 

Consult Rounds: Hyponatremia and AKI- need CRRT- what do we do??

 

Hyponatremia correction is challenging but manageable.
Offering and prescribing CRRT in the ICU is also doable by most nephrologists.

Here comes the challenge.

You are called, “ anuric patient, Na 110, K 5.4, BUN 90, Crt 6.0mg/dl) and altered mental status”
Now you are confronted with correcting the Na slowly and providing good dialytic clearance as well given anuria and hyperkalemia.

CRRT has advantages in its ability to correct plasma sodium values in a predictable and slow manner. Compared with standard hemodialysis machines, where the lowest dialysate sodium concentration is 130 mEq/l, CRRT solutions can be customized to any desired sodium level, allowing for personalized therapy. 

To act on these advantages and prescribe CRRT to target an increase in serum sodium no >6 mEq/L per day, there are three options: either (1) customize the CRRT circuit or (2) customize CRRT solutions. (3) add D5W infusion separate line with standard CRRT

So how is this rate calculated if we were to use Method 3( the easiest of the 3 options)

If D5W rate will be used – the formula is (140 -- target Na value)/( 140 X clearance)
So if we take 110 meq/L as the starting Na value and goal is in 24 hours to be 118. Given the patient was symptomatic, using 3% saline bolus- we get him to 112-113meq/L range. Then if we do 30cc/kg/hour clearance of CVVHDF, that would be roughly 2.4 liters/hour and hence the rate of D5W would need be 375cc/hour. If we use clearance of 25cc/kg/hour- then around 300cc/hr of D5W would be needed.

In an article by Rosner et al, in CJASN, method 1 is well discussed using this figure- changing the post filter fluid or replacement fluid to sterile water( d5W) and rate calculated similarly as stated above.

For method 2: Adding sterile water to commercial dialysis solutions to achieve a desired final sodium concentration would be next way. For instance, if a 5-L bag of replacement solution has a sodium concentration of 140 mEq/L, then the addition of 1 L of water would result in a final sodium solution of the replacement solution of 116.7 mEq/L. 

An important caveat, once desired Na is reached, D5W needs to be changed back to standard replacement fluids and or D5W drip discontinued. 

Topic Discussion: Electrolytes Disorders with COVID19

AKI has been reported with COVID19 ,electrolyte disorders have been less well described. A recent paper in CKJ describe the full spectrum of electrolyte disorders seen with COVID19.

The most common presentation was hyponatremia and hypochloremia together (second vertical bar) in 1289 (12.4%), followed by hyponatremia alone (third vertical bar) in 1150 (11.1%).

What about patients with eGFR<60 but >15? 30.3% had hyponatremia, 11.1% had hyperkalemia, and 19.7% had hypochloremia. Hypocalcemia was seen in 19.2% of patients. Hyperphosphatemia (13.9%) and hypermagnesemia (12.2%) were seen in fewer patients.

What about ESKD patients?

In these patients the most common disorders were hypochloremia (62%), hyponatremia (40.9%), and hyperkalemia (23.4%). Hyperphosphatemia was seen in 45.7% of patients but we had some missing phosphorus data.

What about kidney transplant recipients? The most commonly seen were hyponatremia (42.4%), hyperkalemia (16.7%), and hypochloremia (19%).

Limitations: Purely descriptive.

But highlights for the first time and the largest to date on the various electrolyte disorders in hospitalized COVID-19 patients. Further studies are needed to look at mortality outcomes related specifically to each electrolyte disorder.

Prevalence of Hyponatremia related to COVID19 has been described in the NY region. Looking at the spectrum of both hyponatremia and hypernatremia and it's relation to patient outcomes has not been well studied.

To take this further, Na disorders were evaluated in detail with outcome of mortality. This is published in NDT. Among 9946 patients included in the study ,4808 (48.3%) had normonatremia, 3532 (35.5%) had mild hyponatremia, 904 (9.1%) had moderate/severe hyponatremia, 319 (3.2%) had mild hypernatremia, and 383 (3.8%) had moderate/severe hypernatremia. When examined by decile of age, dysnatremia occurred in 46-54% of patients in each group, with hyponatremia the predominant disorder across all age groups. The proportion of patients who experienced in-hospital death was highest for those with moderate/severe hypernatremia (232/383 [60.6%]), followed by mild hypernatremia (163/319 [51.1%]), moderate/severe hyponatremia (261/904 [28.9%]), mild hyponatremia (818/3532 [23.2%]) and normonatremia (1089/4808 [22.6%]), a trend seen across all age groups. 

U-shaped pattern was seen in the relationship between admission serum sodium level and the odds of in-hospital death, with hyponatremia and hypernatremia both significantly associated with mortality, even after full adjustment for demographics, comorbid conditions and illness severity. Compared to hyponatremia, hypernatremia carried a strong association with in-hospital death, in both mild and moderate/severe categories, and across all ages, a relationship that persisted even following correction for serum glucose. While hypernatremia has  been shown to be  a strong predictor of mortality in prior studies, this finding is novel for COVID-19. 

Both hyponatremia and hypernatremia were also associated with a prolonged hospital length of stay. The magnitude of the odds ratio was substantial, especially for moderate/severe hypo- and hypernatremia, and was not substantively changed after multivariable adjustment. This suggests that at least a portion of the prolonged hospitalization may be directly related to electrolyte disorder management. 

This is the largest study to describe prevalence and outcomes of both hyponatremia and hypernatremia in a diverse population of almost 10,000 patients hospitalized with COVID-19. Other similar studies just published in the endocrine literature as well.

Consult Rounds: Hyponatremia from Anti depressants

 As nephrologists we often get called on SIADH from medications. Anti depressants a class of agents that we do consider to cause hyponatremia. Which ones are more likely vs others has always been interesting to know? A study from Denmark has a detailed look into this matter. 

The odds of developing hyponatremia in one large study was the highest in clomipramine, followed by nortriptyline, citalopram, paroxetine, duloxetine, venlafaxine, sertraline and amitriptyline. It had the least odds of association with mirtazapine, mianserin and escitalopram. The development was highest in the first 2 weeks of starting treatment( with the highest incidence of hyponatremia in the first 2 weeks in citalopram and lowest in mianserin. 

So, SSRI had the most association, SNRIs had slightly lower and non adrenergic specific serotogenic antidepressants had the least association. 

Concept Map: Thiazide induced hyponatremias(TAH)

We see this form of hyponatremia in several cases, but recently there has been some newer findings on the mechanisms of TAH(*).  In one study published in JCI in 2017, Ware et al showed that there is a subset of patients with a genetic baseline( SLCO2A1 mutation) decrease in prostaglandin(PGE) transport activity which then becomes a risk factor for TAH.  So these patients have increased urinary PGE2 and low AVP levels leading to a pure "nephrogenic" cause of tubular water absorption and dilution hyponatremia. PGE2 is critical in insertion and removal of AQP2 channels in the apical membrane. Increased PGE2 signaling leads to insertion of AQP2 channels into membrane and increase water absorption in an ADH independent manner. This is fascinating. Perhaps then mechanism in NSAIDS as well?
Check out this amazing review in AJKD on this topic. 

In the News: Selinexor induced hyponatremia

A new drug just got approved for treatment for myeloma. It is called selinexor. The correct localization of molecules between nucleus and cytoplasm is fundamental for cellular homeostasis and is controlled by a bidirectional transport system. Exportin 1 (XPO1) regulates the passage of numerous cancer-related proteins. The development of a novel class of antitumor agents, known as selective inhibitors of nuclear export (SINEs) have shown good results in studies and clinical trials in multiple myeloma, non-Hodgkin lymphomas, lymphoblastic leukemia, and acute and chronic myeloid leukemia, sarcomas, and gastric cancer. Selinexor is one of the first to be approved in this class of drugs. In a recent NEJM trial published this year, Chari et al showed that oral selinexor- dexamethasone worked well for  triple class refractory multiple myeloma(MM). We wrote a letter back to the authors published in NEJM few weeks later noticing that  one of the most common grade 3 or 4 adverse event was hyponatremia(<130mmol/l) ( 22%).  In reviewing the prior studies( table below), this is a class effect of selinexor as other trials with the use of this agent had similar rates of hyponatremia ranging from 7%-26%. 

Table: Summary of major trials that led to Grade 3,4 hyponatremia

Phase trial	Incidence of hyponatremia	Intervention	Dose modifications	Reference
Phase 1 in MM	25%(40mg/m2), 47% (60mg/m2)	Not reported	Not reported Resolved in most cases	https://www.ncbi.nlm.nih.gov/pubmed/29203585
Phase 2 in MM	22%(80mg)	6% got salt tablets, Dose reduction	Yes, reduced Resolved in most cases	https://www.ncbi.nlm.nih.gov/pubmed/29381435
Phase 1 in solid tumors	13%	Not mentioned	Resolved in most cases	https://www.ncbi.nlm.nih.gov/pubmed/26926685
Phase 1 in sarcomas	7%	Not mentioned	Resolved in most cases	https://www.ncbi.nlm.nih.gov/pubmed/27458288
Phase 1 in Non Hodgkin lymphomas	10%	Not mentioned	Resolved	https://ashpublications.org/blood/article/129/24/3175/36283/Selective-inhibition-of-nuclear-export-with

The rates of hyponatremia are higher in the MM studies compared to solid tumor studies.  No workup or cause was found in many of the studies. Another recent study in AML ( phase 1) has close to 70% incidence of hyponatremia. Likely this could be related to the GI effects such as severe nausea leading to an ADH release causing hyponatremia or could this be a direct effect of the mechanism of this agent. Could this drug effect the AQP channels or V2 receptor- not sure as mechanism has not been worked out. A serum osmolarity testing along with urine studies can answer this question. As the drug enters clinical practice, It is very possible that we shall see an even increased incidence given other confounders patients might be on such as thiazides, and or increased free water intake.  Involvement of nephrology consultation in the trials ongoing might be essential to investigate the mechanism of this toxicity. Serum and urine studies would help in assessment of the cause and pathophysiology of the hyponatremia. This will then allow for preventive strategies in further trials and clinical practice. Once out in the real world, it will be more important as lot of our patients could be on thiazides, SSRi and drinking a lot of water and then are given this agent. While most cases the hyponatremia might be asymptomatic, subtle symptoms and appropriate early management can prevent seizures and complications of hyponatremia.

As nephrologists, we need to be aware of this drug as we usually see myeloma patients. 

Concept map: Hyponatremia in the cancer patient

This concept map was adapted and inspired by Umut Selamet and Ala Abudayyeh, both onconephrologists.

Consult Rounds: Causes of Osmotic Demyelination unrelated to hyponatremia correction

Osmotic Demyelination syndrome (ODS) is classically been associated with rapid correction of hyponatremia. But sometimes, in some rare cases, we observe other causes of this syndrome.
Here is a list that encompasses other known causes of ODS

Hyperglycemia
Hypernatremia( acute formation)
Hypoglycemia
Hypokalemia( this is well known entity causing it)
Alcoholism( This is probably the most important one)
Liver disease and liver transplantation
Malnutrition( another important one)
Hypophosphatemia
Use of CNI( not sure of the mechanism of this one)
Lithium use

This article from AJKD is an amazing reference.

Consult Rounds: Esclicarbazepine induced hyponatremia

Carbamazepine and oxcarbazepine are the most common anti epileptic drugs( AEDs) which induce hyponatremia in patients with epilepsy. Recently, other AEDs, such as eslicarbazepine(ESL), sodium valproate, lamotrigine, levetiracetam and gabapentin have also been reported to cause hyponatremia.

In a two year, single center open labeled observational study of ESL in patients with imaging proven stroke with new onset post stroke seizure were included. ESL was titrated between 400 mg and 1200 mg once daily during 1 month observation period. The titrated dose of ESL was continued during 96-week maintenance period. The patients were followed up for seizure control and side effects, including serum sodium on first examination, at the end of 1 month and then at three monthly intervals for 24 months (total eight visits). Hyponatremia developed in four out of 32 (12.5%) patients; it was symptomatic in three and asymptomatic in one patient.

Compared to other studies, this one study incidence of hyponatremia is higher than that reported in the literature where it has been reported in only 0.6% to 1.3% in the premarketing clinical trials.

In three controlled epilepsy studies, 1/196 patients (0.5%) treated with 400 mg, 4/415 patients (1.0%) treated with 800 mg, and 6/410 patients (1.5%) treated with 1200 mg of ESL had one or more serum sodium values less than 125 mEq/L during treatment whereas none in placebo group. In contrast hyponatremia is the most frequently reported adverse drug reactions in the post-marketing database for Aptoim (ESL brand approved by the US FDA). In this database there were 140 cases of hyponatremia, in half of them hyponatremia occurred within the recommended range of 400-1200mg of ESL and sodium level as low as 103 mEq/L had been reported. In the above study all four patients who developed hyponatremia were in ESL 800 mg group, and lowest sodium level recorded was 113 mEq/L. As hyponatremia develops across all dose ranges of ESL, thus it appears that ESL induced hyponatremia is probably not dose dependent but most appeared in the 800mg group or higher.

What is the mechanism? Possible mechanism of ESL induced hyponatremia can be understood by the mechanism of hyponatremia in oxcarbazepine. Sachdeo et al. found that oxcarbazepine intake results in significant reductions in serum osmolality and serum sodium concentration after a water–load test, This hypotonic hyponatremia, which is not associated with a significant change in serum ADH, is the result of both a relative inability to dilute the urine and a reduction in the percentage of water excreted after the water–load test. He suggested that oxcarbazepine induced hyponatremia is not attributable to the SIADH. Possible mechanisms include a direct effect of the drug on the renal collecting tubules or an enhancement of their responsiveness to circulating ADH. 

It responds well to fluid restriction, salt supplementation with or without ESL withdrawal.

Consult Rounds: Hyponatremia and Rhabdomyolysis

A lesser known complication of hyponatremia or its correction is rhabdomyolysis. While recognized causes of rhabdomyolysis (Rb) include injury, seizures, drugs such as statins, hypokalemia and hypophosphatemia are known in the literature, less is known re association of hyponatremia leading to Rb.  

It was first described in 1979. In that patient, the low Na was from psychogenic polydipsia.
Multiple case reports following them( listed below) have been described in the literature. Most recently, this has been described in marathon runners that get both hyponatremic and Rb. In that study, the hyponatremic runners with the lowest post race Na demonstrated the highest CPK values at subsequent checkpoints. This is interesting.

What could be the mechanism?  What does the literature say?
1. Change in osmotic pressures results in failure of regulation of cell volume and cell lysis( so this could occur during hyponatremia or treatment of hyponatremia).
If the Na is corrected too rapidly, the cell has no time to compensate for the osmotic shifts and perhaps leads to Rb.
2. Na/Ca pump in muscle cells might be effected. As extracellular Na drops, Ca leaves the muscle cell and ensuing activation of cellular proteases leading to cell lysis.
3. Seizures leading to the rise in CPK

Situations where this has been described in the literature:
Most commonly: Psychogenic polydipsia
Others: use of thiazides, PPIs, Bactrim, marathon runners, adrenal insufficiency

Hmmm... Should we be checking CPKs in our severe hyponatremia cases? Should we be concerned about Rb in rapid correction ( more than CPM) as Rb is likely more commonly seen then CPM?


Here are some interesting references
http://link.springer.com/article/10.1007%2Fs00421-015-3324-4

https://www.ncbi.nlm.nih.gov/pubmed/25909317

http://www.ncbi.nlm.nih.gov/pubmed/21532723

https://www.ncbi.nlm.nih.gov/pubmed/22975551

http://www.revistanefrologia.com/en-publicacion-nefrologia-articulo-rhabdomyolysis-secondary-hyponatraemia-X2013251411052095

https://www.ncbi.nlm.nih.gov/pubmed/21168782

https://www.ncbi.nlm.nih.gov/pubmed/22778200

https://www.ncbi.nlm.nih.gov/pubmed/11696527

https://www.ncbi.nlm.nih.gov/pubmed/10396001

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1238676/

A novel look at hyponatremia in the alcoholics

Tavare and Murray in a recent NEJM image had an interesting case of hyponatremia correction. The case highlights development of central pontine myelinolysis(CPM) despite slow correction of hyponatremia.  CPM is known to occur in alcoholism, liver disease and malnourishment in the absence of hyponatremia, hypokalemia or hypophosphatemia. 

We wanted to suggest an algorithm that can be used in settings where alcoholics present with moderate to severe hyponatremia with similar symptoms as presented in this case and are at risk of CPM.  The figure below is a novel algorithm that uses brain imaging to help us guide the therapy for moderate to severe hyponatremia in alcoholics.  

If the patient is symptomatic with seizures, the correction of hyponatremia should be promptly started.  If the patient is asymptomatic  or with milder symptoms and is encephalopathic ( with several  confounding  etiologies : hyponatremia, alcoholism, liver disease), a MRI of the brain should be performed. If the MRI confirms cerebral edema, hyponatremia should be treated with the usual slow rate of correction of 6-9mmol/L per 24 hours.  If the MRI confirms CPM, the correction of hyponatremia should be put on hold.  

We hypothesize that often the hyponatremia  in alcoholics is  chronic  and correction, regardless of the rate, might cause harm in these patients.

We welcome comments from experts on this concept. 

Kenar D. Jhaveri, MD
Rimda Wanchoo, MD
Alessandro Bellucci, MD