How I Manage –Inpatient

Diuretics?
Dipen Zalavadia, MD
10/4/2023
Objectives:
• Uncertainty in diagnosis of heart failure
• An evidence-based approach to diuresis dose selection
• What is the optimal diuresis response?
• Approach to diuresis resistance
• When to transition to oral diuresis?
Heart Failure Definition:
• Complex Clinical syndrome with symptoms and signs
• Structural or functional impairment of ventricular filling or ejection of blood.
 Its Clinical Diagnosis:
Framingham Heart Failure Criteria
Major Minor
• PND or Orthopnea • Ankle edema
• Neck vein distension • Night Cough
• Hepatojugular reflux • Dyspnea on exertion
• Rale • Hepatomegaly
• Acute Pulmonary edema • Pleural effusion
• S3 gallop • Vital capacity increased 1/3rd
• Cardiomegaly from the maximum
• Increase venous pressure ≥ 16 cmH20 • Tachycardia ≥120 mins
• Circulation time ≥ 25 seconds
Weight loss ≥ 4.5 kg in 5 days in
response to treatment

2 Major Criteria
OR
1 Major + 2 Minor Criteria

McKee PA, NEJM 1971; 285 (26): 1441-6

Use of Biomarkers
NT-proBNP is used to support a diagnosis or exclusion of HF
Chronic HF
• BNP or NT-proBNP is recommended for risk stratification.
Hospitalized HF
• BNP or NT-proBNP levels at admission are recommended to establish a prognosis.
(Class I)
Predischarge Level
• Useful to inform the trajectory of the patient and establish post-discharge
prognosis (Class 2a)

Heidenreich et al. ACC/AHA/HFSA Guideline for heart failure 2022

Other Causes of Elevated pro-BNP:
• Acute coronary syndrome
• Advanced Age
• Pulmonary diseases (e.g., ARDS, COPD with core-pulmonale)
• Atrial Fibrillation
• Pulmonary embolism
• High-output state ( sepsis, anemia, hyperthyroidism)
• Renal dysfunction
When to repeat ECHO?
• Significant clinical change
• Received GDMT
• Being considered for invasive procedures or device therapy

In the absence of the above, a repeat assessment of LV Function is not indicated.

Heidenreich et al. ACC/AHA/HFSA Guideline for heart failure 2022

Classification:
Type of HF according to LVEF
HFrEF (HF with reduced EF)
HFimpEF (HF with improved EF)
HFmrEF (HF with mildly reduced EF)
HFpEF (HF with preserved EF)
Criteria
LVEF ≤40%
Previous LVEF ≤ 40% and follow up
measurement of LVEF > 40%
LVEF 41–49%
LVEF ≥50%
Evidence of spontaneous or provokable
increase LV filling pressures (e.g.,
elevated natriuretic peptide, non-invasive
and invasive hemodynamic
measurement)
HFpEF is a Challenging Diagnosis:
H2FPEF SCORE
< 2: Low Likelihood

≥ 6: High Likelihood

2–5: Further evaluation of

hemodynamics with exercise
echo or cardiac catheterization
to confirm or negate a
diagnosis.
Case:
• A 72-year-old male with a prior history of AMI presents with increasing shortness of
breath and lower extremities edema.
• He has a CRT-D, implanted 2-years ago.
• The outpatient regiment includes:
• Lisinopril 5 mg daily
• Coreg 3.125 mg twice a day
• Simvastatin 20 mg daily
• Aspirin 81 mg daily
• Spironolactone 25 mg daily
• Furosemide 80 mg daily in AM
On examination:
• Afebirle, HR 62 bpm, BP 110/70 mg daily, JVP – elevated, lungs - Crackles at the
bibasilar, Heart – 3/6 pan systolic precordial murmur, S3 gallop, Extremities – 3+
pitting edema, warm to touch.
Labs:
• Hgb 8 g/dl, Na 127, K 4.5, BUN 42, S Cr 1.9
EKG
• 100% AV paced
CXR
• Pulmonary vascular congestion
 Stevenson Classification of Heart Failure
Congestion
Orthopnea, rales, JVD, Ascites, Edema,
No Weight Yes

Diuresis first
Yes Warm and Dry Warm and Wet Vasodilator
Tap
Perfusion
Pulse pressure, Cold extremities
Mental status (sleepy, obtunded)
Inotropes
No Cold and Dry Wet and Cold Diuresis
Vasodilators
Inotropes
Fluid challenge
MCSD

Stevenson LW, EJHF; 2005

Sodium Reabsorption in Renal Tubules
5%
1–2%

DCT
PT

65-70%
Collecting
Duct
25%

Loop of Henle
 (NCC) Aldosterone
+
Na+/CI- Cotransporter
K sparing Amiloride,
Thiazides ENaC
diuretics Triamterene,
Aldactone
Eplerenone

DCT
CA
inhibitors NaHCO3 PT
Acetazolamide 65-70%
Collecting
Duct
Loop Diuretics

Na+-K+-Cl-
Cotransporter
(NKCC-2)

Loop of Henle
Loop Diuretics Pharmacodynamics

• Loop diuretics have a steep dose-response curve,

meaning that little effect until a threshold is
achieved, beyond which a ceiling effect is reached.

• In a patient with heart failure, the dose-response

curve is shifted downwards and to the right.

Felker et al. JACC 2020

Diuretic “NAÏVE”
• Furosemide 20-40 mg IV
• Torsemide 10 – 20 mg IV (low albumin states)
• Bumetanide 1 mg IV
• Double at 2-hour intervals to response or maximal dose
• CKD may require higher bolus (i.e., up to 200 mg furosemide)
 Diuretics in patients with chronic exposure
DOSE TRIAL
308 ADHF patients
2X2 Factorial Design
Lose dose (out pt) vs. High dose
(2.5x Output)
Bolus (q12h) vs. continuous infusion
Primary endpoints
Global assessment of symptoms at 72h
Change in serum cr at 72 h
• Low dose vs. high dose (2.5x out pt)
• High-dose more likely to be euvolemic at 48 h
• High-dose with greater net fluid loss, weight loss, and relief from dyspnea
• High dose is more likely to have an increase in Cr by 0.3 mg/dl
• There was a nonsignificant trend towards reduced hospitalization (36% vs.
27%)
• Bolus vs. continuous
• Bolus is more likely to require a dose increase at 48 h
• No difference in other endpoints
• Bottom line
• No difference

My take-home point is to give a high dose !!!

Felker GM et al. NEJM 2011; 364: 797-805

Diuretics in patients with chronic exposure
• The initial IV dose should be equal to or greater than (2.5 x )
maintenance oral dose
• e.g., 40 mg oral Furosemide =IV Lasix 40 mg or 100 mg
 What do the guidelines say?
AHA/ACC Heart Failure Guidelines (2013)
Class I
• HF patients should be promptly treated with IV loop diuretics
• Initial IV dose ≥ chronic oral dose as a bolus or continuous infusion
• Monitor I/O, weight, VS, lytes, renal function

Yancy CW et al. ACC/AHA Chronic HF Guideline 2013

Heidenreich et al. ACC/AHA/HFSA Guideline for heart failure 2022
Diuretics conversion ”math”

PO IV
Torsemide Bumetanide
Furosemide Furosemide
20 mg 1 mg
40 mg 20 mg
Adjusting of diuretics dosing
• Urine output should be measured within 2-hrs
• If there is not an adequate response to the initial dose, there is no need to wait
until the next scheduled dose to increase dosing.
• Urine Na+ monitoring may also be an effective strategy to guide diuretic dosing,
although not yet been tested in large studies.
 Decongestion: More = Better

Aggressive diuresis  Hemoconcentration 

Targeting 3-5 L urine output  more weight
More weight loss, more reduction in filling
loss, more fluids loss, no change in Cr
pressure, and better survival
Testani J et al. circulation 2010; 122: 265–272.
Grodin J et al. J cardiac Fail 2016; 22: 26–32
 Elevated Creatinine in a volume overload
• Rule out alternative causes of hyper-creatinemia
• Urinary obstruction
• Nephrotoxic agents (IV contrast, antibiotics, NSAIDs)
• If exam and/or invasive hemodynamics data are consistent with volume overload,
renal vascular congestion may be contributing to elevated creatinine and is
expected to improve with euvolemia.
• Increases in serum creatinine up to 0.5 mg/dl is expected during the diuresis
treatment.
#Kittlesonrules on Diuretics
• Warm + Wet = Faster is better. (Every day spent in the hospital is a chance to get
C. diff. Now it’s COVID.
• Each (+) of edema is 5 lbs
• I/O neg 2 L but weight is 2 Lbs  Trust weight
• Furosemide drips are your friend
• Sleep is important. Be Nice and consider the timing of diuresis.
• K pills are awful: spironolactone is the patient’s friend

Kittleson Rules AHF, Curbsider podcast; August 2020

 Diuretics Resistance
Pharmacology Extra Renal
• Inadequate dose • Cardiac output
• Poor absorption • Central venous congestion
• Hypoalbuminemia
Intra Renal
• Proximal tubule Na
reabsorption
• Hypo-chloremic alkalosis
• Compensatory distal tubule
Na reabsorption (Braking
phenomenon)
• renal perfusion pressure

Start with IV loop Inotropic support

diuretics at least 2.5x RHC to confirm filling pressure
home dose Mechanical support
OR • Sequential blockade with
Double the dose until thiazide diuretics
maximum diuresis (Metolazone, Chlortalidone)
effect is achieved. • Acetazolamide
• High-dose MRA
(spironolactone)
• SGLT-2 inhibitors
 The Neglected Electrolyte:
Chloride in Heart Failure
• Hypochloremia (Low serum chloride level) is an independent predictor of adverse
outcomes in acute on chronic HF.
• Various HF therapies may cause hypochloremia.
• Hypochloremia itself can initiate and exacerbate diuretic resistance in HF
• Upregulation of Na-K-2CI and Na-CI-cotransporters
• Decrease CI- delivery to tubular macula densa  Increase renin release  RAAS activation
• Chloride abnormalities may be managed through a number of medical therapies.

Zandijik et al, JACC 2021

 Serum chloride level in patients with HF

Hypochloremia
S CI < 96 mmol/L

normal S. Na, S. Na,

U. Cl-, Alkalosis Normal/ U. Cl-

Cl- depletion Hemodilution

• Co-administration of • Fluid restriction

acetazolamide • Loop diuretics
• Change to Cl- sparing diuretics • Adjuvant thiazide
(Spironolactone, Amiloride) • Vaptans
• SGLT2 inhibitors • Electrolytes repletion

Zandijik A.J.L et al JACC HF 2021

 Persistent Resistant to diuresis
• Ultrafiltration or HD is considered in diuretics unresponsive patients
• UF: No clear benefit upfront over diuresis
• Does not preserve renal function compared to diuresis
• Consider safety, cost, access
• UF is reserved for congested patients unresponsive to aggressive
diuresis.
 Can not take furosemide due to allergy?

Ethacrynic Acid
PO IV
Furosemide Furosemide Torsemide Bumetanide Etacrynic acid
40 mg 20 mg 20 mg 1 mg 50 mg
 (NCC) Aldosterone
+
Na+/CI- Cotransporter
K sparing Amiloride,
Thiazides ENaC
diuretics Triamterene,
Aldactone
Eplerenone

DCT
CA
inhibitors NaHCO3 PT
Acetazolamide 65-70%
Collecting
Duct
Loop Diuretics

SGLT2 inhibitors Na+-K+-Cl-

Cotransporter
(NKCC-2)

Loop of Henle
 Management of Diuretics therapy in patients with acute heart failure

On Oral Loop Diuretics

No Yes

≥20-40 mg IV Furosemide 1-2.5x daily oral dose IV

Urine Output after 2-3 hr ≥100–150 ml/hr

Urine spot sodium 2-3 hr ≥ 50–70 mEq/L
NO
YES

Repeat a similar dose Double dose IV until

every 12 hrs the maximum IV dose

Urine Output ≥100–150 ml/hr

Urine spot sodium ≥ 50–70 mEq/L at 2–6 hr
YES NO

Cont. until complete Check Na, SCr and Combination diuresis

decongestion electrolytes q24h therapy