The Co‐Administration of Albumin and Furosemide in Edema
Theories of Refractory Diuresis
Should we believe the long tail?
Furosemide
• Pharmacokinetics
– F=0.5 avg (range 0.1‐1)
• ↓ ka with HF
– PB: 95% Albumin – 50% excreted unchanged in urine
– 50% conjugated in kidneys
– t1/2 = 1.5‐2 hrs
– Cleared: 6‐8hrs Ann Pharm 2009; vol 43:1836-1847
Drug Therapy 1998; vol 339(6): 387-395
Hospital Pharmacy 2009; vol 44(2):129-149
Reasons for Persistent Fluid Retention Furosemide
• Pharmacodynamics
•
Site of action: Na+/K+/Cl‐
ascending Loop of Henle (lumen)
• Actively excreted (proximal tubule cells)
• Rate of response linked to rate of loop excretion • Effect of diuretic dissipates with infreq dosing
– Nephron ↑ Na+ reabsorption = rebound
• Side effects
•
•
•
•
Allergic reactions
Interstitial nephritis
Transient tinnitus (>160‐200 mg IV/dose; ototoxic drugs)
Fluid and electrolyte abnormalities (Na+,K+,Mg2+ )
Excess NA+ intake
Delayed intestinal absorption of diuretic
Inadequate diuretic dose
↑ NA+ re‐absorption at sites other than those blocked by loops
• ↓ diuretic excretion in urine
•
•
•
•
Drug Therapy 1998; vol 339(6): 387-395
Reasons for Persistent Fluid Retention Rate of Diuresis vs Loop Concentration
Excess NA+ intake
Delayed intestinal absorption of diuretic
Inadequate diuretic dose
↑ NA+ re‐absorption at sites other than those blocked by loops
• ↓ diuretic excretion in urine
•
•
•
•
Drug Therapy 1998; vol 339(6): 387-395
Reasons for Persistent Fluid Retention Excess NA+ intake
Delayed intestinal absorption of diuretic
Inadequate diuretic dose
↑ NA+ re‐absorption at sites other than those blocked by loops
• ↓ diuretic excretion in urine
•
•
•
•
Drug Therapy 1998; vol 339(6): 387-395
Reasons for Persistent Fluid Retention Excess NA+ intake
Delayed intestinal absorption of diuretic
Inadequate diuretic dose
↑ NA+ re‐absorption at sites other than those blocked by loops
• ↓ diuretic excretion in urine
•
•
•
•
Drug Therapy 1998; vol 339(6): 387-395
Drug Therapy 1998; vol 339(6): 387-395
Diuretic Tolerance
• Short‐term admin: (braking) • ↓ in response post 1st dose
• Protecting intravascular volume (RAAS and/or Symp?)
• Long‐term admin:
• Hypertrophy of distal portions of nephron
• Distal ↑ Na+ absorption = ↓ diuresis
• Logic of co‐administration of thiazide Drug Therapy 1998; vol 339(6): 387-395
Hypoalbuminemia and Decreased Furosemide Response
• PB: 95% • PD: Urine Concdiuretic dependent
• ↓ Albumin conc Æ ↑ Interstitial Concfuro
• ↓ Serum Concfuro Æ ↓ Concfuro at renal secretory sites
Drug Therapy 1998; vol 339(6): 387-395
Edema Treatment Guidelines
• Nephrotic Syndrome (2009)
•
•
•
•
IV Loop diuretics (↓ 0.5 to 1 kg/day)
Increase dose (80 to 120 mg IV)
Add alt diuretic (eg. metolazone)
Albumin not recommended (No evidence , ADRs, Cost)
• Cirrhosis (2009)
Initial tense ascites: paracetesis (<5 L no albumin)
Spironolactone
Furosemide (100mg:40mg ratio)
< 10% refractory routine medical therapy
Refractory: serial therapeutic paracenteses; liver transplant and TIPS
• Experimental medicine (Regular Albumin Infusions)
•
•
•
•
•
Albumun Indication Hypotension in hemodialysis Volume replacement/Expansion Hypoalbuminemia Indication not given Plasmapheresis Cardiac surgery: Postop volume expansion
Cardiac surgery: Prime pump Thermal injury Diuretic resistant peripheral edema/ Ascites Other Cerebral ischemia/Closed head injury/ Subarachnoid hemorrhage Post‐op, not specified Paracentesis and ascites Organ transplantation Nonhemorrhagic shock Prevention of peripheral edema/ Pulmonary edema/Ascites Hypovolemic and/or hemorrhagic shock Hepatic resection Nephrotic syndrome
% of total
albumin use 18.9% 15.0% 14.8% 9.4% 6.3%
5.6%
5.3% 3.0% 2.7%
2.4% 0.2% 20.7% 2.2% 11.6% 19.7% 10.2% 8.0%
0.6% 0.4%
2.9% 27.8%
12.3%
20.7%
8.4%
0% 3.4%
4.0%
4.1%
3.8%
2.2%
2.3% 2.2% 2.1%
2.0% 1.8%
7.0% 6.2% 0.1% 3.0%
2.4%
0%
0.2%
3.1%
1.5%
1.6%
1.6%
1.5% 1.1% 0.7% 0.6% 0.3% 2.5% 1.8% 0.1% 0.1% 2.2%
1.1%
0.7%
1.0%
0.8%
Am Fam Physician 2009;80(10):1129-1134
Hepatology 2009;49(6):2087-2107
Pharmacoeconomics
• Albumin costs approx $66 Cdn for 25g
• Not including administration cost
• BC 2003 Albumin Usage:
• 5.1% for Diuretic Resistant Peripheral Edema
% of 5%
% of 25%
albumin use albumin use
BCMJ 2005; vol 47(8):438-444
Clinical Question
• Should hospitalized edematous hypoalbuminemic patients be co‐
administered albumin with their diuretic therapy to improve diuresis?
• BC Albumin Expenditures 2006/2007
• $1.97 million
• Estimated cost for BC:
• $100,000 per year
Outline
•
•
•
•
•
•
•
Inoue study
Cirrhosis (Ascites)
Nephrotic Syndrome
Acute Lung Injury
Safety
Answer Clinical Question
Questions
Inoue, M et al (1987): Aka‐The Rat Study
Mechanism of Furosemide Resistance in Analbuminemic Rates and Hypoalbuminemic Patients
• Purpose: To elucidate the mechanism of resistance of hypoalbuminemic patients to furosemide.
• Two parts: – Analbuminemic Rats (NAR) vs Normal Rates
– Cross‐over study of edematous hypoalbuminemic patients
Kidney International 1987; vol 32: 198-203
Inoue, M et al (1987): Part One
Inoue, M et al (1987): Part One
o NAR
A. NAR
B. Normal
Drug Therapy 1998; vol 339(6): 387-395
Inoue, M et al (1987): Part One
Drug Therapy 1998; vol 339(6): 387-395
Inoue, M et al (1987): Part Two
Hypoalbuminemic/ Resistant Pts
‰ Brain Tumor (19 g/L)
o Cholangiocarcinoma (10 g/L)
Δ Pulmonary Edema (22g/L)
X CRF (22g/L)
• NAR alone
ƒ NAR with Albumin
o Normal Furosemide 20‐60 mg/dose IV
Drug Therapy 1998; vol 339(6): 387-395
Drug Therapy 1998; vol 339(6): 387-395
Ascites Formation
• Cirrhosis – Obstruction of hepatic vein Cirrhosis: Ascites
• ↑ Portal Vein Pressure
• Transudate (peritoneal cavity)
– SAAG > 11 g/L – Arterial vasodilation • Baroreceptors Æ Na+ and Water reabsorption
– ↓ renal function
– ↑ Aldosterone level
– ↓ Albumin production Æ ↓ Oncotic Pressure
Uptodate
Hepatology 2009;49(6):2087-2107
Cirrhosis: Albumin/ Furosemide Co‐administration Studies
Gentilini, Paolo et al. Albumin improves the response to diuretics in patients with cirrhosis and ascites: results of a randomized, control trial. Journal of Hepatology 1999; 30: 639‐645
Chalasani, Naga et al. Effects of Albumin/ Furosemide Mixtures on Responses to Furosemide in Hypoalbuminemic Patients. J Am Soc Nephrol 2001; 12:1010‐1016
Gentilini, Paolo et al. (1999) • RCT: N= 141 Cirrhotic patients admitted to hospital for ascites – Diagnosis confirmed via U/S and paracentesis
– Two parts:
• Bed rest and Diet (2.35 g NaCl/day) x 1 wk • Non‐responders
• Outcomes: Disappearance of Ascites, LOS;
Gentilini, Paolo et al.(1999) Gentilini, Paolo et al. • Method:
• 126 non‐responders (63 pts Group A; 63 pts Group B)
– Response: resolved ascites (U/S) and/or ↓ wt > 2.5 kg
• 200 mg/day K+ Canrenoate x 1wk (aldosterone antag)
• Group A:
– Post 1 wk: furosemide 25mg/day
– Non‐responders: (K+ Canrenoate/ Furosemide) ↑ 250/50, 300/75, 350/100, 400/130, 400/160 mg EOD
– Furosemide 25 mg tabs; > 100 mg/day = IV
– Non‐response ↑ EOD to 400/160 mg = Refractory
• Group B: – Received above plus 12.5 g Albumin/day
Responders: (A/B)
K+ Canrenoate- 34/34
K+ Canrenoate/ Furosemide- 13/23
Total: 47 (74.7%) / 57 (90.5%) sig
Responders (No Furosemide):
Group A and B: 34/63 and 34/63
Non‐Responders (Low Dose)
Group A and B: 16/62 and 6/62
Responders: (A/B)
K+ Canrenoate- 34/34
K+ Canrenoate/ Furosemide- 13/23
K+ Canrenoate/ ↑Furosemide- 10/4
Total: 57 (90.5%) / 61 (97%) sig(?)
Chalasani, Naga et al.(2001)
• N=13 (cirrhosis + ascites)
• No active infection or acute illness
• Intervention:
– Spironolactone
– Each pt received:
•
•
•
•
40 mg Furosemide
25 g Albumin
40 mg Furosemide + 25 g Albumin pre‐mixed ex vivo
40 mg Furosemide + 25 g Albumin admin different arms
• Outcomes: – Urine vol, Urine Na+, Nephron response, PK Chalasani, Naga et al.(2001)
Chalasani, Naga et al.(2001)
Chalasani, Naga et al.(2001)
Chalasani, Naga et al.(2001)
Urine Na+ Excretion
Urine Furosemide Excretion
Chalasani, Naga et al.(2001)
Conclusion: Cirrhosis(Ascites)
Serum Furosemide Conc:
• Trials did not use refractory patients
• No evidence of benefit beyond standard therapy.
Nephrotic Syndrome Edema
• Nephrotic Syndrome
Nephrotic Syndrome
– Losses of large quantities of protein in urine
• Hypoalbuminemia
– Reduced vascular colloid osmotic pressure
– Water: vascular Æ interstitial space
• ↓ Vascular volume Æ ↓ CO Æ Na+ and Water reabsorption
– Presentation: lower extremity edema, weight gain and fatigue (advanced: periorbital, genital edema, ascites, pleural/pericardial effusions)
– Proteinuria > 3.5 g/24hrs
Nephrotic Syndrome:
Albumin/ Furosemide Co‐
administration Studies
Davison, A et al. Salt‐poor Human Albumin in Management of Nephrotic Syndrome. BMJ 1974; 1:481‐484
Davison, A.M et al. (1974)
• N=12; nephrotic syndrome
• Edema resistant to conventional diuretics
• Intervention:
Akcicek, Fehmi et al. Diuretic Effect of Furosemide in Patients with Nephrotic Syndrome: Is it Potentiated by Intraveneous Albumin? BMJ 1995;310:162‐
163
Fliser, Danilo et al. Coadministration of Albumin and Furosemide in Patients with the Nephrotic Syndrome 1999;55:629‐634
Haws, Robert et al. Efficacy of Albumin and Diuretic Therapy in Children with Nephrotic Syndrome. Pediatrics 1993;91:1142‐1146
•
•
•
•
High protein diet, 1.3 g NaCl
Escalating furosemide 120 mg/day PO
EOD ↑ Furosemide (max 500 mg/day PO)
Spironolactone 50 mg QID
• Outcome:
• Resistance: failure to lose 1 kg daily for a period 5 days
– Added Albumin
Davison, A.M et al. (1974)
Davison, A.M et al. (1974)
Davison, A.M et al. (1974)
Davison, A.M et al. (1974)
Davison, A.M et al. (1974)
Akcicek, Fehmi et al. (1995)
• Issues:
• 12 pts with nephrotic syndrome
– Not hospitalized pts
– Not an RCT
– Small size
– Furosemide oral dosing to 500mg?
– 1 kg/day wt loss may have been high • (Recommended: 0.5‐1kg)
– Renal function during trial
– 1974 (ACEi and Steroid use?)
Akcicek, Fehmi et al. (1995)
– Failure to ↓ wt after bed rest and NaCl 2.3 g/day
• Not diuretic resistant
– Minimal lesions or well preserved glomerular histology
– Three treatments:
• 20% Albumin (0.5 g/kg) over 4 hrs
• Furosemide 60 mg IV followed by 40 mg/h x 4hrs
• Both Conclusion: Nephrotic Syndrome
• Trials did not use refractory patients
• Davison et al (?)
• Fluid status of pts?
• No RCT
• No evidence of benefit beyond standard therapy.
Acute Lung Injury
• Acute Phase:
Acute Lung Injury
• Alveolar flooding of protein rich fluid secondary to loss of integrity of alveolar capillary
• 12 to 72 hrs
• Resolution Phase:
• Dependent on repair of alveolar epithelium and clearance of pulmonary edema and removal of proteins from alveolar space. Hypoxemia improves.
• 7 days after onset of ALI
ALI: Albumin/ Furosemide Co‐
administration Studies
Martin, Greg et al. Albumin and Furosemide Therapy in Hypoproteinemic Patients with Acute Lung Injury. Crit Care Med 2002;30(10)
Martin, Greg et al (2005) • DB RCT PC
• N=50 MV ALI pts • Pa02/FiO2 <300 mmHg
• MV > 48 hrs
• Excluded: hemodynamic instability; renal insufficiency, hepatic failure
Martin, Greg et al. A Randomized, Control Trial of Furosemide With or Without Albumin in Hypoproteinemic Patients with Acute Lung Injury. Crit Care Med 2005; vol 33(8): 1681‐1687
• Treatment: (72 hrs)
• Albumin 25g q8h plus Furosemide 20 mg IV followed by 1mg/ml (max 10 mg/hr)
• Placebo plus Furosemide therapy
Martin, Greg et al (2005) Martin, Greg et al (2005) Martin, Greg et al (2005) Martin, Greg et al (2005) •
•
•
•
No electrolyte changes; 3/9 Hypotension
Pts had no other organ dys
Faster weight loss Difference in oxygenation early
• But would it be maintained longer
• Did not measure Na+ urine output
• ↔ Mortality (not powered)
• Overall: A larger is required that is powered to detect mortality
Safety
Clinical Question
• Not well reported in presented trials
– Small trials
– Not powered to look at ADRs
• Hyper/hypotension, tachycardia, fever, N/V
• Critical care (trauma, burns, surgery)
– Albumin for fluid resuscitation
• No difference in mortality vs crystalloids in fluid resuscitation
Should hospitalized edematous hypoalbuminemic patients be co‐
administered albumin with their diuretic therapy to improve diuresis?
NO
Cochrane Review CD000567
Way Ahead
– Future research required in ALI
– Maximize diuretic doses (↓Na+, Ø NSAID)
•
•
•
•
•
•
IV
Push Loop dose
Frequent dosing
Add additional diuretic
Continuous Infusions
Disease specific medical interventions
– Aggressiveness: Depends on pt
• Renal function, Electrolytes, Volume Status, Disease Status
Questions