What is the literature to support albumin 25% infusion rates faster than 2 ml/minute?

Comment by InpharmD Researcher

Data demonstrating infusion of albumin 25% at more rapid infusion rates than 2 mL/min are sparse, appearing to be limited to a single dated in vivo study that included 9 patients (see Table 1). Generally, rapid infusion is not recommended due to safety concerns. The appropriate dosage, infusion rate, and concentration should ultimately be determined by individual patient characteristics, including the presence of comorbidities.

Background

A 2009 publication details a comprehensive set of recommendations for the use of albumin and immunoglobulins based on a systematic review of existing literature and guidelines. Albumin plays a critical role as a plasma expander, particularly highlighting its limited availability and high cost, necessitating clearly defined indications for its use. Albumin is generally well-tolerated as a therapeutic agent, although there is the possibility of immediate allergic-type reactions. Additionally, rapid infusion rates, ranging from 20 to 50 mL per minute, may lead to a sudden drop in systemic blood pressure. This can be particularly problematic in elderly patients and those susceptible to congestive heart failure, especially when more concentrated albumin solutions are used, with the risk of inducing overt congestive heart failure. [1]

A 1999 prospective investigation (Table 1) examined the effects of 25% human serum albumin on calcium concentrations in a cohort of nine patients, primarily situated in an intensive care unit. The administration of albumin infusions for study inclusion was based on the typical infusion rates observed at the study hospital, specifically 100 ml given over less than 30 minutes. This rate is notably faster than the commonly recommended rate of 1 ml/min found in medication handbooks for 25% albumin. There is a possibility that administering 100 ml infusions of a 25% albumin solution very rapidly, such as in less than 5 minutes, could lead to clinically significant decreases in ionized calcium concentrations. The study collected arterial blood samples to measure ionized and total calcium concentrations at three critical time points: one hour before the albumin infusion, immediately after the infusion, and six hours post-administration. The findings indicated no significant differences in ionized calcium concentrations across these time periods (1.09±0.23, 1.06±0.22, 1.06±0.21 mmol/l, respectively) as well as in total calcium levels (2.03±0.18, 2.05±0.20, 2.08±0.23 mmol/l, respectively). Although patients exhibited the expected rise in albumin concentration, there was no substantial change in calcium measurements that could suggest a clinically significant effect.These results imply that intensive monitoring of calcium concentrations might not be necessary during the administration of 25% albumin for most adult patients, although it suggested further research in other populations, such as neonates, where compensatory responses may be inadequate. [2]

References: [1] Liumbruno GM, Bennardello F, Lattanzio A, Piccoli P, Rossettias G; Italian Society of Transfusion Medicine and Immunohaematology (SIMTI). Recommendations for the use of albumin and immunoglobulins. Blood Transfus. 2009;7(3):216-234. doi:10.2450/2009.0094-09
[2] Erstad BL, Richards H, Rose S, Nakazato P, Fortune J. Influence of twenty-five per cent human serum albumin on total and ionized calcium concentrations in vivo. Crit Care. 1999;3(4):117-121. doi:10.1186/cc353
Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What is the literature to support albumin 25% infusion rates faster than 2 ml/minute?

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Influence of twenty-five per cent human serum albumin on total and ionized calcium concentrations in vivo
Design

Prospective study

N= 9
Objective To determine the interaction between exogenous 25% albumin administration and calcium concentrations in patients
Study Groups All patients (n= 9)
Inclusion Criteria English speaking patients aged ≥18 years who received 100ml 25% albumin over less than 30min
Exclusion Criteria Patients with parathyroid disease, acute renal failure, pancreatitis, marked acid-base imbalances, or receiving medications affecting calcium or albumin concentrations
Methods Patients received 100ml of 25% albumin over less than 30 minutes. Arterial blood samples were collected before, at the end, and 6 hours after infusion to measure albumin, total calcium, and ionized calcium concentrations
Duration Not specified
Outcome Measures Primary: Changes in ionized calcium concentrations Secondary: Changes in total calcium concentrations
Baseline Characteristics   All patients (n= 9)
Age, years 27 to 84
Sex - Male 5
Sex - Female 4
Primary problem - Liver disease 3
Primary problem - Post-liver transplant 3
Primary problem - Trauma 2
Primary problem - Intestinal complications 1
Results   Ionized calcium (mmol/l) Total calcium (mmol/l)
Baseline 1.09 ± 0.23 2.03 ± 0.18
End of infusion 1.06 ± 0.22 2.05 ± 0.20
6 hours after infusion 1.06 ± 0.21 2.08 ± 0.23
Adverse Events No acute events or adverse reactions were observed during the 6-hour monitoring period
Study Author Conclusions In patients receiving infusions of 25% albumin, circulating calcium concentrations are well regulated by homeostatic mechanisms, and albumin infusions had no effect on calcium concentrations.
Critique The study was limited by a small sample size and the lack of a control group. The rapid infusion rate may not reflect typical clinical practice, and more intensive blood sampling might have revealed transient changes in ionized calcium concentrations.
References:
[1] Erstad BL, Richards H, Rose S, Nakazato P, Fortune J. Influence of twenty-five per cent human serum albumin on total and ionized calcium concentrations in vivo. Crit Care. 1999;3(4):117-121. doi:10.1186/cc353

 

Fast versus slow infusion of 20% albumin: a randomized controlled cross-over trial in volunteers

Design

Open-labeled, randomized, interventional, controlled, cross-over trial

N= 12

Objective

To investigate whether plasma volume (PV) expansion of 20% albumin is larger when the fluid is administered rapidly compared with a slow infusion

Study Groups

All participants (N= 12)

  • Albumin administered over 30 minutes (fast infusion)
  • Albumin administered over 120 minutes (slow infusion)

Inclusion Criteria

Age between 18 and 60 years, absence of medical disease and medication

Exclusion Criteria

Pregnancy, difficulties with placement of venous cannulas, and severe allergy

Methods

Eligible patients underwent two infusions experiments, 3 to 20 weeks apart, where they received 3 mL/kg of 20% albumin (approximately 225 mL) over 30 minutes and 120 minutes in a cross-over fashion. Blood hemoglobin and plasma albumin were measured on 15 occasions during 6 hours to estimate the PV expansion and the capillary leakage of albumin and fluid. 

Duration

February 2018 and November 2018

Outcome Measures

Primary: plasma dilution, which equals the relative change in plasma volume, at 6 h and at the end of the infusions of hyper-oncotic albumin

Secondary: intravascular half-life of the excess amount of albumin and the plasma dilution

Baseline Characteristics

  

All participants (N= 12)

 

  

Age, years

 28 ± 10    

Female

50%    

Body weight, kg

 75 ± 10    

Body mass index, kg/m2

 24.2 ± 2.8    
Plasma albumin concentration, g/L

40.0 ± 2.2 (fast infusion)

40.0 ± 2.0 (slow infusion)

    
Colloid osmotic pressure, mmHg

25.0 ± 1.0 (fast infusion)

25.1 ± 1.4 (slow infusion)

    
Volume of infused 20% albumin, mL

225 ± 31

    

Results

Endpoint

30-minute infusion

120-minute infusion

p-value

Plasma volume expansion (mL/kg)

0.5 h

2 h

6 h

Largest PV expansion, %

 

5.4 ± 2.2

4.2 ± 2.6

2.5 ± 2.4

16.1% ± 6.5%

 

1.5 ± 1.6

4.9 ± 1.6

2.5 ± 2.5

12.8% ± 4.0%

 

0.001

0.46

0.92

0.52

Area under the curve (AUC) excess albumin (g*min/kg)

0-2 h

50.3 (40.5–58.2)

28.2 (24.8–31.8)

0.003

Half-life albumin mass, h

8.0 (5.4–11.6)

6.3 (4.4–8.4)

0.028

AUC ∆plasma volume (L*min/kg)

0–2 h

0–6 h

 

0.44 (0.40–0.65)

1.08 (0.73–1.90)

 

0.26 (0.19–0.42)

0.97 (0.67–1.68)

 

0.034

0.31

Half-life plasma volume, h

5.6 (3.4–7.7)

5.4 (2.0–10.1)

0.347

Increase in colloid osmotic pressure, mmHg

2.7 ± 1.5

3.0 ± 1.1

0.65

Recruited extravascular fluid, mL/mL

3.1 ± 1.3

3.1 ± 1.4

0.84

Increase in plasma albumin, g/L

 6.6 ± 2.3 7.1 ± 2.3 g/L 0.62

Intravascular half-life of the excess albumin, hour

 8.0 6.3  0.028

Cumulative urinary output at 6 h, mL

 631 ± 354 612 ± 242 0.83

Adverse Events

No adverse events were reported

Study Author Conclusions

The intravascular persistence of albumin was longer, but the fluid kinetics was the same, when 20% albumin was infused over 30 min compared with 120 min. We found no disadvantages of administering the albumin at the higher rate.

InpharmD Researcher Critique

Since the subjects of this study were healthy volunteers, the data may not be extrapolated to severely ill patients. A comprehensive report of adverse events was not disclosed. The study is also subject to limitations and biases inherent to its small sample size, cross-over, and single-center design. Lastly, it remains unclear if the kinetic results of the 20% albumin can be extrapolated to the 5% albumin infusion.   



References:
[1] Zdolsek M, Sjöberg F, Hahn RG. Fast versus slow infusion of 20% albumin: a randomized controlled cross-over trial in volunteers. Intensive Care Med Exp. 2022;10(1):31. Published 2022 Jul 18. doi:10.1186/s40635-022-00458-3

 

Albumin Infusion Rate and Plasma Volume Expansion: A Randomized Clinical Trial in Postoperative Patients After Major Surgery

Design

Single-center, prospective randomized physiological trial

N= 70

Objective

To test if plasma volume expansion by 5% albumin is greater if fluid is administered slowly rather than rapidly

Study Groups

Slow infusion (n= 33)

Rapid infusion (n= 31)

Inclusion Criteria

Scheduled for non-emergent Whipple operation or major gynecological cancer surgery, ≥ 40 years of age, indication for fluid therapy as judged by the physician caring for the patient and at least one of the following criteria: positive "leg raising test" (pulse pressure increase > 9%), central venous oxygen saturation < 70%, arterial lactate > 2.0 mmol/L, urine output < 0.5 mL/kg the hour prior to inclusion, respiratory variation of the inferior vena cava of more than 15%, and systolic blood pressure < 100 mmHg or mean arterial blood pressure < 55 mmHg

Exclusion Criteria

Hypersensitivity to the active drug or the tracer; signs of postoperative bleeding; history of heart failure; physician caring for the patient considered there to be strong reasons to administer another fluid or the same fluid, but in another way or in a different volume than stated in the protocol; pregnancy; clinical judgment by the investigator or treating physician that the patient should not participate in the study for reasons other than described above

Methods

Eligible patients were randomized (1:1) to receive 5% albumin at a dose of 10 mL/kg of predicted body weight in either 30 minutes (rapid infusion) or 180 minutes (slow infusion). No other fluids other than maintenance (2.5% or 5% glucose with electrolytes at a rate of 1 mL/kg/h) and study fluids were given during the intervention period. Hemodynamic data were recorded immediately prior to the start and at 180 min after the start of albumin infusion. Diuresis was recorded 4 h before and 6 h after the start of infusion.

Duration

Follow-up: 30 days postoperatively

Outcome Measures

Primary: change in plasma volume from the start to 180 minutes after the start of albumin infusion

Secondary: change in the area under the plasma volume curve from the start to 180 minutes after the start of infusion of albumin, transcapillary escape rate (TER), changes in hemodynamic parameters, diuresis, plasma concentrations of hormones involved in fluid homeostasis, and plasma concentration of glycocalyx components and incidence of postoperative complications up to 30 days posteropatively

Baseline Characteristics

  

Slow infusion (n= 30)

Rapid infusion (n= 31)

  

Age, years

 69 68  

Female

76% 52%  

Body mass index, kg/m2

 25 25  

ASA class

1

2

3


0

65%

33%


6%

68%

26%

  

Inclusion criteria met

PLR

ScvO2

Lactate

Urine production

Systolic blood pressure


70%

29%

62%

38%

27%


65%

29%

65%

42%

26%

  

Operation time, min

368

418

  

Intraoperative bleeding, mL

600

500

  

Intraoperative fluids

Crystalloids, mL

Colloids, mL


4,250

500


4,250

700

  

Pre-treatment hemodynamics

HR, beats/min

Systolic blood pressure, mmHg

MAP

CVP, cmH2O

Urine production, mL/kg/h


84

114

77

3

0.8


88

112

77

3

0.8

  

Pre-treatment laboratory data

Albumin, g/L

Lactate, mmol/L

ScvO2, %

Hematocrit, %


31

2.2

73

36


33

2.7

73

35

  

Glycocalyx components and hormones

Hyaloronan, ng/mL

Syndekan-1, ng/mL

Glypican-4, ng/mL

Copeptin, pmol/L

MR-proANP, pmol/L

Renin, mU/L


153

56

13

138

85

51


174

91

13

113

94

40

  

Norepinephrine at inclusion

 9% 3%  

Data are presented as the median values unless otherwise indicated.

ASA, American Society of Anesthesiologists; PLR, passive leg raising; ScvO2, central venous oxygen saturation; HR, heart rate; MAP, mean arterial pressure; CVP, central venous pressure; MR-pro-ANP, mid-regional pro-atrial natriuretic peptide

Results

Primary outcome

Slow infusion (n= 30)

Rapid infusion (n= 31)

Mean difference (95% CI); p-value

Increase in plasma volume from the start to 180 min after the start of infusion, mL/kg

 7.4 ± 2.6 6.5 ± 4.1 0.9 (-0.8 to 2.63); 0.301

Secondary outcomes

 Slow infusion (n= 30) Rapid infusion (n= 31) Absolute difference/risk reduction (95% CI); p-value

Hemodynamics

Δ plasma volume over time, min·mL/kg

TER, %/h

ΔHR, beats/min

ΔScvO2, %

ΔHematocrit, %

ΔMAP, mmHg

ΔCVP, cmH2O

ΔAlbumin, g/L

ΔLactate, mmol/L


866 ± 341

5.3 ± 3.1

0 ± 12

1 ± 5

-4 ± 2

4 ± 12

2 ± 3

4.9 ± 1.6

-0.4 ± 0.8


1,226 ± 419

5.4 ± 3.0

1 ± 10

2 ± 9

-4 ± 2

5 ± 13

1 ± 3

3.8 ± 1.4

-0.3 ± 1.2


360 (169 to 550); < 0.001

0.1 (-1.6 to 1.5); 0.931

1 (-7 to 4); 0.665

1 (-3 to 5); 0.682

0 (-1 to 1); 0.912

1 (-7 to 6); 0.830

1 (-3 to 1); 0.164

1.1 (0 to 2); 0.017

0.1 (-0.4 to 0.6); 0.565

Postoperative complications, n

 8 6 2 (-2.2 to 0.5); 0.765

Diuresis, mL/kg/h

 1.0 ± 0.4 1.1 ± 0.6 -0.1 (-0.1 to 0.4); 0.325

Glycocalyx components and hormones

ΔHyaloronan, ng/mL

ΔSyndecan-1, ng/mL

ΔGlypican-4, ng/mL

ΔCopeptin, pmol/L

ΔRenin, mU/L

ΔMR-proANP, pmol/L


-2.6 (-29.7 to 19.1)

31.1 (-0.3 to 49.3)

1.2 ± 5.8

-73.9 (-140.8 to 26.9)

-14.3 (-48.0 to -5.3)

20.6 (10.5 to 33.2)


2.8 (-26 to 51)

-1.6 (-17 to 64.4)

-2.5 ± 7.9

-59.3 (-150.1 to 39.5)

-29.9 (-82.8 to -7.6)

47.8 (31.8 to 71.8)


16.6 (-52.8 to 19.6); 0.461

2.9 (-39.1 to 44.9); 0.160

3.6 (0 to 7.3); 0.048

20.6 (-40.3 to 81.6); 0.785

27.4 (-6.2 to 60.9); 0.186

-25.3 (-40 to -10.7); < 0.001

Values are presented as either the mean ± standard deviation or median (interquartile range).

CI, confidence interval

Adverse Events

Common Adverse Events: Not disclosed

Serious Adverse Events: Not disclosed

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

This study does not support our hypothesis that a slow infusion of colloid results in a greater plasma volume expansion than a rapid infusion. Instead, our result of a smaller change in the area under the plasma volume curve indicates that a slow infusion results in a less efficient plasma volume expansion, but further studies are required to confirm this finding. A rapid infusion has no effect on vascular leak as measured after completion of the infusion.

InpharmD Researcher Critique

It was identified that a protocol amendment extended the inclusion criteria to include postoperative patients after major gynecological cancer surgery (open ovarian and endometrial debulking surgery) to promote recruitment. Specific postoperative complications were not identified for each group, but there does not appear to be an increased safety concern when administering albumin 5% rapidly (over 30 minutes) based on these results.



References:
[1] Statkevicius S, Bonnevier J, Fisher J, et al. Albumin infusion rate and plasma volume expansion: a randomized clinical trial in postoperative patients after major surgery. Crit Care. 2019;23(1):191. Published 2019 May 28. doi:10.1186/s13054-019-2477-7