# Presentation: 135024

## Albumin: Should It Be Used In Clinical Practice?

- Presented By: Paul Hebert

## What is Albumin?

- _Description_
- Human plasma protein
- Molecular weight of 66 Kd
- Most common plasma protein
- Synthesized in the liver
- Negatively charged
- _Function_
- Responsible for oncotic
- pressure
- Binds drugs and other
- substances
- Free radical scavenger

## What do we use Albumin for?

- Treatment of Hypovolemia
- Burns
- Nutritional replacement with TPN
- Hypoalbuminemia
- Hyperoncotic therapy

## What do we use Albumin for?

- 	Following large volume paracentesis
- 	Nephrotic syndrome resistant to potent diuretics
- 	Volume/Fluid replacement in plasmapheresis
_**Possibly indicated**_
- 	Adult respiratory distress syndrome
- 	Ovarian hyperstimulation syndrome
- 	Cardiopulmonary bypass pump priming
- 	Fluid resuscitation in shock/sepsis/burns
- 	Neonatal kernicterus
- 	To improve enteral feeding intolerance
_**Not indicated**_
- 	Correction of measured hypoalbuminemia or hypoproteinemia
- 	Nutritional deficiency, total parenteral nutrition
- 	Pre-eclampsia
- 	Red blood cell suspension
- 	Simple volume expansion (surgery, burns)
- 	Wound healing

- Bucur et al.  Hematology:Basic Principles and Practice.  2000; 2266

**What do we use Albumin for?**

## What do we use Albumin for?

- 	Cadaveric renal transplantation
- 	Cerebral ischemia
- 	Stroke
_**Common Usages**_
- 	Serum albumin <2.0 g/dl
- 	Nephrotic syndrome, proteinuria and hypoalbuminemia
- 	Labile pulmonary, cardiovascular status
- 	Cardiopulmonary bypass, pump priming
- 	Extensive burns
- 	Plasma exchange
- 	Hypotension
- 	Liver disease, hypoalbuminemia, diuresis
- 	Protein losing enteropathy, hypoalbuminemia
- 	Resuscitation
- 	Intraoperative fluid requirement > 5-6 L in adults
- 	Premature infant undergoing major surgery

- Bucur et al.  Hematology:Basic Principles and Practice.  2000; 2266

**What do we use Albumin for?**

## Back to Basics

## General Schema

- Interstitial

## EC

- What happens when you infuse H2O?

**Interstitial**

**Interstitial**

**Intracellular**

## EC

- What happens when
- you infuse 0.9% Saline in health?

**Interstitial**

**Interstitial**

**Intracellular**

## What happens when you infuse 

- What happens when you infuse
- 0.9% saline to edematous patients?

- Marked edema

- EC

**Intracellular**

**Intracellular**

**Interstitial**

**Interstitial**

## What happens when you infuse

- EC

-  5% Albumin (Iso-Oncotic Colloid)?

**Interstitial**

**Interstitial**

**Intracellular**

**Intracellular**

## EC

- What is the effect of hypertonic saline?

**Intracellular**

**Intracellular**

**Interstitial**

**Interstitial**

## Effect of “Hyper”-Oncotic Colloid

- EC

- Plasma

- ie 25% Albumin

**Interstitial**

**Interstitial**

**Intracellular**

**Intracellular**

## 30 RCTs in systematic review
1419 critically ill patients
Indications included hypovolemia, burns and hypoalbuminemia
All doses and concentrations of albumin (2.5, 4%, 5% and 25%)
Any control group (nothing, saline, Ringers, dextrose/Ringers)
No protocols of care
Limited assessment of quality

- 1419 critically ill patients
- Indications included hypovolemia, burns and hypoalbuminemia
- All doses and concentrations of albumin (2.5, 4%, 5% and 25%)
- Any control group (nothing, saline, Ringers, dextrose/Ringers)
- No protocols of care
- Limited assessment of quality

**Cochrane Injuries Group Albumin Reviewers, BMJ 1998;317:235-240**

**The controversy?...Albumin revisited**

## The controversy?...Albumin revisited

- Copyright ©1998 BMJ Publishing Group Ltd.

**Cochrane Injuries Group Albumin Reviewers, BMJ 1998;317:235-240**

**The controversy?...Albumin revisited**

- Favors control

- Favors Albumin

## The controversy?...Albumin revisited

- Copyright ©1998 BMJ Publishing Group Ltd.

**The controversy?...Albumin revisited**

**Cochrane Injuries Group Albumin Reviewers, BMJ 1998;317:235-240**

- Favors Albumin

- Favors Control

## The controversy?...Colloids versus crystalloids

**The controversy?...Colloids versus crystalloids**

- _Types of trials:_ 37 RCTs (n=1622)
- Excluded 11 RCTs in systematic review
- Mortality information on 1315 patients in 19 RCTs
- _Patients_:
- All critically ill patients requiring volume replacement
- Trauma, surgery, Burn, Sepsis, ARDS,
- _Interventions:_ Any colloid (2.5% and 5% and 25% albumin, pentaspan, Dextran-70, 6% Dextran, Hydroxyethyl starch, Haemacell,plasma and combination
- Colloid in hypertonic (n=10 trials)
- Controls included Ringers, .9% and 7.5% saline, 5% dextrose)
- No protocols of care
- _Methods:_
- Fixed effect models
- Limited assessment of quality

## The controversy?...Colloids versus crystalloids

- Copyright ©1998 BMJ Publishing Group Ltd.

**Schierhout and Roberts. BMJ 1998;316:961-964**

**The controversy?...Colloids versus crystalloids**

- Favors colloids

- Favors crystalloids

## The controversy?...Colloids versus crystalloids

- Copyright ©1998 BMJ Publishing Group Ltd.

**Schierhout and Roberts. BMJ 1998;316:961-964**

**The controversy?...Colloids versus crystalloids**

## Inferences by Authors

- “No evidence supporting that albumin administration reduces mortality”
- “Should not be used outside the context of rigorously conducted RCTs”
- “Resuscitation with colloid solutions was associated with an absolute increase in the risk of mortality of 4%”
- Inferences supported by BMJ Editorials

## But...Significant Limitations with meta-analyses

- Primary studies were very weak...most neither concealed or blinded
- Significant statistical heterogeneity
- Use of fixed effect models in analysis
- Combined different interventions (2.5%, 5%, 25%)
- Clinical heterogeneity a major concern
- Populations (neonates, adults) very different
- Many Indications
- Different control groups
- No protocols for administration
- Trials span 2 decades
- Mortality primarily driven by a few unbalanced studies

## *RR<1 favors crystalloids

| Author
Year | Population | Comparator | # Studies | RR*

 | 95% CI |
| --- | --- | --- | --- | --- | --- |
| Alderson
2002 | Critically ill | Albumin | 31 | 0.66 | 0.50 – 0.85
 |
| Wilkes
2001 | No restriction | Albumin | 55 | 0.90 | 0.78 – 1.05
 |
| Roberts
1998 | Critically ill | Albumin | 30 | 0.60 | 0.45 – 0.79 |
| Alderson
2002 | Critically ill
 | Colloids | 38 | 0.66 | 0.49 – 0.93 |
| Choi
1999 | All adult pts. | Colloids | 17 | 0.86 | 0.63 – 1.17 |
| Schierhout
1998 | Critically ill
 | Colloids | 19 | 0.84 | 0.69 – 1.02 |
| Wade
1997 | Trauma | 7.5% Saline/Dextran | 8 | 1.20** | 0.94 – 1.57 |
|  |  |  |  |  |  |

- ** Odds ratios

**Notes:**
7 published systematic reviews. 3 of these reviews compare albumin to crystalloids and three a number of different colloidal solutions to crystalloids for the most part in heterogeneous critically ill patient populations. The exception to this is the systematic review published by Wade and colleagues where he examined the effect of hypertonic saline in Dextran in comparison to saline in a set of trauma patients. 

A relative risk < 1 is in favor of crystalloid solutions and these relative risk ratios are the pooled sum of all studies. At first glance, all of the RR’s appear to be in favor of crystalloid solutions, with some reaching statistitcal significance. 

The exception is the review by Wade that which suggested a trend toward a reduction in the risk of death with hypertonic saline in dextran.  

## *RR < 1 favors crystalloids

| Author
Year | Some Sub-group 
Analyses:                       Pooled RR   (95% CI’s)
 |
| --- | --- |
| Wilkes
2001(A) | Surgery/trauma                     0.89        (0.69 - 1.18)
Ascites                                  1.08        (0.78 – 1.49) |
| Alderson
2002 (A) | Hypovolemia                        0.68        (0.90 - 1.03)
Burns                                    0.42        (0.19 - 0.90)
Hypoalbuminemia                0.73        (0.49 – 1.06) |
| Schierhout
1998 (C) | Trauma                                  0.77       (.057 – 1.05)
Surgery                                  1.82       (0.61 – 5.56)
Burns                                     0.83       (0.60 – 1.14) |
| Choi
1999 (C) | Trauma                                  0.39       (0.17 - 0.89)        
Non-Trauma                          0.98       (0.70 - 1.36) |
| Alderson
2002 (C) | HES                                       0.86       (0.51 - 1.47)
Gelatin                                   2.0         (0.33 – 12.5) 
Dextran                                 0.81        (0.61 – 1.06) |

**Notes:**
This slide demonstrates some of the sub group analyses from the 5 of the systematic reviews.
I am highlighting the sub – group analyses to illustrate that when you start to analyze these trials according to either patient population or type of colloid administered, the relative effectiveness of crystalloid therapy becomes more discordant.
Further, when you begin to analyze the individual studies you notice that the trials have very:
Inconsistent methodology employed (few trials blinded or used allocation concealment as a method of reducing bias)
Lack of description of co-interventions employed
Absent/ill defined/ or outdated resuscitation protocols

Finally, when you start to search for resuscitation trials conducted specifically on a septic shock population, there is really little out there.

One trial conducted by Rackow in 1983 published in CCM.
Total of 26 patients with hypovolemic and septic shock (18 had sepsis) compared 5% albumin to 6% hetastarch to 0.9% saline
Endpoints cardiorespiratory function (plasma COP, COP – PAW gradient, development of pulmonary edema)
Inclusion criteria: SBP < 90 mm hg, CI < 2.2, arterial lactate > 18 mg/dl, WP < 15 mm hg.
End point was a WP > 15 then fluid given to meet this endpoint next 24 hours
Fluid increased COP in A and H and decreased in S group
A and H group had greater COP – WP gradients
At 12 hour mark, 75% in S group vs 11% in each A and H group had interestitial edema on cxy

Rackow in 1989 CCM
20 patients with severe sepsis randomized to 5% albumin or 10% HES (pentastarch)
Fluid until WP > 15 mm hg
Amount of colloid to reach WP similar both groups
Similar increases in  CO, SV, SW.
Effect on coagulation similar but bigger decrease in factor VIIIc

## Why do meta-analyses report discordant results?

**Clinical Question****	****	****	****Study selection and inclusion**
- Populations of patients			Selection criteria
- Interventions				Application of the selection criteria
- Outcome measures			Strategies to search the literature
- Settings
**Data Extraction****	****	****	****	****Assessment of study quality**
- Methods to measure outcomes		Methods to assess quality
- End points				Interpretations of quality assessments
- Human error (random or systematic)		Methods to incorporate quality
- 					 assessments in review
**Assessment of the ability to combine ****	****Statistical methods for data synthesis**
**Studies****	****	****	****	****	**Fixed versus random effects
- Statistical methods
- Clinical criteria to judge
- the ability to combine studies

- Jadad, Cook, Browman  CMAJ 1997:156(10); 1411-1416

## 	Type					Example

- Jadad, Cook, Browman  CMAJ 1997:156(10); 1411-1416

- 	Type					Example
- ___________________________________________________________________
**Results**
- Direction of Effect			One review favors the experimental treatment 				and another favors the control treatment.
- Magnitude of Effect		One review suggests that the intervention results 				in a 30% reduction in mortality and another 					suggests that it results in a 5% reduction in 					mortality.
- Statistical Significance		One review shows a statistically significant 					difference between the experimental and the 					control treatments and another review shows a 				non-significant difference between them.
- Interpretation** ****	****	****	**Authors interpret same results differently

## Has use of Albumin decreased? 

- Copyright ©1999 BMJ Publishing Group Ltd.

**Roberts, I. et al. BMJ 1999;318:1214b**

- Has use of Albumin decreased?

## What type of fluid would you administer in the first 6 hours of resuscitation? (N=210)

## Does albumin supplementation improve oxygenation? 

- _Objective:_ to determine if 25% albumin added to furosemide improve urine output and pulmonary physiology
- _Design:_Double blind RCT
- _Patients:_ 37 mechanically ventilated patients with low total protein and ALI
- _Interventions:_5 day infusion of 100 mls of Albumin TID plus furosedmide infusion versus furosemide alone

- Martin et al, CCM,2002; pp2175-2182

## What did they find?

- 5.3 kg more weight loss in albumin group (p=0.04)
- Improved PaO2/FIO2 ratio (171 vs 236, p=0.02)
- Improved hemodynamics with decreased heart rate and increased blood pressure
- No change in other measures of lung mechanics

- Martin et al, CCM,2002; pp2175-2182

## Does albumin supplementation improve outcomes in spontaneous bacterial peritonitis?

- _Objective:_ to determine whether plasma expansion with 20% albumin prevents renal impairment and reduces mortality
- _Design:_ randomized trial involving 7 tertiary centres
- _Patients:_ 126 patients with cirrhosis and spontaneous bacterial peritonitis
- _Interventions:_ cefotaxime versus cefotaxime and albumin infusion of 1.5 g/kg with cefotaxime.
- No active controls and not blinded

- Sort et al, NEJM 1999 pp 403-9

## What did they find?

- Outcomes			Albumin		Control		p value
- 					(n=63)		(n=63)
- Resolution of infection 		98%		94%		0.36
- Renal impairment n(%)		21(33%)	6(10%)		0.002
- Hospital mortality n(%)		18(29%)	6(10%)		0.01
- 3 month mortality		26(41%)	14(22%)	0.03

- Sort et al, NEJM 1999 pp 403-9

- Do protocols of care
- and timing matter?

## Slide 33

**Notes:**
The basis for early goal directed therapy was to prevent the harmful aspects of previous outcome studies.  Such as the use of over 200 micrograms per kilogram per minute of dobutamine to reach a cardiac index of 4.5 liter per minute per meter squared  as Hayes did in the New Journal of Medicine study in 1994.  We also decided to take high risk patients, with evidence of global tissue hypoxia and to treat at an earlier stage of disease presentation.

## Does early treatment of global tissue hypoxia improve outcome?

**The Rivers Hypothesis**

## Oxygen Debt: To Pay or Not to Pay

**Oxygen Debt: To Pay or Not to Pay**

## Optimization Trials“Every hemodynamic study is not Shoemaker”

- (Boyd, New Horiz, 1996)

- Early

- Late

- (Kern, Crit Care Med, 2002)

**Notes:**
However, if we examine the meta-analyses, we can see that these optimization studies do have merit. If you categorize those patients as having late optimization versus those as having pre-operative or early optimization, earlier optimization has better outcome.  This was also recently confirmed by Kern and Shoemaker in the journal of critical care medicine this year.  They showed that patient optimized before organ failure had the better outcomes.

## Goal Directed Therapy in the Critically Ill

- _Goal: _to determine if early Goal-directed therapy targeting
- treatment of venous hypoxia improved clinical outcomes
- _Setting: _Single centre study
- _Study Population:_263 patients with EARLY sepsis and septic
- shock
- _Study Design:_ Open labeled RCT
- _Intervention:_Goal-directed vs standard therapy initiated in ER for 6 hours
- _Outcome:_ In-hospital mortality

**Rivers et al NEJM 2001;345:1368**

## Early Goal-directed Therapy

**Supplemental oxygen ± endotracheal intubation and mechanical ventilation **

**Rivers et al NEJM 2001;345:1368**

**Notes:**
In the EGDT group the patients received supplemental oxygen or endotracheal intubation and mechanical ventilation.   After central and arterial catheterization, patients were sedated if mechanically ventilation.  Patients received the same fluid administration to a central venous pressure of at least 8 to 12, a mean arterial pressure of greater than 65 millimeter of mecury with vasopressors or less than 90 with vasodilatiors.  If goals were achieved this management was suffice.  However, if the central venous oxygen saturation was less than 70 percent the patients received a red cell transfusion to a hematocrit of greater than 30.  If the central venous saturation remained less than 70 millimeter of mercury, dobutamine was used but maintaining the heart rate less than 100.  These patients were continuously cycled during a mandatory 6 hour stay in the emergency department.

## More Details About the Intervention

- Goal-directed vs standard therapy initiated in ER for 6 hours:
- Both Groups were maintained with:
- CVP  8 – 12
- MAP ≥ 65
- Urine output ≥ 0.5 ml/kg/hr
- Treatment group had CVP with continuous O2
- Monitoring with target of mixed saturation ≥ 70%
- Targets of therapy were:
- Oxygen saturation ≥ 93%
- HCT ≥ 30%
- Cardiac Index
- Systemic oxygen consumption

**Rivers et al NEJM 2001;345:1368**

## Goal Directed Therapy in the Critically Ill

- 0 – 6 hours, Goal vs Standard Therapy
- Fluids: 4981 ml vs 3499 ml, p < .001
- RBC:  64.1% vs 18.5%, p < .001
- Vasopressor:  27.4% vs 30.3%, p = 0.62
- Inotropes:  13.7% vs 0.8%, p < .001

**Rivers et al NEJM 2001;345:1368**

## Early Goal directed therapy(1)

|  | Dead | Alive | %Dead |
| --- | --- | --- | --- |
| Goal-directed  | 
38 | 
92 | A=38/130=30.5% |
| Control | 
59 | 
74 | B=59/133=46.5% |

- Absolute Risk Reduction(ARR)= 16%

- 	Relative Risk (RR)= 30.5 /46.5=0.66 (95% CI of 0.38 – 0.87)

- Relative Risk Reduction(RRR)= (1- 0.66) x 100= 34%

- Odds Ratio (OR)= a*d /b*c = 0.52

- Number needed to treat (NNT)= 1/0.16= 6

- (1)Rivers et al, NEJM, 2001,1368-77

## What can we infer?

- The type, timing and quantity of fluid resuscitation may impact on mortality
- Complex area of care with few high quality trials
- Meta-analyses primarily highlight deficiencies in literature
- Can’t and should not infer treatment choices based upon meta-analyses
- Albumin may be beneficial in improving oxygenation in ALI and supporting patients with cirrhosis who have bacterial peritonitis
- Early aggressive fluid resuscitation may save lives
- Less evidence in support of other colloids

## What do I recommend?

- Further clinical trials addressing following questions:
- Different % albumin versus crystalloid in various settings
- Different colloids versus crystalloids in various settings
- All crystalloids not created equal either???
- Treatment protocols versus usual care

## And then we were SAFE’ed

## Thank You