1104/22/2304/22/23

Ammar AlsughayirAmmar AlsughayirTM fellowTM fellow

University of Ottawa University of Ottawa

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BackgroundBackground

• The administration of intravenous fluids to The administration of intravenous fluids to maintain or increase intravascular volume is a maintain or increase intravascular volume is a common intervention in the intensive care unit common intervention in the intensive care unit (ICU), but there is uncertainty whether the choice (ICU), but there is uncertainty whether the choice of fluid significantly influences patients’ outcomes.of fluid significantly influences patients’ outcomes.

• There is uncertainty about the best choice of fluids There is uncertainty about the best choice of fluids due to the lack of adequately powered due to the lack of adequately powered randomized, controlled trialsrandomized, controlled trials

• both crystalloid-based and colloid-based both crystalloid-based and colloid-based resuscitation strategies have been advocatedresuscitation strategies have been advocated

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Background Background • The Saline versus Albumin Fluid Evaluation (SAFE) The Saline versus Albumin Fluid Evaluation (SAFE)

study compared the effect of fluid resuscitation with study compared the effect of fluid resuscitation with albumin or saline on mortality in a heterogeneous albumin or saline on mortality in a heterogeneous population of patients in intensive care units (ICUs).population of patients in intensive care units (ICUs).

• Overall, the study showed no significant difference Overall, the study showed no significant difference in the risk of death among patients who received in the risk of death among patients who received albumin as compared to those who received salinealbumin as compared to those who received saline

• Evidence of heterogeneity of treatment effects Evidence of heterogeneity of treatment effects among patients who did and those who did not have among patients who did and those who did not have a diagnosis of trauma; this evidence resulted from a diagnosis of trauma; this evidence resulted from an increased number of deaths among patients with an increased number of deaths among patients with traumatic brain injury who received albumintraumatic brain injury who received albumin

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Background Background Uncertain clinical significance for two main Uncertain clinical significance for two main

reasonsreasons1.1. did not collect sufficiently detailed data to did not collect sufficiently detailed data to

demonstratedemonstrate that baseline factors known to influence outcomethat baseline factors known to influence outcome

2. The primary outcome of the SAFE study was the rate 2. The primary outcome of the SAFE study was the rate of death within 28 days after randomization, whereas of death within 28 days after randomization, whereas current consensus recommendations cite mortality current consensus recommendations cite mortality and functional neurologic outcomes between 6 and and functional neurologic outcomes between 6 and 24 months as appropriate outcome measures after 24 months as appropriate outcome measures after traumatic brain injury.traumatic brain injury.

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ObjectivesObjectivesThe aims of the study were The aims of the study were 1.1. to document baseline characteristics that are to document baseline characteristics that are

known to influence outcomes from traumatic known to influence outcomes from traumatic brain injury in the albumin and saline groups brain injury in the albumin and saline groups and and

2.2. to compare death and functional neurologic to compare death and functional neurologic outcomes in the two groups 24 months after outcomes in the two groups 24 months after randomizationrandomization..

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MethodsMethods

Study DesignStudy Design• Post hoc follow-up study of patients Post hoc follow-up study of patients

from the SAFE study who had from the SAFE study who had traumatic brain injury.traumatic brain injury.

• Double-blind, Double-blind, • randomized, controlled trial randomized, controlled trial • was conducted in multidisciplinary ICUs of 16 hospitals in was conducted in multidisciplinary ICUs of 16 hospitals in

Australia and New Zealand Australia and New Zealand • between November 2001 and June 2003between November 2001 and June 2003

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Study designStudy design• 4% albumin (Albumex, CSL) or normal saline for all 4% albumin (Albumex, CSL) or normal saline for all

fluid resuscitation in the ICU until death, discharge, fluid resuscitation in the ICU until death, discharge, or 28 days after randomizationor 28 days after randomization

• Randomization was stratified by a diagnosis of Randomization was stratified by a diagnosis of trauma (defined as an injury to the body caused by trauma (defined as an injury to the body caused by mechanical forces, excluding burns)mechanical forces, excluding burns)

• Traumatic brain injury was defined as a diagnosis of Traumatic brain injury was defined as a diagnosis of – trauma plus a score of 13 or less on the Glasgow Coma trauma plus a score of 13 or less on the Glasgow Coma

Scale (GCS) at first hospital presentation and Scale (GCS) at first hospital presentation and – an abnormality on a computed tomographic (CT) scan of an abnormality on a computed tomographic (CT) scan of

the head consistent with traumatic brain injurythe head consistent with traumatic brain injury

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Study designStudy designInclusion criteriaInclusion criteria• The patients presented in the main SAFE study The patients presented in the main SAFE study

report report • plus any additional patients with a diagnosis of plus any additional patients with a diagnosis of

head injury that was recorded on admission to the head injury that was recorded on admission to the hospital hospital

• review the clinical records and CT scans to confirm review the clinical records and CT scans to confirm that all patients satisfied the SAFE–TBI study that all patients satisfied the SAFE–TBI study criteria.criteria.

• Determined Determined prospectivelyprospectively the vital status and the vital status and functional neurologic outcomes 24 months after functional neurologic outcomes 24 months after randomization.randomization.

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Baseline assessmentBaseline assessment

1.1. Age, sex, and the severity of the illness and the Age, sex, and the severity of the illness and the injury injury

2.2. APACHE II score was calculated from worst APACHE II score was calculated from worst values in the 24 hours values in the 24 hours

3.3. Brain injury indices used were the Brain injury indices used were the – last recorded GCS score before randomizationan last recorded GCS score before randomizationan – separate recording of the motor component of the GCSseparate recording of the motor component of the GCS– an assessment of the severity of brain injury from the an assessment of the severity of brain injury from the

last CT scan performed before randomizationlast CT scan performed before randomization

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Baseline assessmentBaseline assessment

• Groups similar at start of trial? YESGroups similar at start of trial? YES• Aside from experimental intervention - Aside from experimental intervention -

groups treated similarly? Uncleargroups treated similarly? Unclear– Compliance 96% in prophylaxis groupCompliance 96% in prophylaxis group– 98% in episodic98% in episodic

• But did participants receive additional rFVIII?But did participants receive additional rFVIII?• RR of joint damage in the episodic group RR of joint damage in the episodic group

– by MRI is 6.1 (95% CI, 1.5 to 24.4)by MRI is 6.1 (95% CI, 1.5 to 24.4)– by x-ray 5.2 (95% CI, 0.65 to 41.5)by x-ray 5.2 (95% CI, 0.65 to 41.5)

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Baseline assessmentBaseline assessment

4. The presence or absence of traumatic 4. The presence or absence of traumatic subarachnoid hemorrhage and CT scores, subarachnoid hemorrhage and CT scores, calculated according to the Marshall calculated according to the Marshall classification.classification.

5. the incidence and frequency of5. the incidence and frequency of– Systemic hypotensionSystemic hypotension– The presence or absence of a monitoring The presence or absence of a monitoring

device for intracranial pressure,device for intracranial pressure,– Episodes of intracranial hypertension Episodes of intracranial hypertension

occurring before and after randomizationoccurring before and after randomization

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Follow-up assessment and outcome Follow-up assessment and outcome measuresmeasures

• The primary outcome measures wereThe primary outcome measures were1.1. the mortality rate and the mortality rate and 2.2. functional neurologic outcome 24. months functional neurologic outcome 24. months

after randomizationafter randomization– hospital records--------more than 28 day hospital records--------more than 28 day

mortality mortality – Patients surviving beyond hospital discharge Patients surviving beyond hospital discharge

were located, and deaths occurring between were located, and deaths occurring between the time of discharge from the hospital and 24 the time of discharge from the hospital and 24 months after randomization were recordedmonths after randomization were recorded

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Follow-up assessment and outcome measuresFollow-up assessment and outcome measures

• Patients who were alive 24 months after Patients who were alive 24 months after randomization were interviewed by a single, randomization were interviewed by a single, trained assessortrained assessor

• Neurologic outcomes were then defined asNeurologic outcomes were then defined as– favorable (grades 5 to 8) orfavorable (grades 5 to 8) or– unfavourable (grades 1 to 4). using a standardized unfavourable (grades 1 to 4). using a standardized

structured telephone questionnairestructured telephone questionnaire• For patients who died within 28 days after For patients who died within 28 days after

randomization, the primary cause of death was randomization, the primary cause of death was determined using a classification designed by determined using a classification designed by three of the investigators during the conduct of three of the investigators during the conduct of theSAFE study theSAFE study

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Statistical analysisStatistical analysis• Intention-to-treat basis.Intention-to-treat basis.• Baseline covariates known to be associated with Baseline covariates known to be associated with

increased mortality from traumatic brain injury increased mortality from traumatic brain injury (age older than 60 years,17 GCS score of ≤8,18 (age older than 60 years,17 GCS score of ≤8,18 systolic pressure of <90 mm Hg,19 and traumatic systolic pressure of <90 mm Hg,19 and traumatic subarachnoid hemorrhage20) were fitted to a subarachnoid hemorrhage20) were fitted to a multivariate logistic- regression model, and the multivariate logistic- regression model, and the odds ratio at 24 months was adjusted accordingly.odds ratio at 24 months was adjusted accordingly.

• Survival times were compared in the two groups Survival times were compared in the two groups with the use of the log-rank test and are presented with the use of the log-rank test and are presented as a Kaplan–Meier curve unadjusted for baseline as a Kaplan–Meier curve unadjusted for baseline covariatescovariates

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ResultsResults

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Baseline characteristicsBaseline characteristics

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Fluids administered and treatment Fluids administered and treatment effectseffects

• During the first 48 hours in the ICU, patients During the first 48 hours in the ICU, patients in the albumin group received significantly in the albumin group received significantly less study fluid than did patients in the saline less study fluid than did patients in the saline groupgroup

• No significant difference in the volumes of No significant difference in the volumes of study fluid administered after the first 2days.study fluid administered after the first 2days.

• Apart from an increased requirement for red Apart from an increased requirement for red cell transfusion on the second day in the cell transfusion on the second day in the albumin group, the volumes of non study albumin group, the volumes of non study fluid administered during the first 4 days fluid administered during the first 4 days were similar in the two groups.were similar in the two groups.

• no significant difference in mean systemic no significant difference in mean systemic arterial pressure or heart rate between the arterial pressure or heart rate between the groups on any of the first 4 daysgroups on any of the first 4 days

• Mean central venous pressure was Mean central venous pressure was significantly higher in the albumin group than significantly higher in the albumin group than in the saline group during the first 24 hours.in the saline group during the first 24 hours.

• The serum albumin concentration was The serum albumin concentration was significantly higher in the albumin group than significantly higher in the albumin group than in the saline group on each of the first 4 in the saline group on each of the first 4 days.days.

• There was no significant difference in the There was no significant difference in the incidence of post-randomization intracranial incidence of post-randomization intracranial hypertension between the two groups.hypertension between the two groups.

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OutcomeOutcome• The majority of deaths had The majority of deaths had

occurred by 28 days in both occurred by 28 days in both groups groups

• Most of the deaths occurred in Most of the deaths occurred in the ICU (82 vs 69%)the ICU (82 vs 69%)

• Traumatic brain injury was Traumatic brain injury was identified as the primary cause of identified as the primary cause of death at 28 days in 75 vs 83 %death at 28 days in 75 vs 83 %

• Fewer favorable neurologic Fewer favorable neurologic outcomes at 24 months in the outcomes at 24 months in the albumin group than in the albumin group than in the saline group( 47 vs 63%)saline group( 47 vs 63%)

• The probability of survival was The probability of survival was significantly different significantly different

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OutcomeOutcome

• The probability of survival The probability of survival was significantly differentwas significantly different

• (P = 0.007)(P = 0.007)

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DiscussionDiscussion1.1. The demographic characteristics and severity of brain injury at The demographic characteristics and severity of brain injury at

baseline were similar in the patients assigned to saline and in baseline were similar in the patients assigned to saline and in those assigned to albumin for fluid resuscitation.those assigned to albumin for fluid resuscitation.

2.2. The mortality and functional outcomes at 24 months and The mortality and functional outcomes at 24 months and found that the rate of death was significantly higher among found that the rate of death was significantly higher among patients assigned to albumin than among those assigned to patients assigned to albumin than among those assigned to salinesaline. .

– Due to a higher mortality rate within 28 days Due to a higher mortality rate within 28 days after randomization in the subgroup of patients after randomization in the subgroup of patients with with severe traumatic brain injurysevere traumatic brain injury (GCS score, 3 (GCS score, 3 to 8) who were treated with albuminto 8) who were treated with albumin

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Discussion Discussion Crystalloid-based fluid Crystalloid-based fluid strategiesstrategiesCrystalloid-based fluid strategiesCrystalloid-based fluid strategies• Limited supporting evidenceLimited supporting evidence• Based on the assumption that prompt restoration Based on the assumption that prompt restoration

of the volume of circulating blood and the of the volume of circulating blood and the prevention of hypotension may improve the prevention of hypotension may improve the outcome in patients with brain injuryoutcome in patients with brain injury

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DiscussionDiscussionColloid-based fluid-resuscitation strategiesColloid-based fluid-resuscitation strategies• maintaining or augmenting plasma oncotic maintaining or augmenting plasma oncotic

pressure to minimize extravasation of pressure to minimize extravasation of intravascular fluid into the brain interstitium.intravascular fluid into the brain interstitium.

• Eker et al ; reported reduced mortality after Eker et al ; reported reduced mortality after the institution of a treatment strategy that the institution of a treatment strategy that included the administration of included the administration of albuminalbumin(Crit Care Med (Crit Care Med 1998;26:1881-6.)1998;26:1881-6.)

– but have had unfavorable neurologic outcomes but have had unfavorable neurologic outcomes after using this strategy (after using this strategy (Brain Inj 2000;14:605-19).Brain Inj 2000;14:605-19).

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DiscussionDiscussion• there was no difference in hemodynamic resuscitation end there was no difference in hemodynamic resuscitation end

points or in the cause and time of death between the two points or in the cause and time of death between the two groupsgroups– may be exacerbation of vasogenic or cytotoxic cerebral may be exacerbation of vasogenic or cytotoxic cerebral

edema induced by the administration of albuminedema induced by the administration of albumin• Initial intracranial pressure tended to be higher in the Initial intracranial pressure tended to be higher in the

albumin groupalbumin group• post-randomization intracranial hypertension may have post-randomization intracranial hypertension may have

occurred and could explain the difference in outcome weoccurred and could explain the difference in outcome weobservedobserved..

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ConclusionConclusion• higher mortality rates among patients with higher mortality rates among patients with

severe traumatic brain injury who received severe traumatic brain injury who received 4% albumin than among those who 4% albumin than among those who received saline received saline

• These findings suggest that saline is These findings suggest that saline is preferable to albumin during the acute preferable to albumin during the acute resuscitation of patients with severe resuscitation of patients with severe traumatic brain injurytraumatic brain injury

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Critical appraisalCritical appraisal

• Post hoc follow-up study of patients with traumatic Post hoc follow-up study of patients with traumatic brain injury recruited into the brain injury recruited into the SAFE studySAFE study

• Randomized? YES Randomized? YES • Were patients and clinicians blinded? Were patients and clinicians blinded? yesyes• Follow-up complete Follow-up complete sufficiently long sufficiently long ? Yes? Yes

– 2-year follow-up completion rates in excess of 90%.2-year follow-up completion rates in excess of 90%.– 24 month is long enough24 month is long enough

• Intention-to-treat analysis? YESIntention-to-treat analysis? YES• Patients with traumatic brain injury were identified Patients with traumatic brain injury were identified

a priori in the SAFE studya priori in the SAFE study