THERAPY

Criteria abstracted from The Users' Guides to the Medical Literature series in JAMA

N Engl J Med. 2007 357:874-884.[abstract]

Review posted April 03, 2008

1. What is being studied?
   
   
   1. There are two study objectives:
      
      
      1. To document baseline characteristics that are known to influence outcomes from traumatic brain injury (TBI) in a subgroup of patients from the SAFE trial “A Comparison of Albumin and Saline for Fluid Resuscitation In Intensive Care Unit”(1).
         
         
      2. They compared 24-month mortality rates and functional neurologic outcomes of patients with traumatic brain injury (TBI) who received normal saline versus albumin for fluid resuscitation.
         
         
   2. The study design:
      
      This is a post hoc analysis of baseline characteristics of patients who had traumatic brain injury and a two-year follow up of patients from the SAFE study.
      
      The original SAFE study was a prospective, multi-center, double-blind, RCT, conducted to compare the effect of fluid resuscitation with albumin or normal saline on mortality in a heterogeneous population of patients in the ICU. The primary outcome measure was death from any cause during the 28-day period after randomization (1).
      
      The authors proposed that one month follow-up of patients in the original SAFE study is an insufficient outcome measure for patients with TBI.
      
      
   3. Patients included:
      
      From the original SAFE study:
      
      
      • Adult patients needing IV fluid resuscitation including trauma (defined as an injury to the body caused by mechanical forces)
        
      • HR > 90 bpm, SBP < 100 mmHg or MAP < 75 mmHg or 40 mmHg drop in systolic BP or MAP from baseline
      • CVP < 10 mmHg
      • PCWP <12 mmHg
      • Pulsus paradoxus of 5 mmHg
      • Capillary refill time > 1 second
      • Oliguria <0.5 ml/kg/hr

   For this study-Patients with traumatic brain injury:

   • History of trauma
   • Non-sedated GCS <13 or less at initial hospital presentation
   • Head CT scan finding consistent with traumatic brain injury

   4. Patients excluded:
      
      
      • History of adverse reaction to human albumin solution
      • Religious objection to administration of any human blood products
      • Plasmapheresis during ICU admission
      • ICU admission post cardiac surgery
      • ICU treatment for body burn
      • ICU admission post liver transplant
      • Age <18 years old
      • Brain dead or likely to be diagnosed in 24 hours
      • Patient expected to die within 24 hours
      • Patients enrolled and completed follow up from the SAFE study
      • Patient who received fluid resuscitation in the study ICU and current hospital admission
      • Patient from non-study ICU transferred to the study ICU and received fluid resuscitation for volume depletion.
        
        
   5. The interventions compared:
      
      Patients were given either normal saline or 4% albumin for all fluid resuscitation.
      
      
   6. Outcomes evaluated:
      
      Mortality rate and functional neurologic outcome 24 months post randomization.
      
      
2. Are the results valid?
   
   
   1. Was the assignment of patients to treatments randomized?
      
      Yes. Patients with traumatic brain injury were randomly assigned to receive either 4% albumin or normal saline for fluid resuscitation in the ICU until death, discharge or 28 days after randomization. The randomization was stratified by a diagnosis of trauma/traumatic brain injury and was carried out centrally through the internet with the use of minimization algorithm.
      
      
   2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
      
      
   3. Was the follow up complete?
      
      Yes. A total of 515 patients with traumatic brain injury were eligible, 492 were identified from the original cohort of patients reported in the SAFE study and 23 additional patients from a review of all the SAFE study enrollees. Patients were randomly assigned and followed up for 24 months. Out of 255 patients in the albumin group, 24 withdrew, 17 were lost to follow up, and the remaining 214 had primary outcomes obtained. Whereas in the normal saline group of 260, 31 withdrew, 23 were lost to follow up, and only 206 patients were included in the primary outcome analysis.
      
      
   4. Were patients analyzed in the groups to which they were randomized?
      
      Yes. In the present subgroup analysis, all 515 patients with traumatic brain injury were analyzed using intent to treat analysis, and there was no cross over between the groups.
      
      
   5. Were patients, health workers, and study personnel “blind” to treatment?
      
      Yes. Patients, medical staff, radiologist who interpreted the CT scan, trained assessors who collected the baseline data and who followed up the patients were all blinded.
      
      During the study period, normal saline and 4% albumin were supplied in an identical 500 ml bottle with specially designed cartoon covering containers and manufactured intravenous administration sets.
      
      
   6. Were the groups similar at the start of the trial?
      
      Yes. This was one of the objectives of the study, to ensure that the patients with TBI had similar baseline characteristics, since many of the characteristics that could affect outcome in TBI were either not collected or analyzed as part of the initial SAFE trial.
      
      Patients with traumatic brain injury in both saline and albumin groups were similar in their baseline characteristics such as age, sex, injury severity, physiologic vital signs, GCS, CT scan scores, pre-randomization hypotension and presence of traumatic subarachnoid hemorrhage.
      
      The ICP on insertion was higher in the pre-randomization period in the albumin treated group compared to the saline group (15±12.9 vs 12.4±7.2 respectively) though this did not reach statistical significance (p=0.06). However, the percentage of patients with intracranial hypertension during the study did not appear to be different between the two groups (10.2% vs 9.6% respectively, p=0.89).
      
      Therefore, we feel reasonably comfortable that the albumin group did not have more severe brain injury at the start of the trial.
      
      
   7. Aside from the experimental intervention, were the groups treated equally?
      
      Presumably yes. Although treating physicians were allowed at their own discretion to manage electrolyte imbalances, mechanical ventilatory adjustments, nutrition, blood product administration, and vital signs monitoring, we expected them to render the medical standard of care.
      
      As is true for the original study, this post hoc analysis demonstrated that patients who were given saline received more total fluid during the first 48 hours (but not overall), had a lower serum albumin and, lower CVP (only during the first 48 hours following randomization) compared to those who received albumin. The number of patients with post-randomization intracranial hypertension in albumin group (29.7%) versus in the saline group (33.8%) was not statistically significant (p=0.47).
      
      We are reviewing this paper along with the original study in the context of subgroup analysis and there are specific analyses and information that should be reported. As per the recommendations of Wang R et al (2) the following questions should be addressed:
      
      
   8. Was the subgroup analysis prespecified or post hoc analyzed?
      
      As per Wang: “A prespecified subgroup analysis is one that is planned and documented before any examination of data, preferably in the study protocol. This analysis includes specification of the end point, the baseline characteristic, and the statistical method to be used to test for an interaction”.
      
      In the original SAFE study, patients were stratified during randomization by diagnosis of trauma. In addition, those with traumatic brain injury were “prespecified” as patients with history of trauma, GCS <14 while not sedated and CT scan findings consistent with traumatic brain injury. In the present report, the authors included all SAFE patients with TBI and found additional patients they had “missed” from the original study. Therefore, the investigators prespecified the group of trauma in the original SAFE study but missed some patients they had identified in the posthoc analysis. Thus, perhaps TBI was not identified a priori (though trauma was).
      
      
   9. Was heterogeneity and statistical interactions dealt with in the study protocol?
      
      In the original SAFE study, heterogeneity of treatment effects among subgroups was assessed with the use of test for a common relative risk. The relative risk of death during the 28-day study period among patients with trauma in the albumin group was 1.36 as compared with patients in the saline group. The relative risk of death among patients without trauma was 0.96 (p=0.04 by the test for a common relative risk). Thus, there was an “interaction” in that if a patient had trauma the risk of death increased when given albumin for fluid resuscitation. In contrast, albumin had no effect or lower risk of death in the non-traumatic group.
      
      At the 28 day post randomization, the death rate among patients with trauma in the albumin group was 13.6% (81/596) as compared to saline group with 10% (59/590), relative risk of 1.36 (95% CI 0.99 to 1.86, p=0.06)(1). The investigators added that patients with trauma AND TBI who received albumin had a relative risk of death of 1.62 compared to those who received saline (95% CI 1.12 to 2.34 (p=0.009). Lastly, there was no difference between treatment groups among patients with trauma without TBI.
      
      
   10. Did the authors account for “multiplicity” of statistical tests?
       
       As outlined in the Wang article on subgroup analysis: “It is a common practice to conduct a subgroup analysis for each several and often many baseline characteristics for each of several end points, or for both. When multiple subgroup analyses are performed, the probability of false positive finding can be substantial”.
       
       In the original SAFE study, the authors did not specifically address this. However, the p values were much less than 0.01 in the subgroup analysis presented here. Thus, we can feel fairly comfortable that there is no type 1 error.
       
       In summary, the authors of the original SAFE study prespecified that they would perform a subgroup analysis in trauma patients. They also defined TBI a priori but it was not clear whether it was a prespecified group as per the recommendations of Wang et al. The authors also demonstrated that there was a heterogeneous effect of outcome based on subgroup, and trauma patients receiving albumin had a worse outcome. Most notably, when TBI group alone was analyzed, there was a highly significant effect of albumin on outcome (p<0.009). Though they did not perform a multiplicity test. Clearly, this level of significance is highly relevant and very unlikely due to type 1 error. Hence, we concur that further evaluation of TBI group is indicated based on the original SAFE study design and outcomes.
       
       
3. What were the results?
   
   
   1. How large was the treatment effect in the present study?
      
      Primary outcome: Death

      Within 28 days there were 26.4% (61/231) deaths in the albumin group as compared with 15.7% (36/229) in normal saline group. At 24 months post randomization, in the albumin group 33.2% (71/214) had died, while in the saline group 20.4% (42/206); relative risk, 1.63 (95% CI, 1.17 to 2.26); p=0.003. Most of the deaths were patients with GCS 3-8, 41.8% in albumin group and only 22.2% from saline group (p=<0.001).

Based from total deaths, most occurred in the first 28 days with 61/71 (85.9%) in the albumin group and 36/42 (85.7%) in saline group.

Secondary outcome: Favorable neurologic outcome

For all patients with TBI, at 24 months post randomization the albumin group had significantly fewer patients with favorable neurologic outcome compared to saline group (47.3% vs 60.6% respectively; p=0.007). This is mainly due to less favorable neurologic outcome in patients with GCS score of 3-8 in the albumin group (p<0.002).

At 24 months post randomization, the albumin and saline groups with GCS of 9-12 their survival rate (81.8% vs 72.7% respectively) and favorable neurologic outcome (73.5% vs 66.7% respectively) were not statistically different.

2. How precise was the estimate of the treatment effect in the present study?
   
   The 95% confidence intervals were narrow. This indicates significantly more deaths and less favorable neurologic outcome within 24 months post randomization in patients with GCS 3-8 who were given albumin for fluid resuscitation.

4. Will the results help me in caring for my patients?
   
   
   1. Can the results be applied to my patients?
      
      Maybe. Although this study was done in patients over 18 years of age, the mechanism of traumatic brain injury in adults is generally the same as in children (except shaken baby and falls). There is no data that treatment recommendations should be different overall between adults and children.
      
      In adults, there is no specific recommendation of which type of intravenous fluid is best for resuscitation (3). Likewise, in pediatrics there is no contributing scientific literature on (prehospital administration) type of fluid therapy in improving hypotension and outcome from pediatric TBI (4).
      
      
   2. Were all clinically important outcomes considered?
      
      No. They focused on death and neurologic outcomes, minor to major adverse reactions include hypernatremia, allergy, coagulopathy, and pulmonary edema.
      
      
   3. Are the likely treatment benefits worth the potential harms?
      
      Yes. This study clearly favors normal saline that is readily available, cheap and is safer than albumin (at least) in adult patients. Therefore, we believe that albumin should also be avoided in children with TBI for fluid resuscitation.

References:

1. A Comparison of Albumin and Saline for Fluid Resuscitation in Intensive Care Unit
   The SAFE Investigators. The New England Journal of Medicine 2004; 350:2247-56
   
   
2. Wang R, Lagakos S, Drazen JM, et al: Statistics in Medicine-Reporting of Subgroup Analyses in Clinical trials. The New England Journal of Medicine 2007; 357:2189-2194
   
   
3. Bratton SL, Wright DW, et al: Guidelines for the management of severe traumatic brain injury. I. Blood pressure and Oxygenation . Journal of Neurotrauma 2007;24:S7-13.
   
   
4. Adelson PD, Selden NR, et al: Guidelines for the acute medical management of severe traumatic brain injury in infants, children, and adolescents. Chapter 4. Resuscitation of blood pressure and oxygenation and prehospital brain-specific therapies for the severe pediatric traumatic brain injury patient. Ped Crit Care Med. 2003 Jul;4 (3 Suppl):S12-8.
   
   
5. Online calculator used for this review: http://www.healthcare.ubc.ca/calc/clinsig

Last Updated: April 03, 2008

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