Drummond et al.1 are concerned that proscribing the use of albumin in head injury patients is not warranted by the strength of a post hoc 2-year follow-up analysis of a subgroup from the SAFE trial (SAFE–TBI)2 and cite several studies suggesting that albumin has no harmful effects and may even be beneficial in these patients. However, the cited clinical studies have severe methodological limitations. They are uncontrolled or retrospective cohort studies with small patient numbers in different clinical conditions yielding much less convincing data than does the SAFE–TBI study. Naredi et al.3 and Rodling Wahlstrom et al.4 both reported outcomes from patients with TBI receiving treatment based on the hypothesis that posttraumatic vasogenic edema is the major factor causing late intracranial hypertension and transcapillary filtration and is therefore controlled by reducing mean arterial blood pressure and maintaining normal colloid osmotic pressure (“Lund concept”). The first study3 included 31 patients prospectively receiving prostacyclin infusions along with unspecified amounts of albumin, crystalloids, or both, and the second study4 retrospectively analyzed a cohort of 93 patients receiving a similar treatment regimen. In contrast to these nonrandom observations on a total of 124 patients without any control group, and given that there are no clinical data from randomized controlled trials showing benefit for albumin in these patients, Myburgh et al.2 reported primary outcome data from 420 patients with TBI, prospectively and randomly enrolled to receive exclusively either 4% albumin or normal saline. Myburgh et al.'s findings that albumin—after confirmation of equivalence in baseline and injury-specific parameters—was associated with a significantly greater 2-year mortality in comparison with saline (33.2% vs 20.4%; relative risk, 1.63; 95% confidence interval, 1.2 to 2.38; P = 0.003), and a significantly greater proportion of patients with unfavorable neurological outcomes should raise considerable concern. The authors suggest albumin extravasation through an impaired blood–brain barrier with increased intracranial edema and hypertension as a possible mechanism.5 Palesch et al.6 reported outcomes from an uncontrolled study with 82 patients with acute ischemic stroke receiving 25% albumin in different doses and used historical cohort data as control. The study of Frontera et al.7 was an uncontrolled cohort study in 95 patients with subarachnoid hemorrhage (SAH) and symptomatic vasospasm treated with hypervolemic hemodilution and received 5% albumin, crystalloid solution, or both. Suarez et al.8 retrospectively analyzed data from 84 patients with SAH before and after albumin was abandoned for hypervolemic hemodilution. Of note, according to 2 Cochrane reviews, there is no scientific support from randomized controlled trials either for hemodilution in the routine treatment of patients with acute stroke9 nor for the use of volume expansion therapy in patients with aneurysmal SAH,10 and findings from uncontrolled observations are merely hypotheses that need to be verified by adequately designed clinical trials. Christiane S. Hartog, MD Michael Bauer, MD Konrad Reinhart, MD Department of Anesthesiology and Intensive Care Friedrich Schiller University Jena, Germany [email protected]