Korean Journal of Cerebrovascular Surgery 2005;7(2):109-112.
Published online June 1, 2005.
The Influence of Hypoalbuminemia on Neurological Outcome in Patients with Subarachnoid Hemorrhage.
Lee, Yong Woo , Ahn, Jung Yong , Han, In Bo , Chung, Young Sun , Chung, Sang Sup , Kim, Nam Keun
Department of Neurosurgery, Institute for Clinical Research, Bundang CHA Hospital, College of Medicine, Pochon CHA University, Seongnam, Korea. jyahn@cha.ac.kr
Abstract
Subarachnoid hemorrhages (SAH) result in hemodynamic and metabolic abnormalities. The successful treatment of these abnormalities requires active treatment of neuroprotection. Recently, it has been known that albumin has important roles in neuroprotection as well as in hemodilution. We retrospectively studied 64 patients who were treated surgically for aneurysmal SAH to investigate the relationship between serum albumin levels, severity of disease and neurological outcomes. A high proportion of patients developed hypoalbuminemia after aneurysmal SAH. Patients with poor clinical presentation had significantly lower admission and postoperative albumin values than those with good clinical presentation. Comparison of patients with a favorable outcome and those with an unfavorable outcome revealed a significant difference in postoperative albumin values. In the patients with severe clinical presentation, postoperative albumin levels lower than 3.5 g/dL were associated with an unfavorable outcome. As a result of our analysis, albumin is an important prognostic factor in aneurysmal SAH. Therefore, active albumin replacement therapy might improve neurological outcomes as a neuroprotective agent. We therefore suggest that albumin offers great promise in the therapy of complications of SAH and we propose that it may now be appropriate to consider the initiation of early-phase clinical trials in patients with aneurymal SAH.
Key Words: Hypoalbuminemia, Subarachnoid hemorrhage, Neurological outcome

Introduction


  
Between 5% and 15% of all stroke cases are secondary to ruptured saccular aneurysms.12)19) Despite improvements in both the diagnosis and treatment of cerebral aneurysms, the 30-day mortality rate following rupture is about 50%, with half the survivors sustaining irreversible brain damage.5)15) Following subarachnoid hemorrhage(SAH), consistent intracranial findings include increased intracranial pressure(ICP), reduced cerebral blood flow(CBF), decreased tissue oxygen supply and cerebral metabolic rate of oxygen(CMRO2), cerebral edema, and impaired autoregulation or CO2 reactivity.6)9)16) The successful treatment of these hemodynamic and metabolic abnormalities ultimately requires reperfusion. The goals of cerebral neuroprotection are to minimize the severity of the initial ischemic insult, to extend the time window for safe reperfusion, and to control the sequelae of the secondary neuronal damage that can follow.
   Recently, albumin is known to have multifaceted intravascular effects. It exerts complex influences on erythrocyte aggregation and increasing low-shear viscosity but decreasing erythrocyte sedimentation under no-flow conditions.17) Albumin is a specific inhibitor of apoptosis in endothelial cells,22) a major antioxidant defense against oxidizing agents,8)21) and plays crucial roles in the transport of fatty acids. Docosahexaenoic acid complexed albumin especially elicits high-grade ischemic neuroprotection.3) In addition, albumin is a very useful drug for the improving of cerebral blood volume and the oncotic effect in cerebral ischemia or cerebral vasospasm.1) In this series, we retrospectively studied 64 patients who were treated surgically for aneurysmal SAH to determine the relationship between serum albumin levels, severity of disease, and neurological outcomes.

Patients and Methods

1. Study population
  
Our series included 64 patients(23 males and 41 females) with aneurysmal SAH who were admitted to the neurosurgical department of our hospital between January 2004 and December 2004. The clinical records for these patients were reviewed in detail. SAH caused by recent head injuries, blood dyscrasias, arteriovenous malformation, or brain tumors were excluded from this study. Eligible patients had to be at least 18 years of age at the time of admission, exhibited SAH, demonstrated an angiographically confirmed saccular aneurysm as the cause of hemorrhage, and were able to begin treatment within 48 hours after SAH onset. Patients with all grades of neurological severity were eligible. Patients were excluded if they had a severe hepatorenal disease or malnutrition.

2. Data collection
  
Baseline factors that were recorded at the admission included Hunt and Hess scale, Fisher grade, and serum albumin level. The location and size of the ruptured aneurysms were determined from a review of conventional angiograms. Trained investigators collected the following information during the 14-day treatment period after SAH:daily neurological examination results, medical and surgical complications, and treatments provided. Surgical clipping was undertaken within 2 days after aneurysmal rupture. Induced hypertension, intentional hypervolemia, and/or hemodilution therapy for symptomatic vasospasm were used at the discretion of treating physicians. No patients received albumin replacement therapy. Serum albumin levels were recorded consistently(levels were available for >93% of participants) at admission(100%) and on Day 2(100%), Day 5(98%), Day 7(96%), Day 14(93%), and Day 21(93%) after SAH and are used for the present analysis. Hypoalbuminemia was defined by a serum albumin concentration of less than 3.5 g/dL. Overall outcomes were assessed at 3 months after SAH, using Glasgow Outcome Scale(GOS).11) The favorable category included patients who made a good recovery or who were moderately disabled (GOS=5 or 4, respectively). The unfavorable outcome category included those who were severely disabled, in a persistent vegetative state, or dead(GOS=3, 2, and 1, respectively).

3. Statistical analyses
  
Statistical analysis of the data was accomplished by using an unpaired Student's t test, χ2 analysis with Yates' correction, and one-way analysis of variance(ANOVA) with Scheffe's test for multiple comparison between groups. Values are presented as mean±standard deviation or mean±standard error of the mean. A statistically significant difference was indicated by a P value <0.05.

Results

   Age and sex distribution, Hunt and Hess scale, Fisher grade, serum albumin levels on admission and postoperatively, and neurological outcome are listed in Table 1. Sex distribution was similar in both groups stratified by Hunt and Hess scale, and there was no significant difference in age between two subgroups. Patients with poor clinical presentation had significantly lower admission and postoperative albumin values than those with good clinical presentation(P<0.05)(Table 1). Comparison of patients with a favorable outcome and those with an unfavorable outcome revealed a significant difference in postoperative albumin values(P<0.001)(Table 2). In the patients with severe clinical presentation, postoperative albumin levels lower than 3.5 g/dL were associated with an unfavorable outcome(p<0.05)(Table 3).
   To provide more specific information, we stratified Hunt and Hess scale of the patients with poor clinical presentation into three subgroups:those with Hunt and Hess scale of 3, 4, and 5, respectively. One-way ANOVA showed a significant difference in both admission and postoperative serum albumin levels among the three groups(Table 3). Moreover, Scheffe's test to explore differences across the Hunt and Hess scale subgroups revealed that Hunt and Hess scale of 5 had lower mean admission and postoperative albumin values than did those with Hunt and Hess scale of 3 or 4. In the severely hemorrhaged patients, one-way ANOVA did not reveal any significant difference in admission albumin values among the four subgroups stratified by Fisher grading system on the computed tomographic finding. Scheffe's test to explore differences across the Fisher grading subgroups revealed that patients with Fisher grade of 4 had lower mean postoperative albumin values than did those with Fisher grade of 1, 2, and 3.

Discussion

   We observed that a high proportion of patients develop hypoalbuminemia after aneurysmal SAH. Hypoalbuminemia was associated with poor outcomes. As the result of our analysis, albumin is an important prognostic factor of aneurysmal SAH. Therefore, active albumin replacement therapy might be improved neurological outcome.
   Therapy with high-concentration serum albumin has led to striking hemodilution.13) In addition to producing hemodilution, concentrated albumin solutions have important oncotic effects, acting as a dehydrating agent on extravascular cerebral tissues and producing a net movement of water from tissue to blood. Cerebral edema may be prevented or significantly reduced by means of albumin solutions.1) Other properties may also have contributed to the therapeutic effect as follows;1) the binding and inactivation of toxic products;2) regulation of plasma and interstitial fluid concentrations of endogenous and exogenously administered substances and drugs;3) participation in anticoagulation;4) maintenance of microvascular permeability to proteins;and 5) scavenging of free radicals and prevention of lipid peroxidation.7)
   Recent reports have shown that high-dose albumin therapy diminishes the volumes of brain infarction and swelling, ameliorates behavioral function, and improves local perfusion into the zones of critical blood flow reduction in focal ischemic stroke.1)2)4)10) Focal ischemia-induced blood-brain barrier dysfunction permitted albumin to penetrate into the brain parenchyma, where it was taken up by cortical neurons with normal morphological features, suggesting that albumin may have protected these neurons from ischemic injury.18) Albumin also mitigated pannecrotic histopathology in tissue zones of residual ischemic injury by fostering the partial preservation of glial and endothelial elements, and it normalized the apparent diffusion coefficient of water on diffusion-weighted magnetic resonance images, even in zones of residual histological injury.4)
  
In current clinical practice, human albumin is being commonly prescribed for a variety of indications. Albumin is administered over prolonged time periods to patients with aneurysmal subarachnoid hemorrhage after surgical clipping of the aneurysm, in an effort to prevent delayed ischemic insult secondary to vasospasm.14) Similarly, patients with putaminal hemorrhage treated with human albumin for 2 weeks showed reductions of cerebral edema and improved outcome.20) Taken together, these findings support the potential clinical feasibility of administering human albumin to patients with acute hemorrhagic or ischemic stroke.

Conclusions

   In summary, the present study has shown that hypoalbuminemia is associated with poor outcomes in aneurysmal SAH. Human albumin therapy may be strongly neuroprotective in cerebral edema or cerebral ischemia in aneurysmal SAH. We therefore suggest that albumin offers great promise in the therapy of complications of SAH and we propose that it may now be appropriate to consider the initiation of early-phase clinical trials in patients with aneurymal SAH.


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