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Anesth Analg 2003;96:1150-1154
© 2003 International Anesthesia Research Society

NEUROSURGICAL ANESTHESIA

Penetration of Intravenous Hydroxyethyl Starch into the Cerebrospinal Fluid in Patients with Impaired Blood-Brain Barrier Function

Hans-Jürgen Dieterich, MD*, Jörg Reutershan, MD*, Thomas W. Felbinger, MD{dagger},{ddagger}, and Holger K. Eltzschig, MD*,{ddagger}

*Department of Anesthesiology and Intensive Care Medicine, University of Tübingen; {dagger}Department of Anesthesiology, University of Munich Medical Center, Germany; and {ddagger}Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts

Address correspondence and reprint requests to Holger K. Eltzschig, MD, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115. Address e-mail to heltzschig{at}partners.org


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Hypovolemic patients with impairment of the blood-brain barrier may receive IV hydroxyethyl starch (HES) to stabilize cardiovascular function and to increase cerebral perfusion pressure. It is not known whether HES can penetrate into the cerebrospinal fluid (CSF) under those conditions. We investigated plasma and CSF levels of HES after IV infusion in patients with suspected disturbance of the blood-brain barrier. Eight adult patients were studied who were being treated for head trauma or subarachnoid hemorrhage, with an external CSF drain in place. All patients exhibited radiographic signs of blood-brain barrier impairment diagnosed by cerebral computed tomography. After IV infusion of 500 to 1000 mL of HES 200,000/0.5, plasma HES levels were measured. Additionally, all CSF that was drained within 8 h after the HES infusion was collected, and HES concentrations were measured. All patients had detectable HES plasma concentrations (3.41 to 9.95 mg/mL). In contrast, no HES could be detected in the CSF of any patient. These data indicate that IV HES 200,000/0.5 does not penetrate into the CSF in patients with disturbed blood-brain barrier function after subarachnoid hemorrhage or head trauma. Further study is required to determine whether HES penetrates into the intracranial interstitium, despite the absence of HES in the CSF.

IMPLICATIONS: Patients may receive IV hydroxyethyl starch (HES) after head trauma or subarachnoid hemorrhage. The results of the present study indicate that in patients with suspected blood-brain barrier impairment, HES does not penetrate from the plasma into the cerebrospinal fluid.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Hypotension in patients with increased intracranial pressure (ICP) after head trauma or subarachnoid hemorrhage (SAH) may compromise cerebral perfusion pressure (CPP), leading to cerebral ischemia and an increase in morbidity and mortality (1). IV fluid administration is common practice in the perioperative management of these patients to achieve a stable hemodynamic status and to increase CPP (2). Because a decrease in colloid oncotic pressure can be associated with an increase in cerebral edema, clinicians may prefer the use of hyperoncotic colloid solutions (3). Because of its low antigenicity, hydroxyethyl starch (HES) has become an often-used colloid in clinical practice (4). In addition to a potentially beneficial effect on edema formation and ICP, hemodilution with IV HES may improve perfusion of salvageable brain tissue surrounding the core injury after closed head trauma (5). Patients with acute stroke comprise a second group of patients with a disturbed blood-brain barrier who may benefit from IV administration of HES. Experimental data indicate that IV HES decreases leukocyte adherence and vascular injury after acute ischemia of the brain (6). In Germany, for example, up to 30% of patients suffering a stroke receive treatment with IV HES in local general hospitals (7).

A major concern regarding the use of hyperoncotic colloid infusions in patients with a suspected disruption of the blood-brain barrier is the potential deposition of HES macromolecules within the brain interstitium. This would lead to an increase in the interstitial colloid osmotic pressure, promoting fluid extravasation into the parenchyma and further increase of ICP. Under the assumption that intravascular HES can penetrate into the intracranial interstitium, further diffusion into the cerebrospinal fluid (CSF) may be possible, e.g., in the presence of ischemia, trauma, or inflammation leading to increased permeability of the meningeal barrier between intracranial interstitium and the CSF space.

An alternate route for HES penetration into the CSF is via the blood-CSF barrier. The blood-CSF barrier comprises a portion of the blood-brain barrier in the periventricular region, including the choroid plexus, median eminence, and the area postrema. The blood-brain barrier consists of capillary endothelial cells that are joined at tight junctions devoid of fenestrae. There is little pinocytosis, and passage of substances depends on their affinity for lipids and the presence of carrier proteins. In the blood-CSF barrier, there is active pinocytosis that allows small molecules into the subependymal interstitial space through the blood-CSF barrier (8). In patients with head trauma or SAH, this barrier has probably been exposed to a similar degree of ischemia as the blood-brain barrier and might undergo similar changes during injury. The detection of HES in CSF after IV administration would strongly support HES deposition in the brain interstitium. This would raise concerns regarding an increase in the tissue colloid osmotic pressure and potential effects on ICP and CPP associated with IV HES infusions in patients with suspected blood-brain barrier impairment. However, the absence of HES in CSF does not exclude an interstitial deposition of the macromolecule.

A single study addressed this question in patients with normal blood-brain barrier function (9). The study population consisted of patients undergoing elective orthopedic surgery under spinal anesthesia. They received 400 to 500 mL of IV HES before spinal puncture. HES was measured in the plasma and in the CSF obtained through the spinal needle. No HES could be detected in the CSF, despite measurable HES concentrations in the plasma. However, that study did not allow conclusions regarding patients with a disrupted blood-brain barrier. Therefore, we measured blood and CSF concentrations of HES in patients after head trauma or SAH who had an external CSF drainage in place after an IV infusion of HES 200,000/0.5 (mean moleculare weight, 200 kDa; degree of hydroxyethyl-substitution, 0.5).


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After approval by the local IRB, we prospectively considered all adult patients who were admitted to the hospital’s intensive care unit after SAH or head trauma with an external CSF drain in place over a 2-yr period. Patients were enrolled only if they received treatment with more than 500 mL of IV hyperoncotic HES 200,000/0.5 (10% HAES-steril®, Fresenius Kabi, Bad Homburg, Germany) infused over a period of <4 h 3–10 days after SAH or head trauma. In addition, patients were included only if they showed signs of an impaired blood-brain barrier function on a cerebral computed tomographic scan performed within 48 h before the HES infusion. Cerebral computed tomographic criteria were defined as presence of focal or generalized edema, as seen by an area of focal lucency (Fig. 1). Informed consent was obtained from the patients’ families for the collection of a 10-mL blood sample and use of wasted CSF to measure HES concentrations.



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  		Figure 1. Cerebral computed tomography of a patient after head trauma demonstrating radiologic findings suggestive of blood-brain barrier impairment. The image was obtained after a right-sided hemicraniectomy. Intracerebral pathologic findings include a left-sided epidural hematoma and right-sided intraparenchymal hemorrhages with perifocal edema.

 
After termination of the HES 200,000/0.5 infusion, a heparinized blood sample was drawn from an arterial line. In addition, all CSF that spontaneously drained via the external drain over 8 h after the HES infusion was collected. Blood samples were immediately centrifuged (10 min at 16°C, 3000 rpm), and 3.5 mL of the plasma was mixed with 1.25 mL of trichloroacetic (TCA) 50%, again centrifuged (10 min at 16°C, 3000 rpm), and then stored at -30°C until analysis. CSF was mixed with TCA (5 mL of CSF with 0.5 mL of TCA; 50%), centrifuged, and stored similar to the plasma samples.

Plasma and CSF samples were analyzed using high performance exclusion chromatography (10). After acid hydrolysis, HES molecules can be measured with this laboratory technique. The measurements reflect different molecular sizes of HES independent of the degree of plasma esterase hydrolysis before sampling (11). The smallest detectable concentration of HES according to the good laboratory practice certificate (Standard Operating Procedures of the robotic laboratory) is <0.05 mg/mL (Fresenius Kabi).


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Eight patients were included in the study. Patients demographic data are displayed in Table 1. Five patients were included after head trauma, including one who developed a traumatic SAH, and three patients were included after aneurysmal SAH. All patients underwent surgical placement of a therapeutic external CSF drain. In all patients, the infusion of HES was given between three and ten days after head trauma or SAH.


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  		Table 1. Patients Characteristics
 
Blood and CSF sampling, processing, and laboratory testing were performed in all eight patients. Serum HES concentrations ranged between 3.41 mg/mL and 9.95 mg/mL. HES could not be detected in the CSF of any patient (Table 2).


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  		Table 2. HES Serum and CSF Concentrations
 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Little is known about penetration of HES through the blood-brain barrier. Many patients who have suffered an insult that potentially impairs blood-brain barrier function have received treatment with IV HES (1,7) . We assumed that impairment of the blood-brain barrier could be associated with a diffusion of HES molecules into the extravascular intracranial tissues and from there into the CSF. Alternatively, HES could reach the CSF space via an impaired blood-CSF barrier. The presence of HES molecules in the CSF would increase concerns regarding deposition of HES molecules within the extravascular intracranial interstitium, leading to cerebral edema and an increase in ICP. To test this hypothesis, we measured CSF and plasma HES 200,000/0.5 concentrations after IV infusion in patients suspected to have an impaired blood-brain barrier function. Whereas plasma levels were 70–180 times higher than test sensitivity, no HES could be detected in the CSF of any patient. These findings suggest that in patients with an impaired blood-brain barrier function, HES does not reach the CSF compartment.

A limitation of this study is the use of only indirect signs of blood-brain barrier impairment. One might argue, although it was impossible to detect HES levels in the CSF despite large plasma levels, that these patients did not have a disruption of their blood-brain barrier or that the test we used was not sensitive enough. Human studies have shown that impairment of the blood-brain barrier occurs with a maximum between three and eight days after a head injury. Todd and Graham (12) showed that by using plasma proteins as an endogenous marker of blood-brain barrier damage in patients dying with traumatic cortical contusions, protein leakage was maximal between three and eight days after the injury. In addition, radiographic studies have revealed a similar time course of blood-brain barrier impairment in head trauma patients (13,14) . Moreover, experimental data indicate that impairment of the blood-brain barrier develops within two to three days after a subarachnoidal injection of blood (15). In the present study, only patients who received IV HES during a time period were included when impairment of the blood-brain barrier seemed likely. In addition, all patients exhibited radiographic signs of cerebral edema, suggestive of blood-brain barrier disruption. Therefore, it seems likely that the included patients had impairment of the blood-brain barrier during the time of HES infusion.

An additional limitation of the study is the small number of patients that were included. Unfortunately, neurosurgical patients with a CSF drain in place who receive HES for treatment of hypovolemia 3 to 10 days after the neurologic event are few. Nevertheless, the fact that we could not find HES in any patient is somewhat reassuring with regard to the small sample size.

It is known that patients with SAH frequently have blood in their CSF. In the present study, half of the patients included were status post-SAH. If a patient is actively bleeding into the CSF compartment and has a detectable blood HES concentration, one would expect to measure HES in the CSF. The most likely explanation why none of the included patients after SAH had detectable HES in their plasma is the time course. In all aneurysmal SAH patients, the HES infusion was given between five and eight days after the event. None of the patients was known to have active bleeding at the time of the HES infusion. In fact, the undetectable HES concentrations in those patients suggest that during the time of HES infusion, no direct connection was present between the intravascular and CSF compartments.

A substance with similar concerns is mannitol. Similar to HES, mannitol is frequently given to patients with impairment of the blood-brain barrier. Under the assumption that mannitol creates an osmotic gradient between the intracranial interstitium and the intravascular space, it is given IV during many neurosurgical procedures. This therapeutic intervention aims to promote movement of brain tissue water from the extravascular intracranial tissues into the vascular space and thus decrease edema and ICP. However, there are data indicating that mannitol enters the brain and over a short period of time appears in the CSF (16,17) . This may account for a rebound increase of ICP after discontinuation of mannitol therapy (18). Also, a reversal of the osmotic gradient between edematous brain and plasma after multiple mannitol injections can lead to exacerbation of vasogenic cerebral edema (19). The data presented in this study indicate a different distribution of HES in patients with impairment of the blood-brain barrier compared with mannitol. The most likely explanation is a difference in moleculare size between mannitol and HES molecules. Mannitol is a single hexatomic alcohol (C6H14O6) with a molecular weight of 0.18 kd, whereas HES has a molecular weight of 200 kd. HES is metabolized in the plasma by {alpha}-amylase until a moleculare weight of 55 kd is reached, less than which the molecules are eliminated by the kidney (20).

A previous study to determine CSF penetration of HES evaluated CSF and plasma concentrations in patients undergoing orthopedic surgery under spinal anesthesia. The authors demonstrated that HES did not penetrate into the CSF (9). In contrast to the present study, the authors’ findings only apply to patients with an intact blood-brain barrier. Permeability through the blood-brain barrier can occur via paracellular or transcellular pathways (21), and several regulatory mechanisms have been described by which human blood-brain barrier function may be influenced (22). However, experimental evidence suggests that, under physiologic conditions, molecules larger than the size of 20 kd cannot pass across the blood-brain barrier (23). Thus, it is not surprising that HES does not penetrate into the CSF of patients with intact endothelial barrier function. Interestingly, HES solutions containing different molecular sizes (100–1000 kd) have been suggested to decrease paracellular permeability of the microvascular endothelium of the brain in the setting of blood-brain barrier impairment (24–26) . This increase in barrier function may be caused by an effect of HES molecules on the tightness of endothelial cellular junctions by directly interfering with paracellular flux of molecules. The present study did not attempt to address mechanisms by which HES infusion may affect the blood-brain barrier. However, this remains a possible mechanism to explain why HES could not be found in the CSF of those patients.

The results of the present study do not allow conclusions regarding the penetration of HES into the brain interstitium. The blood-brain barrier and the blood- CSF barrier are different in their anatomic structure. The blood-brain barrier is comprised of endothelium- basement membrane-glial processes, whereas the blood- CSF barrier is composed of endothelium-basement membrane-ependymal cells (21). Lack of passage of HES into the CSF after systemic infusion is not necessarily indicative of impermeability through a disrupted blood-brain barrier because these structures are different in location and composition. In fact, HES may theoretically penetrate and accumulate into the intersitial spaces without being detected in the CSF. Further studies using, for example, radioactively labeled HES molecules in an animal model are required to exclude transit of HES molecules through the blood-brain barrier. Alternatively, clinical studies in patients with blood-brain barrier impairment measuring cerebral water content and edema before and after HES administration by means of magnetic resonance imaging might be helpful to follow up on the results of the present study. However, there is evidence that in severe diffuse injury, a disruption of the blood-CSF barrier may be similar to changes of the blood-brain barrier (27).

In conclusion, patients with impaired blood-brain barrier who had received IV HES have no detectable levels of HES in their CSF. However, this observation does not exclude the possibility of HES deposition within the intracranial interstitium. Further research is required to address this question.


   Acknowledgments
 
We thank Fresenius Kabi, Research and Development, Bad Homburg, Germany, in particular Dr K. Sommermeyer, for the determination of HES concentrations in serum and CSF.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication November 21, 2002.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2003 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press