FEATURED ARTICLE

Osmotic Gradients and Pathogenesis of Hydrocephalus: Implications for Anesthesia

Satish Krishnamurthy, MD
Stephanie Zyck, MD
Jie Li, MD

Department of Neurosurgery
SUNY Upstate Medical University
Syracuse New York

Satish Krishnamurthy, MD
Satish Krishnamurthy, MD

What Causes Hydrocephalus?

Hydrocephalus is abnormal accumulation of fluid in the cerebral ventricles that results in brain damage. The average adult brain produces approximately 20 milliliters of cerebrospinal fluid (CSF) per day, which then resides between the ventricles of the brain and the subarachnoid space of the brain and spinal cord. In diseased states, CSF is not cleared from the ventricular system adequately, and this results in hydrocephalus.

Identifying mechanisms that determine the onset and relief of hydrocephalus are fundamental to prevent the consequent brain damage. Current theories of pathogenesis are inadequate to explain these mechanisms. For example, the popular circulation theory states that hydrocephalus results from obstruction to CSF pathways1 and assumes that brain tissue lining the ventricles is impermeable to water. However, brain tissue is permeable to water, which is exchanged between the ventricles and the surrounding blood vessels through the brain parenchyma. This is largely due to the presence of aquaporin channels.2,3,4 This fact brings the circulation theory into question, as hydrocephalus cannot occur from obstructed pathways alone.5

Role of Osmotic Gradients and Macromolecules

Osmosis is the only biological force that can draw water into the ventricles despite the water permeability of the brain. Osmotic gradients are a result of osmotically active molecules in the ventricles. Small molecules that can enter and exit the ventricles easily (e.g. glucose) are expected to result in transient fluid influx. Macromolecules (e.g. proteins), on the other hand, are expected to result in longer term fluid influx, thereby resulting in hydrocephalus. Clinical evidence supports this osmotic role of macromolecules. For example, intraventricular hemorrhage (IVH) and infections of the brain are the two most common causes of hydrocephalus6. Both IVH7,8 and infections result in excess proteins in the ventricles as well as an inflammatory response.9,10,11,12 High protein levels have also been detected in hydrocephalus of other causes.13,14 The importance of the role played by proteins is strengthened by the relief of hydrocephalus following drainage of CSF to decrease the protein levels.15,16,17,18 Experimental data supporting the role of osmotic gradients and macromolecular transits are reviewed below and our concept underlying the pathogenesis of hydrocephalus is presented.

We have demonstrated that hydrocephalus can be rapidly induced in the normal rat brain by continuously infusing hyperosmolar dextran into the ventricles.15,19 This increase in size of the ventricles is proportional to the osmotic load infused into the ventricles. Ventricular enlargement occurs within thirty minutes and confirms the role of osmotic fluid influx.19 Therefore, increasing the osmotic load in the CSF is sufficient to induce hydrocephalus. In other words, when excess proteins due to IVH or infection increase the osmotic load in CSF, this leads to water transport into the ventricles and the development of hydrocephalus. It is logical that macromolecular clearance from the ventricles would be a mechanism to establish the normal CSF osmolarity and consequently ventricular volume. Therefore, it is important to determine the mechanisms involved in the clearance of macromolecules from the ventricles.

How are Macromolecules Cleared from the Ventricles?

We have shown that macromolecules are cleared from the ventricles in several ways. These include redistribution between CSF compartments, diffusion along the cranial and spinal nerves including olfactory pathways, along paravascular pathways, and sequestration in the cells of the brain and spinal cord. The major pathway of clearance appears to be the paravascular route. Dextran is rapidly concentrated within the perivascular space throughout the brain parenchyma and is initially sequestered in the cells of the blood brain barrier (BBB). Dextran then undergoes vesicular transport across the BBB from microglia and endothelial cells. This transport is rapid; dextrans are in the serum and then in the urine within an hour of injection in the normal state. There is a significant delay in the clearance of the macromolecules from the ventricles (more than three times the half-life of clearance in normal controls) in the presence of hydrocephalus with perivascular accumulation of the tagged macromolecules.20 Dextrans are ultimately removed from the small capillaries into the venous system. Clearance of macromolecules out of the ventricles into the venous blood through transcellular pathway appears to be critical determinant of hydrocephalus.

Hydrocephalus as a Disorder of Macromolecular Transport Altering Osmotic Gradients

Our concept of osmotic gradients and abnormal macromolecular transport are summarized below (Figure 1). The brain is a water-permeable organ that has free transport of water to and from the ventricles through the brain parenchyma. The composition of CSF in the ventricles is tightly controlled in a normal state. In the presence of excess osmotically active molecules, there is a net flow of fluid into the ventricles that results in hydrocephalus. The degree of hydrocephalus is dependent on the osmotic load. The duration of hydrocephalus is dependent on how fast the brain clears osmotically active molecules. Smaller molecules such as glucose and urea are likely to be cleared faster than larger molecules such as proteins. Excess macromolecules are distributed away from the ventricles as described above, but the clearance out of the brain appears to be mainly along paravascular pathways and olfactory pathways to a limited extent. Delayed macromolecular transport results in accumulation of macromolecules in the paravascular pathways and hydrocephalus. Exact mechanisms involved in this clearance pathway are not yet determined; however, efflux transporters likely play a role. Efflux transporters are protein transporters that exist on cell membranes. Venules in brain parenchyma are abundantly lined by efflux transporters (more so than the arterioles) and appear to be the site of eventual clearance of macromolecules from the brain.21

Figure 1

Figure 1

Role of Efflux Transporters and Implications for Anesthesia

Efflux transporters such as P-glycoprotein (PGP) eliminate a wide variety of macromolecules (known as substrates) from the brain to the blood.22,23,24 P-glycoprotein is the most abundant efflux transporter on the BBB25. Inhibition26,27 of PGP will increase the amounts of substrates in the brain. On the other hand, induction28,29 of PGP has been shown to decrease the amounts of macromolecules that remain within the brain. P-glycoprotein expression in the paravascular pathway was found to be absent in the congenital hydrocephalus animal model HTx rat (Hydrocephalus Texas) when compared with normal animals.30 We have demonstrated that a PGP knock out rat model with IVH induced hydrocephalus had reduced clearance of intraventricularly infused macromolecules and enlarged ventricle sizes compared with normal controls.31 Therefore, it is reasonable to expect that PGP might play a role in the development of hydrocephalus.

P-glycoprotein expression is highly variable in humans. There is a 17-fold variation among different people.32,33 A broad array of nutrients and medications are substrates and modulators of PGP that inhibit or induce PGP.19,24 Some such medications include inhalational agents such as isoflurane,34 dexmedetomidine,35 ondansetron,36 pentobarbitol,34 and antibiotics24 that are routinely used in anesthesia. In addition, intravenous fluids containing dextrose,37 renal failure38, and diabetic ketoacidosis39 can cause changes in the size of the ventricles during surgery. There are reports that surgery and anesthesia are associated with higher incidence of hydrocephalus in patients over the age of 65.40 It is clear that there are patient factors (PGP expression, age, etc), disease factors (diabetes, renal failure, etc), and choice of anesthetic medications and fluids that can predispose a given patient to acute exacerbation of hydrocephalus.

Currently, the standard treatment for hydrocephalus is through cerebrospinal fluid diversion. This is typically accomplished through an external ventriculostomy drain in the acute setting or internalized ventricular shunt that most commonly diverts CSF from the ventricles into the peritoneum. Other distal locations such as the pleura and atrium are sometimes also used, though less commonly due to the complication profiles of diverting CSF to these sites.41 An endoscopic third ventriculostomy by creating an opening between the first and third ventricles is another treatment option for some patients with hydrocephalus, though not all patients respond.42 The treatment of hydrocephalus is complex and depends on the exact etiology, patient anatomy, and response to CSF shunting. Diversion through a CSF shunting has a very high rate of failure either by infection, obstruction, or insufficient clearance of CSF43 and other potential solutions are direly needed. For this reason, it is important to explore factors involving macromolecular transport in order to provide better treatment for hydrocephalus.

In conclusion, we propose that hydrocephalus is a dynamic entity related to excess osmotic load in the ventricles, the duration of which is dependent upon macromolecule transport out of the brain. These dynamics of osmotic disequilibrium can change rapidly and depend on many factors involved, especially during neurosurgical anesthesia.

References:

  1. Rekate LH. The definition and classification of hydrocephalus: a personal recommendation to stimulate debate. Cerebrospinal Fluid Res. 2008;5:2.
  2. Agre, P. Nobel Lecture. Aquaporin water channels. Bioscience reports 2004:24, 127-163.
  3. Bulat, M. & Klarica, M. Recent insights into a new hydrodynamics of the cerebrospinal fluid. Brain research reviews 2011: 65, 99-112.
  4. Bulat, M., Lupret, V., Oreskovic, D. et al. Transventricular and transpial absorption of cerebrospinal fluid into cerebral microvessels. Collegium antropologicum 2008: 32 Suppl 1, 43-50.
  5. Klarica, M Oreskovic D, Bozic B et al. New experimental model of acute aqueductal blockage in cats: effects on cerebrospinal fluid pressure and the size of brain ventricles. Neuroscience 2009: 158, 1397-1405.
  6. Tully, H.M. & Dobyns, W.B. Infantile hydrocephalus: a review of epidemiology, classification and causes. Eur J Med Genet 2014: 57, 359-368.
  7. Chang, C.F, Wan J, Li Q et al. Alternative activation-skewed microglia/macrophages promote hematoma resolution in experimental intracerebral hemorrhage. Neurobiology of disease 2017:103, 54-69.
  8. Garton, T., Hua, Y., Xiang, J., et al. Challenges for intraventricular hemorrhage research and emerging therapeutic targets. Expert opinion on therapeutic targets 2017: 21, 1111-1122.
  9. Sura, P, Srebro Z, Macura B et al. Lipopolysaccharide aggravates cerebral pathology in B10.PL-derived CD1-/-, beta2m-/-, TCRalpha-/-, and TCRdelta-/- knockout mice. Folia biologica 2006: 54, 139-144.
  10. Ito, T, Yoshida K, Negishi T, et al. Plexin-A1 is required for Toll-like receptor-mediated microglial activation in the development of lipopolysaccharide-induced encephalopathy. International journal of molecular medicine 2014: 33, 1122-1130.
  11. Cai, Z., Fan, L.W., Lin, S., et al. Intranasal administration of insulin-like growth factor-1 protects against lipopolysaccharide-induced injury in the developing rat brain. Neuroscience 2011: 194, 195-207.
  12. Pang, Y., Cai, Z. & Rhodes, P.G. Disturbance of oligodendrocyte development, hypomyelination and white matter injury in the neonatal rat brain after intracerebral injection of lipopolysaccharide. Brain research. Developmental brain research 2003: 140, 205-214.
  13. Limbrick, D.D, Baksh B, Morgan CD, et al. Cerebrospinal fluid biomarkers of infantile congenital hydrocephalus. PLoS One 2017: 12, e0172353.
  14. Tarnaris, A., Watkins, L.D. & Kitchen, N.D. Biomarkers in chronic adult hydrocephalus. Cerebrospinal fluid research 2006: 3, 11.
  15. Krishnamurthy, S., Li, J., Schultz, L. et al. Intraventricular infusion of hyperosmolar dextran induces hydrocephalus: a novel animal model of hydrocephalus. Cerebrospinal fluid research 2009: 6, 16.
  16. Whitelaw, A., Pople, I., Cherian, S. et al. Phase 1 trial of prevention of hydrocephalus after intraventricular hemorrhage in newborn infants by drainage, irrigation, and fibrinolytic therapy. Pediatrics 2003: 111, 759-765.
  17. Peretta, P., Ragazzi, P., Carlino, C.F.et al. The role of Ommaya reservoir and endoscopic third ventriculostomy in the management of post-hemorrhagic hydrocephalus of prematurity. Child's nervous system: ChNS: official journal of the International Society for Pediatric Neurosurgery 2007: 23, 765-771.
  18. Brinker, T., Seifert, V. & Dietz, H. Subacute hydrocephalus after experimental subarachnoid hemorrhage: its prevention by intrathecal fibrinolysis with recombinant tissue plasminogen activator. Neurosurgery 1992: 31, 306-311; discussion 311-302.
  19. Krishnamurthy, S., Li, J., Schultz, L., Jenrow, K.A., Increased CSF osmolarity reversibly induces hydrocephalus in the normal rat brain. Fluids Barriers CNS. 2012, 9, 13.
  20. Krishnamurthy S, Li J, Shen Y et al. Normal macromolecular clearance out of the ventricles is delayed in hydrocephalus. Brain Research. 2018;1678:337-355.
  21. Saubamea B, Cochois-Guegan V, Cisternino S et al. Heterogeneity in the rat brain vasculature revealed by quantitative confocal analysis of endothelial barrier antigen and P-glycoprotein expression. Journal of Cerebral Blood Flow and Metabolism. 2012:32, 81-92.
  22. Löscher W, Potschka H. Blood-Brain Barrier Active Efflux Transporters: ATP-Binding Cassette Gene Family. NeuroRx. 2005;2:86-98.
  23. Chan GNY, Iloque T, Cummins CL et al. Regulation of p-glycoprotein by orphan nuclear receptors in human brain microvessel endothelial cells. J Neurochem., 2011:118;163-75.
  24. Krishnamurthy S, Tichenor MD, Satish AG, Lehmann DB. A proposed role for efflux transporters in the pathogenesis of hydrocephalus. Croatian Medical Journal 2014 55(4): 366-376.
  25. Dolghih E, Jacobson MP. Predicting efflux ratios and blood-brain barrier penetration from chemical structure: combining passive permeability with active efflux by p-glycoprotein. ACS Chem Neurosci. 2013;4:361-7.
  26. O’Brien FE, Clarke G, Fitzgerald P, et al. Inhibition of P-glycoprotein enhances transport of imipramine across the blood-brain barrier: microdialysis studies in conscious freely moving rats. Br J Pharmacol. 2012;166:1333-43.
  27. Choo EF, Leake B, Wandel C, et al. Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes. Drug Metab Dispos. 2000;28:655-60.
  28. Müllauer J, Kuntner C, Bauer M, et al. Pharmacokinetic modeling of P-glycoprotein function at the rat and human blood-brain barriers studied with (R)-[11C] verapamil positron emission tomography. EJNMMI Res. 2012;2:58.
  29. Bankstahl JP, Kuntner C, Abrahim A, et al. Tariquidar-induced P-glycoprotein inhibition at the rat blood-brain barrier studied with (R)-11C-verapamil and PET. J Nucl Med. 2008;49:1328-35.
  30. Kuwahara S, Sada Y, Moriki T, et al. Spatial and temporal expression of P-glycoprotein in the congenitally hydrocephalic HTX rat brain. Pathol Res Pract. 1996;192:496-507.
  31. Krishnamurthy S, Li J, Shen Y, Haacke M. Hydrocephalus due to intraventricular hemorrhage is determined by p-glycoprotein expression in an experimental model. Neurosurgery 2018 Vol 65, suppl_1, 1,pp 88.
  32. Kimchi-Sarfaty C, Marple AH, Shinar S,et al. Ethnicity related polymorphisms and haplotypes in the human ABCB1 gene. Pharmacogenomics. 2007;8:29-39.
  33. Jensen BP, Roberts RL, Vyas R, et al. Influence of ABCB1 (P-glycoprotein) haplotypes on nortriptyline pharmacokinetics and nortriptyline-induced postural hypotension in healthy volunteers. Br J Clin Pharmacol. 2012;73:619-28.
  34. Tanobe K, Nishikawa K, Hinohara H, et al. Blood brain barrier and general anesthetics. Masui 2003 vol 52(8) pp 840-5.
  35. He GR, Lin XK, Wang YB, Chen CD. Dexmedetomidine impairs P-glycoprotein mediated efflux function in L02 cells via the adenosine 5’ monophosphate activated protein kinase/nuclear factor kappa B. Mol Med Rep 2018 vol17(4) pp 5049-5056.
  36. Scott JA, Wood M, Flood P. The pronociceptive effect of ondansetron in the setting of P-glycoprotein inhibition. Anesth Analg 2006, Vol. 103(3) pp742-6.
  37. Puri BK, Lewis HJ, Saeed N, Davey NJ. Volumetric change of the lateral ventricles in the human brain following glucose loading. Experimental Physiology 1999. 84. 223-226.
  38. Wang IK, Lin CL, Cheng YK, Chou CY, Liang CC, Yen TH, Sung FC. Increased risk of hydrocephalus in long term dialysis patients. Nephrol. Dial. Transplant 2016. Vol 31(5) pp 807-13.
  39. Gruber TJ, Rozzelle CJ. Transient ventriculomegaly in an adolescent presenting with shunted hydrocephalus, diabetic ketoacidosis and hyperglycemia. Pediatr Neurosurg 2008:44:496-500.
  40. Schenning KJ, Murchison CF, Mattek NC, Silbert LC, Kaye JA, Quinn JF.Surgery is associated with ventricular enlargement as well as cognitive and functional decline. Alzheimer's & dementia: the journal of the Alzheimer's Association. 2016; 12: 590-7.
  41. Craven C, Asif H, Farrukh A et al. Case series of ventriculopleural shunts in adults: a single-center experience. J Neurosurg 2017 vol 126(6):2010-2016.
  42. Zaben M, Manivannan S, Sharouf F et al. The efficacy of endoscopic third ventriculostomy in children one year of age or younger: a systematic review and meta-analysis. Eur J Paediatr Neurol 2020.
  43. Simon, TD, Riva-Cambrin J, Srivatsava R et al. Hospital care for children with hydrocephalus in the United States: utilization, charges, comorbidities, and deaths. Journal of neurosurgery. Pediatrics 1, 131-137 (2008).

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