Acute effect of glycerol on net cerebrospinal fluid production in dogs

Full access

✓ The effect of glycerol administration on cerebrospinal fluid (CSF) formation in dogs was studied by means of a ventriculocisternal perfusion technique. Net CSF production rate decreased after oral administration of glycerol (3 gm/kg) from a baseline level of 42.33 ± 6.68 µl/min (mean ± standard error) to a trough of 10.33 ± 4.88 µl/min at 90 minutes after administration (p < 0.025). Serum osmolality concomitantly increased from a baseline value of 296 ± 2.83 to 309 ± 4.7 mOsm/kg H2O at 90 minutes. The mean percentage change in CSF production inversely correlated to the mean percentage change in serum osmolality, r = −0.85. Thus, glycerol administration decreases net CSF formation, and this effect may be related in part to the rise in serum osmolality.

Glycerol, a water-soluble trivalent alcohol, is widely used in the treatment of intracranial hypertension, cerebral edema, and hydrocephalus in infants.3–6,12,13,19,21,23,27 Several authors have reported the relationship between glycerol administration and the reduction in intracranial pressure.4,5,13,21,24,27 Guisado and co-workers9 have shown a decrease in cerebral water content in normal dogs after the administration of a glycerol dose large enough to raise serum osmolality by between 39 and 45 mOsm/kg H2O. Such an effect was not reproduced in states of cerebral edema.8 Other hyperosmolar agents, mannitol26 and hypertonic glucose,7,11 have been shown to decrease CSF formation. This may be one of the mechanisms of action of glycerol and may be relevant to its therapeutic efficacy. Accordingly, we studied the acute effect of oral glycerol administration on CSF formation in adult dogs.

Materials and Methods

Nine adult mongrel dogs, each weighing 16 to 26 kg, were anesthetized with sodium pentobarbital (20 mg/kg), paralyzed with gallamine triethiodide (7 mg/kg), intubated, and artificially ventilated to maintain arterial pO2 between 80 and 120 torr, pCO2 at 32 to 40 torr, and pH at 7.35 to 7.40. Body temperature was maintained at 37° to 38°C by a heating pad. Arterial pressure and central venous pressure were monitored via a femoral arterial catheter and a central venous catheter, respectively. All dogs were constantly infused with 5% dextrose in lactated Ringer's solution at 1 ml/kg/min. Urine was collected via an indwelling catheter.

To monitor CSF formation, we used a modification of the ventriculocisternal perfusion technique of Pappenheimer, et al.10,20 A catheter was placed in the lateral ventricle and Evans blue dye (0.1 ml, 2% solution) was injected. Staining of the cisternal effluent collected via a previously placed No. 19 spinal needle assured correct placement of the ventricular catheter. Artificial CSF solution (NaCl 7.0 gm/liter, NaHCO3 1.9 gm/liter, NaH2PO4 H2O 0.014 gm/liter, Na2HPO4 0.057 gm/liter, KCl 0.268 gm/liter, MgSO4 0.145 gm/liter, CaCl2 0.128 gm/liter, glucose 0.8 gm/liter, albumin 0.25 gm/liter, osmolarity 270 mOsm/liter, pH 7.35) was infused at a rate of 0.03 ml/min via a Harvard pump.* The intracranial pressure was monitored for the duration of the experiment via the ventricular catheter with a “Y” connector attached to a pressure transducer. For the duration of the experiment, the intracranial pressure varied between 0 and 2 torr with respect to the intraaural line. Each animal was observed for 4 hours prior to the oral administration of 3 gm/kg of 50% glycerol. Formation of CSF was determined every 30 minutes for 3 hours prior to and 4 hours after the administration of glycerol. Blood samples of 1 ml were collected at 30-minute intervals throughout the experiment for measurement of serum osmolality.

To assess the effects of anesthesia, hydration, and prolonged instrumentation on the CSF formation rate, three additional dogs were studied for a 7-hour period without the administration of glycerol (time-control group).

To measure CSF formation, 1 ml of artificial CSF containing 150 µCi of iodine-131-labeled albumin (RISA) was injected into the lateral ventricle. Cerebrospinal fluid was collected from the cisternal drain at 30-minute intervals for the duration of the experiment, and measurements of radioactivity were made on 1-ml aliquots of the collected CSF by a scintillation counter.§ The rate of CSF formation (Vf) was calculated from the dilution of the non-absorbable indicator (RISA), using an adaptation of the equation of Heisey, et al.,10 where:

mu1
In this model, Ci represents intraventricular CSF radio-activity and Co represents outflowing cisternal CSF radioactivity. The Co measured at the end of a 30-minute interval was used as the Ci for the subsequent 30-minute interval. Vi is the rate (ml/min) of inflowing artificial CSF, and Vf measures net bulk flow of CSF in this model.

Results

Net CSF formation rates and serum osmolality measurements in the control and post-glycerol periods are shown in Table 1. Net mean CSF formation rates during the 1st, 2nd, and 3rd hour of the control period were similar: 40.89, 43.44, and 42.89 µl/min, respectively, with an overall mean value of 42.33 ± 6.68 µl/min for the 3 hours. After glycerol administration, net CSF formation decreased in all animals to a trough of 10.33 ± 4.88 µl/min and 10.88 ± 4.04 µl/min at 90 and 120 minutes, respectively (p < 0.025, both values, t-test for the means) (Fig. 1). When comparing each dog's own control rate of CSF formation to that at 90 and 120 minutes after glycerol, the decrease was significant (p < 0.001, paired t-test). The percentage decrease in CSF formation at 90 minutes varied from 10% to 100%, with a mean of 73% (Table 1).

TABLE 1

Net CSF formation rate and serum osmolalities prior to and following oral glycerol administration*

Dog No.Control PeriodCSF Formation Rate (µl/min)Control PeriodSerum Osmolality (mOsm/kg H2O)
306090120180240306090120180
1201182272622298303329
23229462984540285308297
3323227611210288309305
46031181326335307330306
54926457117309313302
647321941312298302304
77858391172527297318318
8495245114028291287303
914222458920296297298
mean42.3332.5630.1110.33§10.88§24.6621.22296307307
± SE± 6.68± 4.80± 4.69± 4.88± 4.04± 7.16± 4.28± 2.83± 4.13± 2.15

CSF = cerebrospinal fluid; SE = standard error.

Three-hour period prior to the administration of glycerol.

At the following times (minutes) post-glycerol.

p < 0.025 compared with the control value.

Fig. 1.
Fig. 1.

Mean net formation rate of cerebrospinal fluid (CSF) and mean serum osmolality after glycerol administration. For statistical analysis refer to Table 1.

The mean serum osmolality prior to the administration of glycerol was 296 ± 2.83 mOsm/kg H2O. Mean serum osmolality increased to a maximum of 309 ± 4.7 mOsm/kg H2O at 90 minutes after glycerol administration (Fig. 1). The range of increase in serum osmolality varied from 3 to 33 mOsm/kg H2O, with an average of 12.8 mOsm/kg H2O at 90 minutes (Table 1). An increase in serum osmolality was observed in each animal. However, it did not reach statistical significance, probably reflecting the wide variability of serum osmolality found in the dogs in this experiment. Mean absolute serum osmolality correlated inversely with mean net CSF formation, r = −0.85. Mean net CSF formation rate in the three time-control dogs was 43.83 ± 4.06 µl/min during the 7-hour perfusion period. No significant decline was noted in the net CSF formation rate during the last 4 hours of the experiment.

Mean arterial pressure, central venous pressure, and urine output remained stable throughout the experiment, suggesting a lack of significant hemodynamic changes after glycerol administration.

Discussion

The results of this study demonstrate that the oral administration of glycerol causes a significant decrease in net CSF formation concomitant with a rise in serum osmolality. The maximum decline in net CSF formation rate occurred at 90 and 120 minutes after glycerol administration, followed by a gradual rise toward baseline production at 180 and 240 minutes post-glycerol. The lack of significant decline in CSF formation rate in the three dogs in the time-control group, as well as the rise in CSF formation rate during the last 2 hours of a 7-hour experiment, argue against this being an artifact of the ventriculocisternal perfusion technique utilized or an effect of prolonged instrumentation and anesthesia. Martins, et al.,14 noted a steady decline of CSF formation rate of 4% each hour during the final 5 hours of a 7-hour ventriculocisternal perfusion, a decline that is far less than that noted in our experimental animal group and not reproduced in our time-control experiments.

The rate of CSF production depends on many factors that include age, integrity of the choroid plexus, choroid plexus oxygen consumption, serum osmolality, and the action of the enzymes carbonic anhydrase and Na+— K+-adenosine triphosphatase (ATPase).7,11,15,17,22,26 The effects of serum osmolality on CSF production have been well demonstrated.7,11,26 The experiments by Hochwald, et al.,7,11 demonstrated that the infusion of hypertonic glucose caused a progressive increase in serum osmolarity, with a corresponding decrease in CSF production. Conversely, the infusion of hypotonic glucose caused a progressive decrease in serum osmolarity and an increase in CSF production. A 1% serum osmolarity change resulted in a 6.7% change in CSF formation. An 18% increase in serum osmolarity to 380 mOsm/liter completely inhibited CSF formation. Sahar and Tsipstein26 demonstrated similar effects with mannitol. An increase in osmolarity of 20 mOsm/liter decreased CSF production by 70%. Our findings with glycerol are in accord with the above studies. An increase of 12.8 mOsm/kg H2O was accompanied by a 73% decrease in CSF production. The effects of mannitol on CSF production seemed to be greater than those of glucose at similar osmolarities, which may be due to the fact that the passage of mannitol from the blood to the CSF compartment is not as free as that of glucose. Hence, a high blood CSF osmotic gradient may be present. This may in part explain the magnitude of the effect of glycerol on CSF production.

The effects of glycerol on brain water content in dogs was evaluated by Guisado, et al.,9 who studied varying doses of glycerol for 3-, 6-, and 12-hour periods. When using a low dose of glycerol, such that the rise of serum osmolality was 14 ± 5 mOsm/kg H2O, no significant change in the water content of either the white or gray matter was detected. In our study, one would not expect significant dehydration of the brain since the glycerol dosage utilized is comparable to the low dose used by Guisado, et al., with a similar rise in serum osmolality of 13 ± 4.7 mOsm/kg H2O. Therefore, the decrease in net CSF formation was due to decreased production rather than increased absorption of CSF into the brain parenchyma. It is possible that the absorption of CSF across the choroid plexus contributes to the net reduction in CSF formation rates. The capacity of the choroid plexus to absorb CSF was proposed by Milhorat, et al.,16 who demonstrated transchoroidal fluid absorption in hydrocephalic children. Sahar,25 using an in vivo preparation of the choroid plexus in dogs, did not detect significant bulk absorption via the choroid plexus at low intraventricular pressures. It is conceivable, however, that absorption may become more significant under very high intraventricular pressures. In our study, with the intraventricular pressure maintained between 0 and 2 torr throughout the perfusion, one would not expect significant transchoroidal absorption.

Changes in serum osmolality may be only one of the mechanisms responsible for the profound effect of glycerol on net CSF production. Among other mechanisms to be considered is the effect of glycerol on cerebral blood flow and, specifically, choroid plexus flow. Muizelaar, et al.,18 demonstrated considerable arteriolar vasoconstriction following the intravenous administration of 1 gm/kg of mannitol in cats. A decrease in blood viscosity was noted with initial increase in cerebral blood flow. Subsequently, vasoconstriction of cerebral blood vessels occurred to maintain relatively constant cerebral blood flow in a state of intact autoregulation. Presumably, vasoconstriction of blood vessels in the choroid plexus may result in decreased CSF production. Another possible mechanism may be related to the effect of glycerol on Na+—K+-ATPase because inhibition of this enzyme will alter the rate of CSF production by the choroid plexus.1,2

In summary, acute oral glycerol administration significantly decreased net CSF formation in dogs. This effect may be related in part to the rise in serum osmolality. However, other effects of glycerol on choroid plexus blood flow, cerebral blood flow, and Na+—K+-ATPase inhibition may play a significant role, and should be further investigated.

References

  • 1.

    Albers RWKoval GJ: Sodium-potassium-activated adenosine triphosphatase. J Biol Chem 247:308830921972J Biol Chem 247:

  • 2.

    Barnett RE: The effects of dimethylsulfoxide and glycerol on Na+,K+-ATPase and membrane structure. Cryobiology 15:2272291978Barnett RE: The effects of dimethylsulfoxide and glycerol on Na++-ATPase and membrane structure. Cryobiology 15:

  • 3.

    Bovet DCantore GGuidetti Bet al: Il glicerolo in neurochirurgio. Gazz Int Med Chir 66:302130341961 (Cited in Reference 5)Gazz Int Med Chir 66:

  • 4.

    Buckell MWalsh L: Effect of glycerol by mouth on raised intracranial pressure in man. Lancet 2:115111521964Lancet 2:

  • 5.

    Cantore GGuidetti BVirno M: Oral glycerol for reduction of intracranial pressure. J Neurosurg 21:2782831964J Neurosurg 21:

  • 6.

    De Souza SWDobbing JAdlard BPF: Glycerol in treatment of cerebral oedema. Lancet 1:8351973 (Letter)Lancet 1:

  • 7.

    DiMattio JHochwald GMMalhan Cet al: Effects of changes in serum osmolarity on bulk flow of fluid into cerebral ventricles and on brain water content. Pflugers Arch 359:2532641975Pflugers Arch 359:

  • 8.

    Guisado RArieff AIMassry SG: Effects of glycerol administration on experimental brain edema. Neurology 26:69751976Neurology 26:

  • 9.

    Guisado RArieff AIMassry SG: Effects of glycerol infusions on brain water and electrolytes. Am J Physiol 227:8658721974Am J Physiol 227:

  • 10.

    Heisey SRHeld DPappenheimer JR: Bulk flow and diffusion in the cerebrospinal fluid system of the goat. Am J Physiol 203:7757811962Am J Physiol 203:

  • 11.

    Hochwald GMWald ADiMattio Jet al: The effects of serum osmolarity on cerebrospinal fluid volume flow. Life Sci. 15:130913161974Life Sci. 15:

  • 12.

    Lin ECC: Glycerol utilization and its regulation in mammals. Annu Rev Biochem 46:7657951977Lin ECC: Glycerol utilization and its regulation in mammals. Annu Rev Biochem 46:

  • 13.

    MacDonald JTUden DL: Intravenous glycerol and mannitol therapy in children with intracranial hypertension. Neurology 32:4374401982Neurology 32:

  • 14.

    Martins ANNewby NDoyle TF: Sources of error in measuring cerebrospinal fluid formation by ventriculocisternal perfusion. J Neurol Neurosurg Psychiatry 40:6456501977J Neurol Neurosurg Psychiatry 40:

  • 15.

    McComb JG: Recent research into the nature of cerebrospinal fluid formation and absorption. J Neurosurg 59:3693831983McComb JG: Recent research into the nature of cerebrospinal fluid formation and absorption. J Neurosurg 59:

  • 16.

    Milhorat THMosher MBHammock MKet al: Evidence for choroid-plexus absorption in hydrocephalus. N Engl J Med 283:2862891970N Engl J Med 283:

  • 17.

    Miner LCReed DJ: Composition of fluid obtained from choroid plexus tissue isolated in a chamber in situ. J Physiol (Lond) 227:1271391972in situ. J Physiol (Lond) 227:

  • 18.

    Muizelaar JPWei EPKontos HAet al: Mannitol causes compensatory cerebral vasoconstriction and vasodilation in response to blood viscosity changes. J Neurosurg 59:8228281983J Neurosurg 59:

  • 19.

    Newkirk TATourtellotte WWReinglass JL: Prolonged control of increased intracranial pressure with glycerin. Arch Neurol 27:95961972Arch Neurol 27:

  • 20.

    Pappenheimer JRHeisey SRJordan EFet al: Perfusion of the cerebral ventricular system in unanesthetized goats. Am J Physiol 203:7637741962Am J Physiol 203:

  • 21.

    Pitlick WHPirikitakuhlr PPainter MJet al: Effects of glycerol and hyperosmolality on intracranial pressure. Clin Pharmacol Ther 31:4664711982Clin Pharmacol Ther 31:

  • 22.

    Plum FSiesjö BK: Recent advances in CSF physiology. Anesthesiology 42:7087301975Anesthesiology 42:

  • 23.

    Reinglass JL: Dose response curve of intravenous glycerol in the treatment of cerebral edema due to trauma. A case report. Neurology 24:7437471974Reinglass JL: Dose response curve of intravenous glycerol in the treatment of cerebral edema due to trauma. A case report. Neurology 24:

  • 24.

    Rottenberg DAHurwitz BJPosner JB: The effect of oral glycerol on intraventricular pressure in man. Neurology 27:6006081977Neurology 27:

  • 25.

    Sahar A: The effect of pressure on the production of cerebrospinal fluid by the choroid plexus. J Neurol Sci 16:49581972Sahar A: The effect of pressure on the production of cerebrospinal fluid by the choroid plexus. J Neurol Sci 16:

  • 26.

    Sahar ATsipstein E: Effects of mannitol and furosemide on the rate of formation of cerebrospinal fluid. Exp Neurol 60:5845911978Exp Neurol 60:

  • 27.

    Wald SLMcLaurin RL: Oral glycerol for the treatment of traumatic intracranial hypertension. J Neurosurg 56:3233311982J Neurosurg 56:

Harvard pump, Model 975, manufactured by Harvard Apparatus Co., The Ealing Corp., 22 Pleasant Street, South Natick, Massachusetts.

Freezing point depression osmometer, Model 3W, manufactured by Advanced Instruments, Inc., Needham Heights, Massachusetts.

RISA obtained from Nuclear Pharmacy, Inc., Houston, Texas.

Gamma well-type scintillation counter, Model 4233, manufactured by Nuclear Chicago Corp., Des Plaines, Illinois.

Article Information

Address reprint requests to: Huda Y. Zoghbi, M.D., Section of Pediatric Neurology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030.

© AANS, except where prohibited by US copyright law."

Headings

Figures

  • View in gallery

    Mean net formation rate of cerebrospinal fluid (CSF) and mean serum osmolality after glycerol administration. For statistical analysis refer to Table 1.

References

1.

Albers RWKoval GJ: Sodium-potassium-activated adenosine triphosphatase. J Biol Chem 247:308830921972J Biol Chem 247:

2.

Barnett RE: The effects of dimethylsulfoxide and glycerol on Na+,K+-ATPase and membrane structure. Cryobiology 15:2272291978Barnett RE: The effects of dimethylsulfoxide and glycerol on Na++-ATPase and membrane structure. Cryobiology 15:

3.

Bovet DCantore GGuidetti Bet al: Il glicerolo in neurochirurgio. Gazz Int Med Chir 66:302130341961 (Cited in Reference 5)Gazz Int Med Chir 66:

4.

Buckell MWalsh L: Effect of glycerol by mouth on raised intracranial pressure in man. Lancet 2:115111521964Lancet 2:

5.

Cantore GGuidetti BVirno M: Oral glycerol for reduction of intracranial pressure. J Neurosurg 21:2782831964J Neurosurg 21:

6.

De Souza SWDobbing JAdlard BPF: Glycerol in treatment of cerebral oedema. Lancet 1:8351973 (Letter)Lancet 1:

7.

DiMattio JHochwald GMMalhan Cet al: Effects of changes in serum osmolarity on bulk flow of fluid into cerebral ventricles and on brain water content. Pflugers Arch 359:2532641975Pflugers Arch 359:

8.

Guisado RArieff AIMassry SG: Effects of glycerol administration on experimental brain edema. Neurology 26:69751976Neurology 26:

9.

Guisado RArieff AIMassry SG: Effects of glycerol infusions on brain water and electrolytes. Am J Physiol 227:8658721974Am J Physiol 227:

10.

Heisey SRHeld DPappenheimer JR: Bulk flow and diffusion in the cerebrospinal fluid system of the goat. Am J Physiol 203:7757811962Am J Physiol 203:

11.

Hochwald GMWald ADiMattio Jet al: The effects of serum osmolarity on cerebrospinal fluid volume flow. Life Sci. 15:130913161974Life Sci. 15:

12.

Lin ECC: Glycerol utilization and its regulation in mammals. Annu Rev Biochem 46:7657951977Lin ECC: Glycerol utilization and its regulation in mammals. Annu Rev Biochem 46:

13.

MacDonald JTUden DL: Intravenous glycerol and mannitol therapy in children with intracranial hypertension. Neurology 32:4374401982Neurology 32:

14.

Martins ANNewby NDoyle TF: Sources of error in measuring cerebrospinal fluid formation by ventriculocisternal perfusion. J Neurol Neurosurg Psychiatry 40:6456501977J Neurol Neurosurg Psychiatry 40:

15.

McComb JG: Recent research into the nature of cerebrospinal fluid formation and absorption. J Neurosurg 59:3693831983McComb JG: Recent research into the nature of cerebrospinal fluid formation and absorption. J Neurosurg 59:

16.

Milhorat THMosher MBHammock MKet al: Evidence for choroid-plexus absorption in hydrocephalus. N Engl J Med 283:2862891970N Engl J Med 283:

17.

Miner LCReed DJ: Composition of fluid obtained from choroid plexus tissue isolated in a chamber in situ. J Physiol (Lond) 227:1271391972in situ. J Physiol (Lond) 227:

18.

Muizelaar JPWei EPKontos HAet al: Mannitol causes compensatory cerebral vasoconstriction and vasodilation in response to blood viscosity changes. J Neurosurg 59:8228281983J Neurosurg 59:

19.

Newkirk TATourtellotte WWReinglass JL: Prolonged control of increased intracranial pressure with glycerin. Arch Neurol 27:95961972Arch Neurol 27:

20.

Pappenheimer JRHeisey SRJordan EFet al: Perfusion of the cerebral ventricular system in unanesthetized goats. Am J Physiol 203:7637741962Am J Physiol 203:

21.

Pitlick WHPirikitakuhlr PPainter MJet al: Effects of glycerol and hyperosmolality on intracranial pressure. Clin Pharmacol Ther 31:4664711982Clin Pharmacol Ther 31:

22.

Plum FSiesjö BK: Recent advances in CSF physiology. Anesthesiology 42:7087301975Anesthesiology 42:

23.

Reinglass JL: Dose response curve of intravenous glycerol in the treatment of cerebral edema due to trauma. A case report. Neurology 24:7437471974Reinglass JL: Dose response curve of intravenous glycerol in the treatment of cerebral edema due to trauma. A case report. Neurology 24:

24.

Rottenberg DAHurwitz BJPosner JB: The effect of oral glycerol on intraventricular pressure in man. Neurology 27:6006081977Neurology 27:

25.

Sahar A: The effect of pressure on the production of cerebrospinal fluid by the choroid plexus. J Neurol Sci 16:49581972Sahar A: The effect of pressure on the production of cerebrospinal fluid by the choroid plexus. J Neurol Sci 16:

26.

Sahar ATsipstein E: Effects of mannitol and furosemide on the rate of formation of cerebrospinal fluid. Exp Neurol 60:5845911978Exp Neurol 60:

27.

Wald SLMcLaurin RL: Oral glycerol for the treatment of traumatic intracranial hypertension. J Neurosurg 56:3233311982J Neurosurg 56:

TrendMD

Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 28 28 28
PDF Downloads 18 18 18
EPUB Downloads 0 0 0

PubMed

Google Scholar