Hypertonic saline for cerebral edema and elevated intracranial pressure - PDF Document

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  1. Hypertonic saline for cerebral edema and elevated intracranial pressure JOSE´I. SUAREZ, MD C to the brain. Improving cerebral edema and decreas- ing ICP has been associated with improved out- come.1However, all current treatment modalities are far from perfect and are associated with serious adverse events:1–4indiscriminate hyperventilation can lead to brain ischemia; mannitol can cause intravascular volume depletion, renal insufficiency, and rebound ICP elevation; barbiturates are associat- ed with cardiovascular and respiratory depression and prolonged coma; and cerebrospinal fluid (CSF) drainage via intraventricular catheter insertion may result in intracranial bleeding and infection. Other treatment modalities have been explored, and hypertonic saline (HS) solutions particularly appear to be an appealing addition to the current therapeutic avenues for cerebral edema. This article succinctly reviews some of the basic concepts and mechanisms of action of HS and discusses some of its possible clinical applications. movements. Because transport through the BBB is a selective process, the osmotic gradient that a particle can create is also dependent on how restricted its permeability through the barrier is. This restriction is expressed in the osmotic reflection coefficient, which ranges from 0 (for particles that can diffuse freely) to 1.0 (for particles that are excluded the most effec- tively and therefore are osmotically the most active). The reflection coefficient for sodium chloride is 1.0 (mannitol’s is 0.9), and under normal conditions sodium (Na+) has to be transported actively into the CSF.5,6Animal studies have shown that in condi- tions of an intact BBB, CSF Na+concentrations increase when an osmotic gradient exists but lag behind plasma concentrations for 1 to 4 hours.5 Thus, elevations in serum Na+will create an effec- tive osmotic gradient and draw water from brain into the intravascular space. erebral edema and elevated intracranial pressure (ICP) are important and frequent problems in the neurocritically ill patient. They can both result from various insults Cerebral edema and intracranial dynamics Cerebral edema is defined as an increase in brain water leading to an increase in total brain mass.7 There are three major categories of brain edema: • Vasogenic edema, which is caused by increased permeability of the endothelial cells of brain capil- laries and is seen in patients with brain neoplasms • Cytotoxic edema, which results from the influx of water into cells. This type of edema may be caused by energy depletion with failure of the ATP-depen- dent Na+-K+pump (ie, cerebral infarction) or low extracellular Na+content (ie, hyponatremia). • Interstitial edema, in which CSF diffuses through the ependymal lining of the ventricles into the periventricular white matter. This type of edema is seen with hydrocephalus. It is important to point out that different types of edema can coexist in the same patient. For instance, brain ischemia is associated with both cytotoxic and vasogenic edema. The presence of cerebral edema, with the subse- ■ PHYSIOLOGIC CONTEXT The blood-brain barrier The blood-brain barrier (BBB) represents both an anatomic and a physiologic structure. The BBB is made up of tight junctions between the endothelial cells of the cerebral capillaries.5Various mechanisms exist for compounds to cross the BBB, including active transport, diffusion, and carrier-mediated From the Department of Neurology and Neurosurgery, Uni- versity Hospitals of Cleveland and Case Western Reserve University, Cleveland, Ohio. Address: Jose ´ I. Suarez, MD, Department of Neurology, Uni- versity Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44106; e-mail:jose.suarez@uhhs.com. S9 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • SUPPLEMENT 1 JANUARY 2004

  2. SUAREZ ■ HYPERTONIC SALINE quent increase in brain mass, alters the intracranial contents (brain, blood, and CSF). Small increases in brain volume can be compensated by changes in CSF volume and venous blood volume. Beyond that, changes in intracranial volume (ΔICV) will result in changes in ICP (ΔICP), which has been termed compliance (ΔICV/ΔICP). When brain compliance decreases, such as when intracranial volume rises, ICP rises.8However, it is important to realize that focal cerebral edema can create ICP gra- dients and cause tissue shifts in the absence of a global increase in ICP.1 • Restoration of normal membrane potentials through normalization of intracellular sodium and chloride concentrations.13 • Reduction of extravascular lung volume, lead- ing to improved gas exchange and improved PaO2.15 ■ EXPERIMENTAL SUPPORT FOR THE EFFICACY OF HYPERTONIC SALINE Animal studies HS solutions have been studied extensively in a variety of animal models, as thoroughly detailed in a recent review.13The literature suggests that fluid resuscitation with an HS bolus after hemorrhagic shock prevents the ICP increase that follows resus- citation with standard colloid and crystalloid fluids for 2 hours or less. This effect can be maintained for longer periods by using a continuous HS infusion. HS may be superior to colloid solutions with regard to ICP response during the initial period of resusci- tation.16,17In animal models of cerebral injury, the maximal ICP-reducing effect of HS is appreciated with focal lesions, such as cryogenic injury or intra- cerebral hemorrhage. Again, the ICP reduction may be caused by reduction in water content in areas of the brain with the BBB intact, such as the nonle- sioned hemisphere and the cerebellum. HS has also been compared with mannitol and was found to have equal efficacy in reducing ICP but to have a longer duration of action and to yield greater improvement in cerebral perfusion pressure.13 ■ HYPERTONIC SALINE: MECHANISMS OF ACTION HS solutions can possibly affect the volume of the intracranial structures through various mechanisms. All or several of them are likely to be interacting to achieve the end result of HS therapy: reduction of cerebral edema and elevated ICP. These mecha- nisms are summarized below: • Dehydration of brain tissue by creation of an osmotic gradient, thus drawing water from the parenchyma into the intravascular space. As men- tioned above, this would require an intact BBB. Experimental evidence suggests that the brain water–reducing properties of HS are accomplished at the expense of the normal hemisphere. • Reduced viscosity. HS solutions enhance intra- vascular volume and reduce viscosity.9The autoreg- ulatory mechanisms of the brain vasculature have been shown to respond not only to changes in blood pressure but also to changes in viscosity.10Thus, a decrease in blood viscosity results in vasoconstric- tion in order to maintain a stable cerebral blood flow (CBF). • Increased plasma tonicity. It has been postulated, based on experimental animal data, that increased plasma tonicity, such as that seen after HS adminis- tration, favors more rapid absorption of CSF.11 • Increased regional brain tissue perfusion, possi- bly secondary to dehydration of cerebral endothelial cells and erythrocytes, facilitating flow through cap- illaries.12 • Increased cardiac output and mean arterial blood pressure, with resultant augmentation of cerebral perfusion pressure, most likely due to improvement of plasma volume and a positive inotropic effect.9,13 • Diminished inflammatory response to brain injury, which has been demonstrated with HS administration.14 Human studies Despite the numerous studies in animal models, most of the evidence in humans is based on the pub- lication of case series and a few randomized studies. Some of the published studies are briefly reviewed here. Readers are referred to a recent review13for a more detailed description. Acute ischemic stroke. HS in two different con- centrations, 7.5% and 10%, has been used to reduce ICP in patients after large cerebral infarcts.18,19 Schwarz et al18compared the effect of 100 mL of 7.5% HS hydroxyethyl starch (osmolarity 2,570 mosm/L) and 200 mL of 20% mannitol (osmolarity 1,100 mosm/L) in 9 patients with stroke randomized to one of the two treatments. HS hydroxyethyl starch caused a greater and earlier peak reduction in ICP, although mannitol caused more improvement in cerebral perfusion pressure. These same researchers studied the effect of 10% saline bolus S10 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • SUPPLEMENT 1 JANUARY 2004

  3. SUAREZ ■ HYPERTONIC SALINE infusions in 8 patients in whom mannitol had failed.19HS reduced ICP by at least 10% in all the instances it was used, and the maximal effect was noted at 20 minutes after the end of the infusion. Even though ICP rose subsequently, it did not reach pretreatment values during the 4 hours of data recording. Intracranial hemorrhage. There has been one report of 2 patients with nontraumatic (presumably hypertensive) intracranial hemorrhage who were treated with continuous HS infusion.20Both patients improved clinically after 24 hours of treat- ment but deteriorated at 48 and 96 hours despite continued HS infusion. Repeat CT scanning showed extension of edema. These findings were attributed to a rebound effect similar to that described with mannitol. Subarachnoid hemorrhage. Two studies have been published on the effect of HS on clinical improvement and CBF in patients with subarach- noid hemorrhage.9,21Suarez et al21retrospectively studied 29 patients with symptomatic vasospasm and hyponatremia who received continuous infu- sions of 3% saline. They found that a positive fluid balance was achieved, and there was short-term clinical improvement without adverse effects. Tseng et al9studied the effect of 23.5% saline bolus infu- sions on CBF, ICP, and cerebral perfusion pressure in 10 patients with poor-grade subarachnoid hemor- rhage. They found that HS caused a significant decrease in ICP and a significant rise in blood pres- sure with a subsequent increase in cerebral perfusion pressure. These effects were accompanied by a sig- nificant elevation in CBF as determined by trans- cranial Doppler ultrasonography and xenon CT. The ICP-lowering effect occurred immediately after the infusion and continued for more than 200 min- utes. The increase in blood flow velocities lasted 175 to 450 minutes. Traumatic brain injury. Most of the human stud- ies have been in patients with traumatic brain injury. Although there is no agreement on the appropriate concentration, dose, or duration of treatment, HS has been reported to have a benefi- cial effect on elevated ICP in patients after trau- matic brain injury.22–33Most of the reported studies are limited by small sample size and the use of vari- ous concentrations of HS. The use of HS in patients with traumatic brain injury deserves more atten- tion, and well-designed studies are needed. Miscellaneous conditions. Other investigators have reported on the use of HS in patients with var- ious intracranial pathologies.34–37 Gemma et al34performed a prospective, random- ized comparison of 2.5 mL/kg of 20% mannitol and 7.5% saline in patients undergoing elective supra- tentorial procedures. They found that the two treat- ments had similar effects on CSF pressure and on clinical assessment of brain bulk. However, the administered solutions used were not equiosmolar. In a retrospective study, Qureshi et al35determined the effect of continuous 3% saline/acetate infusion on ICP and lateral displacement of the brain in patients with cerebral edema and a variety of under- lying cerebral lesions. The authors found a reduction in mean ICP within the first 12 hours, correlating with an increase in serum sodium concentration, in patients with traumatic brain injury and postopera- tive edema, but not in patients with nontraumatic intracranial hemorrhage or cerebral infarction. This beneficial effect was not apparent at later intervals. In a retrospective review of 8 patients with intracranial hypertension refractory to hyperventi- lation, mannitol, and furosemide, Suarez et al36 showed that bolus administration of 23.4% saline was effective in reducing ICP and raising cerebral perfusion pressure. The effect was still present at 3 hours after administration of the HS solution. Horn et al37reported on the administration of 7.5% saline boluses in patients with subarachnoid hemorrhage or traumatic brain injury and refractory intracranial hypertension. The authors demonstrat- ed an increase in cerebral perfusion pressure and a decrease in ICP. The maximal drop in ICP was observed at a mean of 100 minutes after the bolus was given. ■ ADVERSE EFFECTS The administration of HS has been associated with potential adverse effects, both theoretical and real, as summarized below. Intracranial complications • Rebound edema can occur as a result of continu- ous infusion. • Disruption of the BBB (“osmotic opening”) may be due to the shrinking of endothelial cells and a loosening of the tight junctions that form the BBB,38or to an increase in pinocytotic activity and possibly an opening of transendothelial channels.39 • The possibility of excess neuronal death has been postulated after continuous infusion of 7.5% S11 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • SUPPLEMENT 1 JANUARY 2004

  4. SUAREZ ■ HYPERTONIC SALINE administration and HS concentration to be given, and the relative efficacy of HS vis-a `-vis available treatments, particularly mannitol. saline in a rat model of transient ischemia.40This has not been proven. • Alterations in the level of consciousness associat- ed with hypernatremia.6Also, other intracranial alterations have been reported in children with fatal hypernatremia, including capillary and venous congestion; intracerebral, subdural, and subarachnoid bleeding; and sagittal sinus and cor- tical vein thrombosis with hemorrhagic infarction. Severe hypernatremia (>375 mosm/L) has been found to cause similar changes in animal models.6 • Central pontine myelinolysis is a syndrome typi- cally associated with too-rapid correction of (in most cases chronic) hyponatremia.41Such grave complications have not been reported in associa- tion with the use of HS in humans. ■ REFERENCES 1. Bingaman WE, Frank JI. Malignant cerebral edema and intracra- nial hypertension. Neurol Clin 1995; 13:479–509. Smith HP, Kelly DL, McWhorter JM, et al. Comparisons of mannitol regimens in patients with severe head injury undergoing intracranial monitoring. J Neurosurg 1986; 65:820–824. Schwartz ML, Tator CH, Rowed DW, et al. The University of Toronto head injury treatment study: a prospective, randomized comparison of pentobarbital and mannitol. Can J Neurol Sci 1984; 11: 434–440. Lang EW, Chestnut RM. Intracranial pressure: monitoring and management. Neurosurg Clin North Am 1994; 5:573–605. Fishman RA. Blood-brain barrier. In: Fishman RA, ed. Cerebrospinal Fluid in Diseases of the Nervous System. Philadelphia: W.B. Saunders; 1992:43–69. Swanson PD. Neurological manifestations of hypernatremia. In: Vinken PJ, Bruyn GW, eds. Handbook of Clinical Neurology, Vol. 28: Metabolic and Deficiency Diseases of the Nervous System, Part II. Amsterdam: North-Holland Publishing Company; 1976:443–461. Fishman RA. 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Systemic complications • Congestive heart failure can be precipitated sec- ondary to volume expansion.35 • Transient hypotension is possible after rapid intra- venous infusions, but it is followed by an elevation in blood pressure and cardiac contractility.42 • Decreased platelet aggregation and prolonged prothrombin times and partial thromboplastin times have been reported with large-volume infu- sion of HS.43 • Hypokalemia and hyperchloremic metabolic acido- sis can be seen with infusion of large quantities of HS solutions but can be avoided by adding potas- sium and acetate, respectively, to the infusion.36 • Phlebitis can be avoided by infusing HS solutions through a central venous catheter • Renal failure was reported to occur with increased incidence in a single study.44 7. 8. 9. 10. 11. 12. 13. 14. 15. ■ SUMMARY The use of HS solutions has been shown to reduce ICP both in animal models and in human studies in a variety of underlying disorders, even in cases refractory to treatment with hyperventilation and mannitol. There are several possible mechanisms of action, and important complications such as central pontine myelinolysis and intracranial hemorrhage have not been reported in the human studies. Different types of HS solutions with different meth- ods of infusion (bolus and continuous) have been used in the past, and so far there are not enough data to recommend one concentration over anoth- er. Many issues remain to be clarified, including the exact mechanism of action of HS, the best mode of 16. 17. 18. 19. 20. S12 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • SUPPLEMENT 1 JANUARY 2004

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