The focus of this article will be on hyperosmolar therapy with mannitol or hypertonic saline for the treatment of cerebral edema. Mannitol is a sugar alcohol C 6 H 14 O 6 that decreases water and sodium reabsorption in the renal tubule and has been used for the reduction of ICP or cerebral edema since the s. In response, cerebral vasoconstriction occurs due to autoregulation, and cerebral blood volume is decreased.
The second effect occurs through creation of an osmotic gradient across the blood-brain barrier, leading to the movement of water from the parenchyma to the intravascular space. Brain tissue volume is decreased and, therefore, ICP is lowered. Mannitol also acts as an osmotic diuretic, leading to free water clearance and an increase in serum osmolality.
As a result, water moves from the intracellular to the extracellular space, inducing a prolonged dehydrating effect. Reduction in ICP secondary to mannitol administration is dose-dependent, occurring within 10 to 20 minutes with a peak effect seen between 20 and 60 minutes and lasting between 4 to 6 hours. Dosing has historically ranged from 0. Administration of mannitol can occur every 4 to 6 hours after invasive monitoring, such as an external ventricular drain, has been placed.
Hypertonic saline has been utilized for almost a century now, with its first use being documented to decrease brain bulk in to its use for decreasing elevated ICP and increasing CPP in the late s. The mechanism of action behind this effect has several proposed theories, with the most common involving the creation of an osmotic shift of fluid from the intracellular space to the interstitial and intravascular space.
Table 1 compares the osmolality of different mannitol and HTS preparations. Further mechanisms include direct vasodilation, increased cardiac output, and potential neurochemical and immune-modulating effects. The use of HTS is not without concerns for safety and potential adverse effects.
These specific concerns can cause central pontine myelinolysis CPM , metabolic acidosis, cardiac depression, and congestive heart failure. Other safety issues that have been reported in published literature include acute kidney injury AKI , rebound increases in ICP, seizures, altered mentation, coagulopathies, and infusion-rate related hypotension.
Intravenous administration of HTS can also cause local effects such as IV infiltration, thrombophlebitis, tissue ischemia, and venous thrombus. In addition to monitoring for adverse reactions in patients receiving HTS treatment, an astute pharmacist should observe and double-check numerous other components of therapy.
Pharmacists should ensure proper administration technique in terms of correct IV access, rate of infusion, and concentration of HTS products, as well as monitor laboratory values including serum sodium, chloride, potassium, osmolarity, and ICP. Other monitoring parameters, including the use of an electrocardiogram, electroencephalogram, and specific ICP monitors are beyond the scope of this article but important to be aware of.
The decision to use salt-based HTS or sugar-based mannitol osmotherapy has been a long-standing point of contention in hyperosmolar research.
Mannitol was the historical treatment of choice; however, HTS has become established as the preferred initial option for the treatment of elevated ICP based on recent data. Clinical determination of treatment should consider the differences in adverse-effect profiles of each agent. Mannitol can cause hypotension secondary to osmotic diuresis, which could potentially be deleterious in patients who are hypotensive or hypovolemic. Along with hypotension, mannitol may also be associated with an increased incidence of rebound elevated ICP.
This concern is also present with HTS; however, data suggesting this potential side effect is limited. HTS causes hypernatremia, which raises concerns for potential development of CPM with rapid increases in sodium after a hyponatremic state.
It is important to note that a majority of the evidence demonstrating the risk of CPM is from animal studies in which supratherapeutic doses were administered. Further evidence has shown that appropriate administration of high sodium loads may mitigate the apparent risk of developing CPM.
Mannitol increases cerebral blood flow and may be preferable when baseline cerebral hypoperfusion is present. In addition to varying adverse-effect profiles, potential differences in efficacy may exist between HTS and mannitol. Although potential differences in efficacy and outcomes may exist between HTS and mannitol management strategies, further high-quality research is required. Although it may be reasonable to establish treatment goals based on this, it does not necessarily correlate with improved patient outcomes.
Unfortunately, research in this area is inherently biased due to heterogeneity in both treatment and baseline comorbidities of patients and a lack of standardized dosing regimens.
Due to the complexity and critical nature of these patients, pharmacists are essential members of the multidisciplinary team. Listed below are tips for pharmacists to help ensure safe and effective therapy delivered in a timely fashion. In a medical emergency, using IV bags rather than vials can save time and resources. Mannitol frequently crystallizes, requiring inspection of the bag or vial for crystals before administration.
If crystals are present, this is corrected by warming the solution. There is no standard dose or concentration for mannitol or hypertonic saline, so orders should always be double checked for accuracy, especially when taking a verbal or telephone order from the physician.
Table 2 lists hyperosmolar treatment goals and includes a checklist for efficacy and safety for use by pharmacists. One trial suggested a benefit in terms of early outcomes, but this dissipated by 12 months.
The CBF protocol reduced jugular desaturation from When the frequency of jugular desaturation was adjusted for all confounding factors that were significant, the risk of cerebral ischemia was 2. Despite the reduction in secondary ischemic insults, there was no difference in neurologic outcome , probably because 1 jugular desaturation is easily treated and 2 the CBF group suffered a five-fold increase in the frequency of ARDS.
Normal adult CPP is 50 mm Hg. The Brain Trauma Foundation Guidelines claim the following — there is no class I evidence to make any recommendations. Definition Acute Treatment Elevating head of bed to improve venous drainage. Treatment of Elevated Intracranial Pressure The use of sedatives to lower ICP is controversial — in the absence of agitation or anxiety there is no clear evidence that paralysis or sedation are beneficial.
Mannitol Mannitol boluses at 0. Hyperventilation is controversial, most recommend no lower than 35 mm Hg There is no data that barbiturates improve outcome [Cochrane Database ] There is no data that hypothermia improves outcome ICP vs. Inner medullary blood flow is around five times lower than that in the outer medulla, making the inner medulla the most sensitive to hypoxic insults.
Additionally glomerular filtration rate GFR parallels RBF over a wide range and renal oxygen consumption is therefore directly proportional to RBF, rendering the kidney exquisitely sensitive to hypoperfusion. In addition, oxygen delivery to the renal medulla may be reduced during hypoxaemia, endothelial cell swelling, and sludging of cell debris and casts in the renal tubules. Since it is filtered by the kidneys but not reabsorbed, it remains in the renal tubules and causes an increase in the delivery of sodium to the distal tubules and a continued osmotic diuresis.
Osmotic diuresis is not effective once complete tubular occlusion occurs so mannitol must be administered before the ischaemic insult to be effective.
Animal studies have demonstrated that mannitol also improves RBF by changing the pressure—flow relationship within the kidneys, resulting in increased flow at similar levels of perfusion pressure. These changes occur through a variety of mechanisms including local production of vasodilating prostaglandins and a reduction in renin production.
While intuitively it seems that a mannitol-induced improvement in RBF should be beneficial, the overall effect is not so straightforward because of the increased oxygen consumption that occurs secondary to higher rates of energy demanding tubular solute reabsorption related to the parallel increase in GFR.
Mannitol also reduces post-ischaemic endothelial cell swelling and decreases ischaemic—reperfusion injuries through scavenging of hydroxyl and other free radicals. It is particularly common when cardiopulmonary bypass times exceed 3 h. The mechanisms of renal dysfunction after cardiac surgery are multifactorial and include low cardiac output, hypovolaemia, embolic phenomena, pharmacological insults, and reperfusion injury.
In addition, exposure to the cardiopulmonary bypass circuit initiates multiple processes, including complement activation and generation of free radicals and inflammatory mediators. Mannitol is widely used as prophylaxis against ARF after cardiac surgery. Thirty-seven per cent of cardiac surgical centres in the UK include mannitol as part of the prime of the cardiopulmonary bypass circuits. However, recent studies suggest that although mannitol increases urine output, it has no effect on the incidence of ARF.
Mannitol is also used for renal protection in major vascular surgery, especially during aortic surgery. Its potential beneficial effects are likely to occur because of the mechanisms discussed above and also from the temporary mannitol-related increase in intravascular volume and the resultant increase in cardiac output, RBF, and GFR. For greatest efficacy, mannitol must be given before the ischaemic insult.
A commonly used regime is the i. In addition, despite mannitol having been used during aortic surgery for over 30 yr, there is no clear evidence that it reduces the incidence of ARF.
This risk can be reduced by early volume repletion and possibly also by forced diuresis with mannitol within 6 h of rhabdomyolysis. The benefits of mannitol are related to its effect in flushing out intra-tubular myoglobin casts, with free-radical scavenging, reduction in blood viscosity, and reno-vasodilation likely to be contributory.
There are several mannitol regimes described for the treatment of rhabdomyolysis. One recommends the i. However, there are no well-designed studies that demonstrate an advantage of mannitol, either alone or in combination with other diuretics, over adequate hydration in improving urinary flow and prevention of myoglobin casts after rhabdomyloysis.
It was previously believed that mannitol could reduce the incidence of post-transplantation ARF and thereby improve graft survival. Although the routine use of mannitol over adequate hydration in renal transplantation is not supported by controlled clinical trials, it is the authors' practice, in common with that in other institutions, to administer mannitol 20 g 5 min before reperfusion of the transplanted kidney.
Clairmont and Von Haberer first linked renal dysfunction and obstructive jaundice in , and many studies have been subsequently attempted to identify the causative factors.
These are believed to include hyperbilirubinaemia, increased serum level of bile salts, endotoxaemia, renovascular fibrin deposition, and abnormal systemic and renal haemodynamics, including hypovolaemia.
Although renal failure may be associated with any type of jaundice, it is particularly common after obstructive jaundice. The risk of ARF increases as the serum bilirubin increases. Several protocols involving fluid and mannitol administration, whether alone or in combination with other diuretics, have been described to prevent postoperative renal dysfunction in obstructive jaundice, but there is no additional benefit of mannitol over adequate hydration.
Mannitol is poorly absorbed from the gut and has been used as bowel preparation for elective colorectal surgery, colonoscopy, and double contrast barium enema and to facilitate intestinal removal of toxic substances.
For bowel preparation, it is administered orally, usually the day before the procedure and must be accompanied by generous hydration. The Cochrane group analysed 18 randomized controlled trials comparing bowel preparation with no preparation before elective colorectal surgery and identified no difference in the incidence of anastomotic leakage or wound infection. Mannitol is a standard of care for the management of intracranial hypertension and is recommended by consensus guidelines.
There is little evidence to support its continued use for other indications, such as renal protection during cardiac and vascular surgery, or for prophylaxis against ARF in rhabdomyolysis and after renal transplantation, where adequate hydration appears to be effective.
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