Diuretics

Mannitol

Mannitol is an osmotic diuretic. It works by increasing the amount of fluid excreted by the kidneys and helps the body to decrease pressure in the brain and eyes. Rapid administration of mannitol is among the first-line treatments recommended for the management of increased ICP. However, this treatment is reported to be associated with significant diuresis and can cause acute renal failure, hyperkalemia, hypotension, and in some cases rebound increments in ICP (Battison et al. 2005). For these reasons, the Brain Trauma Foundation recommends that mannitol should only be used if a patient has signs of elevated ICP or deteriorating neurological status. Under such circumstances the benefits of mannitol for the acute management of ICP outweigh any potential complications or adverse effects (Bratton et al. 2007). There is also some evidence that with prolonged dosage, mannitol may penetrate the blood brain barrier thereby exacerbating the elevation in ICP (Wakai et al. 2005). Despite mannitol’s effectiveness in ICP management, recent evidence points to hypertonic saline as a potentially more effective hyperosmotic agent.

Table: Effects of Mannitol in the Management of Intracranial Pressure and Hypertension

Discussion

In a recent RCT, patients were randomized to receive either mannitol or a sodium lactate solution for management of acute episodes of elevated ICP (Ichai et al. 2009). The authors report that an equimolar dose of sodium lactate had a significantly more pronounced effect on acute elevations of ICP and lasted longer. Based on these results, further research into sodium lactate is warranted. In another trial, equimolar doses (255 mOsm) of mannitol and hypertonic saline were compared (Francony et al. 2008). In this study both interventions were comparable in reducing ICP in stable patients with intact autoregulation. Mannitol was shown to improve brain circulation through possible improvements in blood rheology, but also significantly increased urine output. The authors suggest that both treatments may be effective, but patient pre-treatment factors should be considered before selection. The finding that mannitol may be effective in the acute management of ABI is largely consistent with findings from studies published more recently, which report that mannitol therapy helps to achieve adequate ICP control (Diringer et al. 2012; Scalfani et al. 2012), as well as CPP and MAP control (Scalfani et al. 2012). One study however did report that mannitol was ineffective in reducing the levels of post-injury elevations of ICP (Colton et al. 2014).

Cruz and colleagues conducted three separate RCTs in patients with ABI to investigate the effects of high dose mannitol on clinical outcomes six months post injury (Cruz et al. 2001; Cruz et al. 2002; Cruz et al. 2004). All three trials reported positive results indicating that high dose mannitol (1.4 g/kg) was superior to conventional mannitol (0.7 g/kg) in improving six-month mortality rates, and clinical outcomes. The implication that ICP response to mannitol is dose-dependent was further explored in a retrospective case series conducted by Sorani et al. (2008) who found that for every 0.1 g/kg increase in mannitol dosage, there was a 1.0 mmHg drop in ICP (Sorani et al. 2008).

Most reports recommend administering mannitol only when elevated ICP is proven or strongly suspected. Some discourage the use of mannitol before volume resuscitation and stabilization of the patient due to the potential osmotic diuresis and hypotension that could result following mannitol administration. These adverse effects could further compromise cerebral perfusion. However, this approach may deprive patients with head injury of the potentially beneficial effects of mannitol upon ICP. With this in mind, Sayre et al. (1996) conducted another RCT to investigate the effects or early mannitol administration in patients with head injury in an out-of-hospital emergency care setting. The authors reported that, compared with patients randomized to receive saline, early out-of-hospital administration of mannitol does not significantly affect blood pressure.

In another RCT by Smith et al. (1986), the authors reported that compared with patients who were randomized to receive empirical mannitol irrespective of ICP measurements, those who received mannitol only after the onset of intracranial hypertension (>25 mmHg) were not significantly different in terms of mortality rates or neurological outcomes.

The findings of a single group intervention study by Hartl et al. (1997) indicate that mannitol is only effective in diminishing ICP when the initial ICP is hypertensive (>20 mmHg) and not when it is below such values. Thus, the use of mannitol as a prophylactic measure against potential elevations in ICP may not be appropriate. This was corroborated by Sorani in a more recent study (Sorani et al. 2008).

Conclusions

Based on a single RCT, there is Level 1b evidence that sodium lactate is more effective than mannitol for the management of acute elevations in intracranial pressure post ABI.

There is Level 2 evidence that higher dose mannitol is superior to conventional dose mannitol in improving acute control, mortality rates and clinical outcomes.

There is Level 1b evidence that early out-of-hospital administration of mannitol does not adversely affect blood pressure.

There is Level 4 evidence that mannitol is effective in diminishing intracranial hypertension only when initial intracranial pressure values are elevated.

 

Sodium lactate is more effective than mannitol for reducing acute elevations in intracranial pressure.

High dose mannitol results in lower mortality rates and better clinical outcomes compared with conventional mannitol.

Early out of hospital administration of mannitol does not negatively affect blood pressure.

Mannitol may only lower intracranial pressure (ICP) when initial ICP values are abnormally elevated.