EPO has a long history: EPO-2 EPO-3 may reduce mortality in trauma but concerns about thromboembolic events and efficacy have limited application.

EPO is a pleiotropic cytokine and receptors exist in the blood-brain barrier. In response to hypoxia EPO is produced within the brain. Hence worthy of investigation:

Double-blind, placebo-controlled multi-centre trial

• GCS < 13
• Non-penetrating TBI
• Hb < = normal
• < 24 h since traumatic injury
• Valid consent

Intervention

• EPO 40 000 IU or placebo SC
  • First dose was administered within 24 h of the estimated time of traumatic brain injury
  • Then weekly for a maximum of three dose
• Baseline screening USS < = 7 of lower limbs for DVT

Main outcome GOS-E at 6 months

• GOS-E of 1–4 (death, vegetative state, and severe disability)
• GOS-E of 5–8 (moderate disability and good recovery)

606 randomised after inclusion / exclusion

Populations well matched

• Mean age 35
• Majority male
• Mainly RTC
• Most had severe TBI (GCS 3-8)

No effect on proportion with severe disability at 6/12

No increase in thrombotic events (including VTE and MI)

May reduce mortality – 5% ARR at 6/12 but does not achieve statistical significance

Becomes significant after sensitivity testing but this is exploratory

Rates of proximal DVT in TBI 17%

Conclusion: Following moderate or severe traumatic brain injury, erythropoietin did not reduce the number of patients with severe neurological dysfunction (GOS-E level 1–4) or increase the incidence of deep venous thrombosis of the lower limbs. The effect of erythropoietin on mortality remains uncertain.

Erythropoietin in traumatic brain injury (EPO-TBI): a double-blind randomised controlled trial

‘Permissive’ hypernatraemia in refractory intracranial hypertension

Continuous infusions rather than bolus osmolar therapy may make physiological sense but concerns have been raised about the hypernatraemia. Continuous hypertonic saline has been used effectively in a number of settings but what about generation of osmotic gradients at the risk of ALI/AKI.

Concerns raised in discussion about inappropriately high targets and picking appropriate patients

Continuous controlled-infusion of hypertonic saline solution in traumatic brain-injured patients: a 9-year retrospective study

New Trends in Hyperosmolar therapy?

Is there a better fluid?

Different dogma’s exist about the suitability of Hartmanns or balanced solution in neuroICU. We know chloride worsens renal function but concerns about using hypotonic or isotonic solutions have meant a preponderance of saline.

Increasing evidence suggests that the chloride can be harmful to the brain as well – we give lots of chloride in hypertonic saline as well. Meta-analyses have suggested hypertonic saline better at reducing ICP but doses were not equimolar, it might not be best for survival and mannitol has additional effects beyond ICP.

What about feeding the brain? Some evidence for lactate containing solutions in treatment of intracranial hypertension. Lactate is a vasodilator and may improve CBF.

Combination therapy might be best – saline + ringers lactate +/- sugar depending on cerebral micro dialysis with control of sugar.

The cellular mechanisms of neuronal swelling underlying cytotoxic edema.

Hypernatremia in patients with severe traumatic brain injury: a systematic review

Hypertonic saline versus mannitol for the treatment of elevated intracranial pressure: a meta-analysis of randomized clinical trials

Half-molar sodium lactate infusion to prevent intracranial hypertensive episodes in severe traumatic brain injured patients: a randomized controlled trial.

Equimolar doses of mannitol and hypertonic saline in the treatment of increased intracranial pressure

Fixed versus auto regulatory driven CPP targets

Where does ICP threshold 20mmHg comes from old data and BTF guidelines are based on poor quality evidence. Ditto CPP.

BEST-TRIP suggested ICP of 20 but it may be the burden of ICP is the main problem – some people won’t tolerate ICP of 15mmHg. Children almost never do

CPP and ICP targets need to be individualised and hence reactivity with respect to auto regulation is important and might change during treatment. THat’s why you measure it! However, we lack prospective trials and need more data. Delta CPP may correlate with outcome.

Visualizing the pressure and time burden of intracranial hypertension in adult and paediatric traumatic brain injury

Continuous determination of optimal cerebral perfusion pressure in traumatic brain injury.

Refractory Status Epilepticus

Status epilepticus definition has changed! Now anything other than a single self-limiting status (i.e. > 5 minutes) is now in status.

Refractory status is fits after benzodiazepines and second line AED (about two hours)

Super-refractory status fitting despite anaesthesia (about 24 hours)

Quicker you treat, more likely you are to terminate seizure

Once convulsive status exists, if becomes refractory will always progress to non-convulsive status equivalent to EMD. 48% of patients who don’t wake continue to fit in non-convulsive way.

Give Loraz > Phenytoin

Then equipoise – valproate? keppra? propofol?

Midazolam infusion may be better in refractory status – loading dose of 0.2mg/kg. Propofol infusion rates may be limited by PRIS issues. What about ketamine + midazlolam rather than barbiturate?!

Oral ketamine in paediatric non-convulsive status epilepticus.