Hypothermia to Prevent High Intracranial Pressure in Patients With Acute Liver Failure

Study Overview
=================
Brief Summary
-----------------
Treatment options in patients with high intracranial pressure due to acute liver failure are limited. This study intends to evaluate the effect of prophylactic hypothermia on preventing high intracranial pressure and compromised cerebral oxidative metabolism.

Detailed Description
-----------------
Acute liver failure (ALF) is associated with a high mortality. With severe hepatic encephalopathy and elevated arterial ammonia concentration (< 200 micromol/L) more than 50% of the patients will develop high intracranial pressure (ICP) and risk cerebral incarceration and death. The therapeutic options are limited in treating and preventing this condition and new interventions are much sought after. As in hypothermia used for patients after cardiac resuscitation it could be speculated that hypothermia and the reduced cerebral metabolic rate would contribute to neuroprotection and reduce the risk of cerebral hypertension in patients with ALF. We have designed this open, randomized and unblinded study in order to evaluate the effect of prophylactic hypothermia on ICP, cerebral hemodynamics and oxidative metabolism. Patients are randomized to standard medical treatment (SMT) or SMT and hypothermia 33° C for 72 hours using a cooling mattress (Blanketrol II, Cincinnati Sub-Zero). All patients will receive mechanical ventilation, antibiotics, inotropic support and monitored with invasive and non-invasive equipment in accordance to local guidelines. In Copenhagen monitoring cerebral hemodynamics includes: Placement of a intracranial pressure measuring catheter (Camino (R), Integra) for monitoring ICP. Furthermore, a microdialysis catheter (CMA-70) placed in brain cortex is used for monitoring brain metabolism. Finally, cerebral perfusion can be monitored by measuring mean flow velocity using transcranial doppler and/or oxygen saturation in blood from the jugular vein. Ethical considerations: The Helsinki II declaration will be followed and informed consent is mandatory for enrollment. In any patient where hypothermia is believed or suspected to be harmful the study should be stopped and the primary investigator should be notified immediately. All adverse effects will be recorded and published together with the full paper.

Official Title
-----------------
Pilot Trial on the Effect of Mild Hypothermia on Intracranial Pressure in Patients With Hyperacute Liver Failure

Conditions
-----------------
Acute Liver Failure, Intracranial Hypertension

Intervention / Treatment
-----------------
* Device: Hypothermia by the use of Blanketrol II, Cincinnati Sub-Zero


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: acute liver failure and hepatic encephalopathy stage 3 or 4 and informed and written consent by closest relative(s) and arterial ammonia concentration above 150 micromol/L or clinical suspicion of cerebral edema and an ICP-measuring device Exclusion Criteria: no or withdrawn informed consent pregnant or breast feeding women uncontrollable infection hemodynamically instable patients active bleeding

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: 1<br>Standard medical treatment | |
| Active Comparator: 2<br>Standard medical treatment plus hypothermia (33°C) maintained for 72 hours | Device: Hypothermia by the use of Blanketrol II, Cincinnati Sub-Zero<br>* The patients are placed on a cooling mattress and body-core temperature is regulated to 33° C.<br>* Other names: Cooling device: Blanketrol II, Cincinnati Sub-Zero;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The effect of hypothermia on preventing development of ICP higher than 25 mmHg |  | 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The effect of hypothermia on preserving normal cerebral oxidative metabolism evaluated by cerebral microdialysis |  | 72 hours | 
| The effect of hypothermia on severity of infections |  | 1 week |