Neurology: CNS Injury ====================== See also about trauma to the head þ Basic mechanism: - free radicals cause lipid peroxidation and causes membrance damage in secondary phase þ Vit E: - works well if given well before injury only - no good for acute injury, as takes too long to get into CNS þ methylprednisolone: - works only at very particular levels, but going above this level actually increases injury. [Hall, Exp Neurol, 1981] - cat study showed great clinical effects [Demopoulos et al, 1982] - NASCIS II study: 487 patients, naloxone vs. methylprednisolone vs. placebo, but only for 24 hours. + outcome assessment: assessed motor and sensory in various dermatomes but not funtional status + no significant effects at 6 weeks and 6 months + criticized for lack of power + if look only at those treated within 8 hours, improved overall, if treated more than 8 hours after injury, made outcome worse [Raymond F. Regan, M.D., Jefferson] + improved only 4/70 points, but in incomplete injury it made a bigger difference + in animal studies, best results in about an hour + will probably never be another placebo-controlled trial - NASCIS III study: in progress - penetrating trauma to CNS + NASCIS trial excluded penetrating trauma + study showed methylprednisolone made penetrating trauma worse [Prendergast et al, J Trauma, 1994.] - 21-amino steroids: in phase III trials, e.g., Tirlizad being studied by Upjohn + steroid nucleus with -OH group removed so won't bind to glucocorticoid receptors + additional free radical scavenger added to molecule + additional group added to molecule to scavenge iron + doesn't work in women as they metabolize steroids faster (may need to use higher doses) + anticonvulsants decrease Tirilizad levels - Glutamate and Aspartate + idea is that excitatory neurotransmitters released in excess, leading to damage. + mouse study showed lots of MSG given to mice resulted in severe obesity; destroyed satiety center (has no blood-brain barrier) + excess glutamate binds to NMDA receptor, allowing Na+ and Ca+ influx; Ca+ influx seems to kill cells, increase free radicals. At the 1994 International Conference on Recent Advances in Neurotraumatology (Gold Coast, Queensland, Australia) there was a general on the following principle aims of management: pO2 > 100 mmHg pCO2 30-35 mmHg Normothermia, Normal biochemistry Paralysis SBP > 90 mmHg CPP > 70 mmHg rather than ICP as an isolated marker Hct > 0.30 (from Gary Wilkes via Internet) I don't see the value of mannitol acutely if the patient is not deteriorating neurologically. It is used in neurosurgical ICUs as (one way of) controlling incresed ICP. It's effects are rather short-lived 45 min to 11 hours (1) but repeated doses may be given. I think that the recommendation is to use it to 'buy some time' if the patient is going to surgery and, even then, only upon consultation with a neurosurgeon. > 2. Is hyperventilation indicated? > > 3. What is the goal for the pCO2 during hyperventilation? > At this point I do not think that there is sufficient evidence to justify with-holding hyperventilation. However, I would moderate it to the extent of keeping the pCO2 in the range of 30 - 35 as Garry suggested to avoid the potential of excaerbating ischemic injury. I would hyperventilate this patient until I was satisfied that there was no immediate threat of herniation and let the neurosurgeon decide what he wanted to do in the ICU based upon his own prejudices. I'm not sure how relevant the (oft quoted) study by Muizzelaar (2) is to ED practice. First of all that study looked at CHRONIC hyperventilation over a period of days. The group that was hyperventilated actually had a LOWER mortality although worse (overall) functional status (neither result was statistically significant at 12 months). Also, it only applied to those with GCS motor scores of 4-5 (the less severely injured). Finally all patients were to some extent hyperventilated. The goal in the 'control group' was 30 - 35 with actual average pCO2 of 35 and 24 - 28 in the HV groups (actual 25). Finally they concluded that if you need to hyperventilate a patient to control ICP it's 'deleterious effects can be overcome' by giving THAM. So? Give THAM. H. Louzon MD (1) James et. al. Analysis of the Response of Therapeutic Measures to Reduce Intracranial Pressure in Head Injured Patients. J Trauma 1976;16(6):437-441 (2) Muizelaar et. al. Adverse Effects of Prolonged Hyperventilation in Patients with Severe Head Injury: A Randomized Clinical Trial. J Neurosurg 75:731-739,1991 Brain Resuscitation =================== Cliff Callaway, 1/4/95, Senior Lecture þ Neurological survival vs. time to onset of CPR and duration of CPR: {insert graph from:} [Abramson et al. CCM 1985; 13:930-931] þ "No-reflow" phenomenon: - after resuscitation, rabbit brains were hyperemic but had areas of "no reflow" [Ames et al. Am J Pathol 1968;52:437-447.] No sludging, but edema of surrounding microglia pressing on small vessels; in dogs, keep BP high after cardiac arrest and neurological outcome is better. þ Hyperglycemia in CNS injury: - exacerbates acidosis and ischemic histology by increasing lactate and acidosis in animal studies but - only an association but not cause-and-effect for humans; no evidence that decreasing glucose levels helps. þ Giving bicarb for CNS injury: - improves intracellular acidosis in brain (N.B. blood-brain barrier nonfunctional after arrest) - bicarb given during CPR elevates brain pH consistent with blood pH by P31 NMR [Elaff et al. Stroke 1995;26:1028-1034.] þ Excess excitatory neurotransmitters in CNS injury: - excess glutamate, GABA, aspartate. þ Apoptosis - programmed cell death as part of development (e.g., CNS, immune system). - may be inappropriately triggered by CNS injury? þ Clinical trials of brain resuscitation - BRCTI (barbiturate coma): didn't work [BRCTI I. NEJM 1986;314:397-403] - Calcium channel blockers: might prevent vasospasm, Ca++ entry: some promising work in animals, but no effect in humans. - Steroids: no benefit - High-dose epi: in progress now (early 1996) - Bicarbonate: being studied by Vukmir and Safar - Hypothermia: mild HT very protective in animals, but doesn't work if more than 15-30 minutes after arrest. Tried in uncontrolled trials in early 1960s, but no controlled trials. Cooled for about 2-3 hours. May reduce free radicals or excitatory transmitters. - Free Radical Scavengers: + Lazaroids (21-amino-steroids): funded by drug companies; free radical scavengers for lipid membranes + Vitamin E (works in lipid membranes) + Defreoxamine (scavenges iron) + normoxic resuscitation (Zwemer et al, 1994) (not giving oxygen) + Dilantin shown to be effective in focal ischmia + NSAIDs not tried yet.