Neuroprotection in neuroanesthesia

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problems and innovational technologies in anesthesiology

1 Neuroprotection in neuroanesthesia Federico Bilotta, MD, PhD Sapienza University of Rome, Rome, Italy Topical problems and innovational technologies in anesthesiology and emergency medicine 31 March, 2018 St Petersburg, Russia

2 No conflicts of interest - Anesthetics for NP in NA - Non anesthetics for NP in NA Leonardo da Vinci The last supper ( )

3 Pharmacological Neuroprotection Anesthetics - Inhalational & i.v. anesthetics - Lidocaine - Ketamine -Dexmedetomidine Non-Anesthetics Jesus from The last supper

4 Anesthetic Neuroprotection is limited to preclinical evidence: Isoflurane: induces an increase in neural stem cell differentiation and improves long-term cognitive performance (in rats). Lidocaine: reduces ischemic penumbra after stroke models (in rats). Propofol: attenuates ischemic brain injury reducing brain oxygen supply/demand, neurotransmitter activity and apoptosis (in cells). Dexmedetomidine: attenuates excitotoxic brain injury and decreases by 30% lesion size (in rats).

5 Thiopental, propofol and etomidate have been tested as neuroprotectant with negative results. Lidocaine has proven neuroprotective effects in non-diabetic patients undergoing cardiac surgery Intravenous anesthetics might have neurotoxic effects. Leonardo da Vinci Benois Madonna (1478)

in 94 patients scheduled for supratentorial craniotomy.

6 RCT evaluating lidocaine administration (bolus 1.5 mg/kg after induction + infusion 2 mg/kg/h until the end of surgery) in 94 patients scheduled for supratentorial craniotomy. No difference in the postoperative cognitive decline between the groups at 1 day, 1 month, 3 months, and 6 months.

7 SR (5 in adults & 2 in pediatric) on ketamine use (continuous infusion or bolus) in a total of 156 TBI patients sedated and ventilated. Induces an increase in cerebral perfusion pressure and decrease in need for vasopressors. Continuos infusion or adjunct to other sedative has equal effectiveness than opiate or benzodiazepines (sufentanil, midazolam) infusions in terms of sedation. Leonardo da Vinci Madonna of the carnation (1473) Bolus injection is associated with a decrease in ICP, both at baseline and during an ICP elevation

Cortical spreading depolarization (CSD) is characterized by loss of neuronal ion homeostasis, mediated by release of glutamate, that leads to neuronal necrosis and poor outcome.

8 Cortical spreading depolarization (CSD) is characterized by loss of neuronal ion homeostasis, mediated by release of glutamate, that leads to neuronal necrosis and poor outcome. In the injured brain, CSD induces a microvascular constriction that cause transient hypoperfusion. Ketamine administration induced an intense and sustained suppression of CSD and an increase in cerebral perfusion pressure. Leonardo da Vinci The last supper ( ) From left to right: James, Andrew, Judas Iscariot, Peter, John, Jesus.

9 - Reduces infarct volume in focal ischemia. - Attenuates deregulation of neuronal calcium homeostasis - Inhibits TNF-α, IL-6 and IL-8 production in both peripheral immune and CNS - Reduces platelet aggregation - Reduces incidence of POD - Interferes with neural cell differentiation Madonna Litta 1490 Hermitage, St Petersburg

Meta-analysis of 8 RCTs to compare Dex with placebo (6 RCTs; sevoflurane or isoflurane) or opioids (2 RCTs; remifentanil) as anesthetic adiuvant for intracranial surgery.

10 Meta-analysis of 8 RCTs to compare Dex with placebo (6 RCTs; sevoflurane or isoflurane) or opioids (2 RCTs; remifentanil) as anesthetic adiuvant for intracranial surgery. Compared to placebo, Dex infusion is associated: -less intraoperative hypertension and hypotension: RR=0.48, p=0.001 and RR=0.66, p= less intraoperative fentanyl consumption: mean reduction 0.78μg/kg, p= less postoperative hypertension and tachycardia: RR=0.37, p=0.01 and RR=0.14, p=0.007 No difference between DEX or remifentanil Leonardo da Vinci Ginevra de Benci ( )

Intraprocedural BP was significantly lower and use of vasopressors higher in Dex

11 No differences in good outcome and in hospital mortality when Dex or propofol is used in AIS patients undergoing IAT. Intraprocedural BP was significantly lower and use of vasopressors higher in Dex treated patients Dex is NOT a first tier sedative agent for intravascular AIS treatment St Jerome 1480 Vatican Museum Rome

- Propofol induces neuroapoptosis and disrupts neurogenesis. - Volatile anesthetics (desflurane, isoflurane, sevoflurane) cause dosedependant cognitive impairment.

12 - Propofol induces neuroapoptosis and disrupts neurogenesis. - Volatile anesthetics (desflurane, isoflurane, sevoflurane) cause dosedependant cognitive impairment. - Ketamine interferes with neural stem cell proliferation, astrocytic and neuronal differentiation - Dex induces neuroapoptosis (in rats) and increase metastatic diffusion. Salvador Mundi 1500 Louvre Abu Dhabi

13 GH ROSUVASTATIN β BLOCKERS ENZOGENOL CEREBROLYSIN ERYTHROPOETIN controversial effects on cognitive function reduces proinflammatory mediators improves survival after TBI reduces cognitive failures 3-12 months after TBI improves cognitive function at 3 months after injury may limit neuronal damage after TBI None of these drugs has proven beneficial in clinical neuroprotection

Placebo or Mg, in 92 patients undergoing

14 Placebo or Mg, in 92 patients undergoing CEA with GA, effects on neurocognitive follow up at 1 postoperative day. Patients assigned to low dose Mg have better neurocognitive postoperative outcome Leonardo da Vinci Adoration of the Magi ( )

15 Meta-analysis, 5 trials with 1981 patients, to evaluate efficacy of Mg administration after asah No benefit on outcome or reduction of DCI after Mg treatment. RR for outcome for Mg vs placebo RR for occurrnce of DCI for Mg vs placebo

NA-1 is a cell-permeant eicosapeptide that perturbs postsynaptic scaffolding protein

years with ruptured or unruptured intracranial aneurysm amenable to endovascular

patients undergoing endovascular aneurysm repair, including those with a ruptured

16 NA-1 is a cell-permeant eicosapeptide that perturbs postsynaptic scaffolding protein with NMDA glutamate receptors: it modulates mitochondrial activity Patients aged >18 years with ruptured or unruptured intracranial aneurysm amenable to endovascular repair: NA-1 ev 2-6 mg/kg over 10 min before coiling NA-1 could be safely given to patients undergoing endovascular aneurysm repair, including those with a ruptured aneurysm. NA-1 treatment reduced MRI-detected embolic strokes Leonardo da Vinci Virgin of the rocks( )

17 Take home massage Inhalational and i.v. anesthetics have no proven neuroprotectant effects. Ketamine reduces ICP in patients with TBI and suppress CSD increasing cerebral perfusion. Dex as anesthetic adjuvant reduced intraoperative opioid consuption but increases neuroapoptosis and spreading of metastasis NA-1 is effective when given BEFORE ischemia Neuroprotection CANNOT be accomplished with a magic bullet Leonardo da Vinci Vitruvian man (1490)

18 Non anesthetics NP in NA -Hemodynamic: arterial pressure and cardiac rhtythm -Ventilation: PaO2 and PaCO2 -Awake craniotomy Jesus from The last supper

19 Arterial hypertension during surgery and in the early postoperartive period is associated with increased risk for postcraniotomy ICH

(modified Rankin Scale grade 0-3, 81% vs. 88.7%; p= 0.

20 New onset postoperative AF after elective or emergency brain surgeryis associated with similar neurological outcome at 6 months follow up (modified Rankin Scale grade 0-3, 81% vs. 88.7%; p= 0.09) but lower survival rate (85% vs. 95%; p<0.05). Leonardo da Vinci Annunciation ( )

Categorized as: - normoxia (PaO2: 60-300 mm Hg): 1,084 (38%) - hypoxia (PaO2: <60 mmhg or PaO2/FIO 2 <300): 1,316 (46%) -

21 Retrospective multicenter cohort study stroke patients mechanically ventilated: 1,404 ICH (49%); 936 SAH (32%); 554 AIS (19%). Categorized as: - normoxia (PaO2: mm Hg): 1,084 (38%) - hypoxia (PaO2: <60 mmhg or PaO2/FIO 2 <300): 1,316 (46%) - hyperoxia (PaO2: >300 mm Hg): 450 (16%) The primary outcome: in-hospital mortality. Mortality was higher in the hyperoxia group as compared with both normoxia (p < ) and hypoxia groups (p < 0.01). Leonardo da Vinci Lady with an ermine ( )

Retrospective multicenter cohort study 252 aneurysmal

ICU stay) - DCI: symptomatic vasospasm & new cerebral

22 Retrospective multicenter cohort study 252 aneurysmal SAH: - 64 were hyperoxic (mean PaO2 >173 mmhg during ICU stay) - DCI: symptomatic vasospasm & new cerebral infarction - Outcome: 3 months with mrs Primary outcome: DCI in 18% vs. 36%, p<0,001 Secondary outcome: mrs <3 in 19.1% vs: 29.6%; P<0087 Lionello Spada

Leonardo da Vinci La belle ferronnière (1490-1495) Retrospective cohort of 102 consecutive mechanically ventilated patients with aneurysmal SAH admitted to an academic neurosurgical intensive care

23 Leonardo da Vinci La belle ferronnière ( ) Retrospective cohort of 102 consecutive mechanically ventilated patients with aneurysmal SAH admitted to an academic neurosurgical intensive care unit (ICU). Primary outcome was 3-month GOS; The secondary outcomes: hospital mortality and symptomatic vasospasm. Hypocapnia was common (92% of patients at least 1 episode <35mmHg and 48% <30mmHg), median duration was 4 days. Associated with unfavorable outcome (OR 1.33) higher incidence of vasospasm (OR 1.25) and higher in-hospital mortality (26% vs. 32%, P<0.05)

CBF 143% & StiO2 111% of BL Both CBF and StiO2 reacted with a sustained elevation upon hypercapnia.

24 To measure the effect of PaCO2 changes on CBF and StiO2, 60 interventions on MV were performed in 6 patients with poor-grade asah PaCO2=30 mmhg CBF 77% & StiO2 94%of BL PaCO2=40 mmhg CBF 98% & StiO2 99%of BL PaCO2=50 mmhg CBF 124% & StiO2 105% of BL PaCO2=60 mmhg CBF 143% & StiO2 111% of BL Both CBF and StiO2 reacted with a sustained elevation upon hypercapnia. Hypercapnia may yield therapeutic potential in patients with asah and represent a promising therapeutic approach during DCI Leonardo da Vinci The beautiful princess (1495)

250 patients (M:F=146:104) undergoing craniotomy for glioma resection 145 patients (58.0%) had at least one site with an intraoperative stimulationinduced speech arrest: anomia 82 and alexia in 23.

25 250 patients (M:F=146:104) undergoing craniotomy for glioma resection 145 patients (58.0%) had at least one site with an intraoperative stimulationinduced speech arrest: anomia 82 and alexia in week after surgery, language function was unchanged in 194 (77.6%) speech deficits in 35 (14.0%) and worsened in 21 (8.4%) 6 months after surgery, only 4 of 243 surviving patients (1.6%) had a persistent language deficit. Craniotomies tailored to limit cortical exposure, even without localization of positive language sites, permit most gliomas to be aggressively resected without language deficits

Literature search 1970-2012 for tumor resection under general anesthesia (GA) or awake craniotomy (AC). 8 studies with 951 patients (in 540 patients GA and in 411 pts AC) were included in this review.

26 Literature search for tumor resection under general anesthesia (GA) or awake craniotomy (AC). 8 studies with 951 patients (in 540 patients GA and in 411 pts AC) were included in this review. Surgery time was shorter in AC vs. GA. Postoperative deficits were less frequent after AC. AC result in a shorter hospital stay than GA. Given the safety of AC for resection of eloquent tumors, the data suggests an expanded role for AC in brain tumor surgery regardless of tumor location. Leonardo da Vinci The lansdowne madonna (1501)

27 Procedure specific skills: - skull block with LA - sedation - hemodynamic management Advanced airway managment including ability of emergency fiberoptic intubation- is a prerequisite!! Leonardo da Vinci Portrait of a young lady (1500)

Conclusions: Pharmacological neuroprotection has limited or no clinical effectiveness, there is no magic bullet Optimal hemodynamic management are associated with better neurological outcome.

28 Conclusions: Pharmacological neuroprotection has limited or no clinical effectiveness, there is no magic bullet Optimal hemodynamic management are associated with better neurological outcome. Ventilation affects outcome: Hyperoxia and hypocapnia are associated with reduced survival rate at 6 months follow up. Hypocapnia after asah increased incidence of vasospasm and in-hospital mortality. Awake craniotomy might be a safe alternative to GA for NP Leonardo da Vinci Vitruvian man (1490)

29 11/04/16

25 RCTs, which include 3274 patients (age range 22-86): - 22 RCTs in cardiac surgery - 2 RCTs in vascular surgery - 1 RCT in major abdominal and urological surgery Tested drugs: lidocaine,

30 25 RCTs, which include 3274 patients (age range 22-86): - 22 RCTs in cardiac surgery - 2 RCTs in vascular surgery - 1 RCT in major abdominal and urological surgery Tested drugs: lidocaine, thiopental, S-ketamine, propofol, nimodipine, GM1 ganglioside, lexipafant, glutamate/aspartate and xenon remacemide, atorvastatin, magnesium sulphate, erythropoietin, piracetam, rivastigmine, pegorgotein, and 17b-estradiol.

31 The incidence of new postoperative neurological deficit was lower in studies that tested atorvastatin and magnesium sulphate and was associated with conflicting results for thiopental The incidence of POCD did not differ between treated patients and control group for tested drugs

RCT to explore the effects of Dex on brain of 60 glioma patients ungergoing craniotomy. Patients received saline or Dex (1µg/kg ) 10 min before anesthesia.

32 RCT to explore the effects of Dex on brain of 60 glioma patients ungergoing craniotomy. Patients received saline or Dex (1µg/kg ) 10 min before anesthesia. Dex premedication was associated with better hemodynamic stability and it can reduce brain damage through, suppression of inflammation and reduction of the effects of free radicals but might favor systemic metastasis Leonardo da Vinci Madonna Dreyfus (1469)

34 Prospective study to evaluate residents learning curve for each of 3 tasks needed for anesthesia for awake craniotomy: local anesthesia,sedationanalgesia, hemodynamic management Leonardo da Vinci Portrait of Isabella d Este (1500)

Postoperative cognitive dysfunction a neverending story

Postoperative cognitive dysfunction a neverending story Adela Hilda Onuţu, MD, PhD Cluj-Napoca, Romania adela_hilda@yahoo.com No conflict of interest Contents Postoperative cognitive dysfunction (POCD)