Lars I. Eriksson, MD, PhD, FRCA

Professor, Academic Chairman Dept of Anesthesiology and Intensive Care Medicine

Function Perioperative Medicine and Intensive Care Karolinska Institutet and

Karolinska University Hospital Stockholm, Sweden lars.i.eriksson@ki.se

SwERAS, World Trade Centre, Stockholm Nov 21-22, 2019

Neuroprotection - the Human Brain after Anesthesia and Surgery

Globally increased focus on postoperative neurocognitive outcomes

M Leslie, Science Magazine June 2, 2017 American Soc Anesthesiologists website

Time course of brain dysfunction after surgery

Hours/days Week/Month Permanent

DSM-code DSM alignment DSM-code with new nomenclature

Delirium Postoperative cognitive decline

Dementia

Postoperative delirium POD

Acute onset of change in mental status inattention, desorganised thinking, altered consciouness Usually within 72 hours postop Hyperactive delirium (most common) agitation, confusion, combativeness Hypoactive delirium (less common) drowsiness, lethargy, slow speech, inattention

Definition and types of POD

POD is associated with -  increased burden of postop care, -  longterm cognitive decline and dementia -  increased postoperative mortality

Patients developing POD cost on averege 2.5 times the care for patients without POD

Overall incidence of POD at 35 % (n=1823 patients) Range 10 – 60 % in older patients

Incidence of POD in the adult

Guenther et al Curr Op Anesthesiol 2011, Allen et al N Am Surg Clin 2013 Rudolph et al Anesth Analg 2011, Leslie et al Arch Intern Med 2008

Risk factors for postoperative delirium Major preexisting risk factors -  age > 65 y -  preop cognitive impairment or dementia -  poor vision or hearing -  severe illness, malnutrition, frailty -  Infection

Additional factor: sleep deprivation, poor functional status, metabolic derangements, polypharmacy, poorly controlled pain, dehydration, neuropsychiatric conditions, alcohol or drug abuse

ESA Guideline for POD, 2017 Am J Surg. 2010, Expert Panel on Postop delirium Journal of the American Geriatrics Society 2015

Risk factors for postoperative delirium Precipitating risk factors and drugs at-risk -  urgency, i.e. acute > elective - anticholinergics -  long duration and invasiveness - opioids -  need admission to the ICU - benzodiazepines -  postop infection - dopaminergics -  postop vascular adverse events - metoclopramide

- barbiturates

ESA Guideline for POD, 2017 Am J Surg. 2010, Expert Panel on Postop delirium Journal of the American Geriatrics Society 2015

Well-established diagnos within DSM V system POD is typically studied with neuropsychological bedside tests CAM (Confusion Assessment Method) DRS (Delirium Rating Scale)

Assessment of POD

Strom, Lancet 2010, Guenther,l Curr Op Anesthesiol 2011, Barnes-Daly CCM 2017, Hishieh JAMA Intern Med 2015, ESA Guidelines on POD 2017, Mahanna-Gabrielli Br J Anaesth 2019

Prevention and Treatment of POD Non-pharmacological care process approach !  ERAS concept (provide clock, visual/hearing aids, day/

night rythm, no indwelling catheters or IV lines, early mobilization and nutrition

Perioperative management still under debate !  Raw EEG to avoid burst suppression - promising but still unclear !  Processed EEG - conflicting impact on outcome !  NIRS-guided anesthesia, small size studies, methodological issues !  Dexmedetomidine perioperatively may reduce POD but not POCD

!  Sedation at BIS > 80 vs < 50 during regional anesthesia

!  Melatonin show conflicting results - unclear evidence

Adapted from Mahanna-Gabrielli Br J Anaesth 2019

Gaps and needs to be explored How should dexmedetomidine be administered perioperatively to reduce POD and prevent cognitive decline? Does EEG-guided anesthesia reduce the incidence or severity of postoperative postoperative delirium or cognitive decline ? Does NIRS-guided anesthesia/ optimization of cerebral perfusion reduce the incidence or severity of postoperative delirium or cognitive decline ? Can maintenance of intraoperative blood pressure above an individual’s cerebral pressure autoregulatory threshold reduce the incidence or severity of postoperative delirium (or cognitive decline) ?

Postoperative cognitive dysfunction

!  Incidence is 20-40 % at 1 week and 10-15 % at 3 months Möller et al, Lancet 1998, Monk et al Anesthesiology 2008

!  No or minimal difference in longterm impact by general anesthesia

v.s. regional techniques !  Rasmussen et al acta Anesthesiol Scand 2002 !  No or minimal difference between IV versus inhaled anesthetics

Shoen et al, Br J Anaesth 2011, Royse et al, Anaesthesia 2011, Qiao Anesthesiology 2015

Cognitive decline after non-cardiac surgery

Patient and Perioperative factors

Perioperative protocols impact early cognitive decline in orthopedics

Incidence of POCD 1 week 3 months n= 220, TKA or THA 9.1 % 8.0 % Ortho part ISPOCD and others 20-40 % 6-15 %

Krenk et al, Anesth Analg 2014

Silbert, Evered, Scott et al Anesthesiology 2015

Is preop cognitive impairment a risk factor?

Preoperative cognitive

screening - the Clock-in-a-box test

Culley et al Anesthesiology 2017

MMSE Mini-COG

Test batteries

Evered et al Anesthesiology 2016

•  57 patients undergoing orthopedic surgery with preop CSF sampling.

•  27.3 % of patients with AD biomarker (a-beta amyloid) had POCD •  Only 4.3 % patients with no AD biomarker had POCD

Patients with preop AD biomarkers have > risk for POCD

Is preop Alzheimer biomarkers in CSF a risk factor for cognitive decline ?

Evered et al JAMA Neurol 2018

30 patients older than 60 years, 73 % joint arthroplasty. Transient increase in plasma NFL and Tau levels during the first 48 hours postsurgery

Plasma Tau Plasma Neurofilament light

Nation-wide large scale outcome study in > 20.000 swedish twins Focus on hospitalization and risk of later dementia Twins aged <65 years at start of follow-up with up to 33 years of follow-up - mean 23.9 years Critical care > non-surgical care > routine surgery are all associated with slightly increased risk for later dementia Eriksson, Lundholm, Narisimhalu, Sandin, Jin, Gatz, Pedersen, Alzheimer and Dementia 2019

The impact of surgery or nonsurgical care disapperad in identical twins – risk for dementia is dependent on genetic predisposition

What we need !  Identify patients at-risk prior to surgery !  Introduce preop cognitive screening

!  Introduce standardized neurological outcome measures –Part of global perioperative outcome measures initiative by P Myles 2016

!  Find biomarker(s) that can identify the development of cognitive decline in postop patients

!  Individualized perioperative care process and follow-up for high risk patients

What we need to know !  Is there a link between delirium and dementia

! Do anesthetic compounds have a built-in property to accelerate a dementia trajectory

! Are there imaging techniques, biomarkers or combinations of them to indicate such risks

! Are there an immune and/or inflammatory signaling pattern in humans that associates with cognitive decline

! Can we find (blood) biomarkers either pre- or postoperatively that can detect those patients

The Research Group

Karolinska Institutet Helena Harris Bob Harris Jinming Han Fredrik Granath Nancy Pedersen Lars Farde Andrea Varrone Anton Forsberg Ulrica Nilsson Nippon Medical School, Japan Shinhiro Takeda Chol Kim Gothenburg University, Sweden Sven-Erik Ricksten Mattias Danielsson Kai Blennow Henrik Zetterberg Bengt Nellgård

University of Pennsylvania Rod Eckenhoff Copenhagen University, Denmark Lars Rasmussen Tokyo Shinhiro Takeda Utrecht MC, The Netherlands Cor Kalkman Monash University, Australia Paul Myles Jennifer Reilly Pasteur Institute, France Jean-Pierre Changeux Uwe Maskos

Marta Gomez, PhD, Malin J Fagerlund, MD, PhD Jessica Kåhlin, MD PhD Andreas Wiklund, MD, PhD Anette Ebberyd, Lab manager Souren.Mkrtchian, PhD Anna Granström, CRNA-research Anna Schening, CRNA-reasearch Malin Hildenborg,MD, PhD-student Pia Glatz, MD, PhD-student Eva Christensson, MD, PhD-student Max Kynning, student Lars I Eriksson, MD PhD, FRCA, Professor, Academic Chair, Research Group Leader

Collaborators