Potentially Modifiable Factors contributing to Sepsis-Induced Encephalopathy

1. Potentially Modifiable Factors contributing to Sepsis-Induced Encephalopathy Intensive Care Medicine (2017) 43:1075-1084

2. Introduction • Sepsis frequently complicated by an encephalopathy – ranging from confusion to coma • Associated with brain injury and adverse outcome • Mechanisms suggested include endothelial alterations with increased blood-brain barrier permeability and microglial activation in brain parenchyma

3. Introduction • Imaging/autopsy suggests sepsis is associated with brain injury: ischaemic lesions, white matter damage, micro abscesses and brain atrophy involving frontal cortex and hippocampus • SAE might be aggravated by severe hypoxia, hypotension, drugs including sedatives, antibiotics and steroids

4. Introduction • In one study, SAE defined by GCS <15 at admission was observed in 54% of patients • Severity of encephalopathy correlated with bacteraemia and renal and hepatic dysfunction • Important impact on SAE on outcomes, with mortality rates over 60% in comatose patients at ICU admission • Sepsis 3 definitions suggest that altered mentation (GCS =<13) in patients with suspected infection outside ICU independently associated with hospital mortality

5. Methods • Retrospective study • Used data from French prospective multicentre (n=12 ICUs) OUTCOMEREA database • Data from patients between 1997-2014 • Included adult patients with diagnosis of severe sepsis or septic shock at admission

6. Methods – Data Recorded • Exposure to antibiotic agents with known neurotoxicity (beta-lactams, fluoroquinolones) • Exposure to benzos, propofol, neuroleptics, barbiturates and/or opioids • Na+ >145 or <135 • Glucose >10 or <3 • CO2>45 mmHg • Excluded patients with acute brain injury as cause of admission • Retrospectively collected: • Medical history • Infection related parameters • Neurological presentation

7. Methods • SAE defined as GCS<15 or abnormal neurological findings consistent with delirium • Used lowest score recorded at admission in the OUTCOMEREA database • Pre-sedation • For post-op patients, used pre-op GCS

8. Results • 18713 ICU admissions over study period • 2647 patients with sepsis at ICU admission

9. Results

10. Results

11. SAE observed in 1341 (53%) patients • 19% GCS 15 and features of delirium • 23% GCS 13-14 • 18% GCS 9-12 • 40% GCS 3-8 (coma) • SAE patients most often presented with clinical features of hypoactive delirium

13. Univariate Analysis Associations • SAE associated with: • Medical admission • Reason for ICU admission • Higer SAPS2 and SOFA • Respiratory failure • Liver failure • Renal failure • Infection source • Bacteraemia • S.Aureus infection • Septic shock

14. Univariate Analysis Associations • SAE patients had more severe circulatory failure: lower sABP, higher HR and higher lactate • PaO2 comparable between the two groups

16. Acute renal failure • Hypoglycaemia • Hyperglycaemia • Hypercapnia • Hypernatraemia • S. Aureus infection

17. Outcomes • 290 patients lost to follow up • Presence of SAE at ICU admission associated with higher mortality, higher use of ICU resources and longer hospital stay

20. Discussion • Retrospective analysis of a prospective database • 1 out of every 2 patients admitted with sepsis had encephalopathy at ICU admission • Those more susceptible to SAE were older with a hx of chronic alcohol abuse, neurological disease, pre-existing cognitive impairment, long term psychoactive drugs

21. Discussion • Identified potentially modifiable factors: • Acute renal failure • High/low glucose • Hypercapnia • Hypernatraemia • Prognostic value of SAE at ICU admission

22. Discussion • Results suggest that “systemic insults” might play a role in the pathophysiology of SAE • Common classes of medication may also play a role • True causal role between antibiotic exposure and SAE remains to be demonstrated • As neurological side effects of antibiotics frequently associated with overdosage, systematic therapeutic drug monitoring may be proposed in patients with SAE

23. Discussion • Timing between exposure to medications and SAE on the day of ICU admission could not be accurately determined • S. Aureus was the only pathogen associated with SAE • A-haemolysin has been identified as neurotoxic • S. Aureus bacteremia associated with increased risk of arterial thrombotic events • S. Aureus is also independent risk factor for neurological complication in patients with severe infective endocarditis

24. Strengths • Large multicentre population • High quality database • One of the largest studies to date in this area

25. Limitations • Causal relationship between identified risk factors and SAE cannot be determined from observational study • Definition of SAE may not include most recent validated criteria for delirium • SAE was defined according to GCS score which may be confounded by mechanical ventilation, sedative and NMB

26. Limitations • Did not analyse impact of transient (1 day) or persistent (more than 1 day) SAE • Focused analysis on occurrence of SAE at ICU admission and therefore didn’t evaluate impact of SAE developing during ICU stay • Absence of neuroimaging therefore can’t assess impact of brain injury on outcome • Long term follow up not available so exact impact on long term neurological outcome remains to be investigated

27. Conclusion • Half of patients admitted to ICU with sepsis had encephalopathy • Identified subset with greater susceptibility were older, history of chronic alcohol abuse, neurological disease, pre-existing cognitive impairment and long term use of psychoactive drugs

28. Conclusion • Potentially modifiable factors associated with SAE at ICU admission included • ARF • Low/high glucose • Hypercapnia • Hypernatraemia

29. Conclusion • Although these factors likely to play key role in SAE pathophysiology, existence of true causal relationship remains to be investigated • Study confirms prognostic significance of mild alteration of mental status in patients with sepsis