Brain dysfunction in the ICU
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- George Lawrence Cameron
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1 High cortisol levels are associated with brain dysfunction but low prolactin cortisol ratio levels are associated with nosocomial infection in severe sepsis Duc Nam Nguyen Luc Huyghens Johan Schiettecatte Johan Smitz Jean-Louis Vincent University Hospital of Brussels, Belgium Erasme University Hospital, Brussels, Belgium
2 Brain dysfunction in the ICU Coma and delirium Increase ICU morbidities Nosocomial infection Prolonged MV length Increase ICU length of stay Ely W, JAMA 2004 Lin SM, J Crit Care 2008 Vincent JL, Lancet 2003 Independent risk factor of ICU mortality
3 Brain dysfunction in the ICU Up to 70% of ICU patients and multifactorial Hypotension Hypoxia Excessive brain inflammation Aging with previous brain degenerative disorders Sedatives and anesthesia administration Harmful excessive stress hormones release (cortisol) Sonneville R et al. Ann Intensive Care 2013 Siami S et al. Crit Care Clin 2008
4 Excessive stress hormone release is harmful for the brain Cortisol as biomarker of delirium in acute coronary syndrome, stroke, Cushing s disease, after cardiac surgery, and in elderly after hip fracture Marklund N, J Intern Med 2006 Mu DL, Crit Care 2010 Michaud K, J Neurosci 2010 van Munster BC, Brain Cognition 2010 In sepsis, high cortisol levels are observed in: Non-survivors from septic shock Annane D, JAMA 2002 In a small number of fatal septic patients who developed delirium. Pfitser D, Crit Care 2008 Immunosuppressive and inflammatory effect
5 Excessive stress hormone release is harmful for the brain High prolactin levels in neuropsychiaric disorders (Schizophrenia, mood alteration, bipolar disorder) Sobrinho LG, Baillieres Clin Endocrinol Metab 1991 Fava M, Psychother Psychosom 1983 Kellner R, Am J Psychiatry 1984 In sepsis, low prolactin levels are observed are frequent in pediatric patients with sepsis Heidermann R, Pediatric Crit Care Med 2013 higher incidence of nosocomial infection Felmet KA, J Immunol 2005 Immunostimulating effect : low levels reduce T-lymphocyte function in rats and increase their mortality in sepsis Bernton EW, Science 1988 Oberbeck R, J Surg Res 2003
6 Aim of the study Investigate the impact of stress hormone cortisol and prolactin levels on the development of brain dysfunction and nosocomial infection in patients with severe sepsis and septic shock
7 Exclusion criteria Age < 18 Pregnancy Advanced malignancy Non-survivors in the first 24 hours in the ICU Concomittant treatment: cortisol, dopamine, levodopa, bromocriptine, haloperidol, metoclopramide, antipsychotic drugs Cardiorespiratory arrest Post-neurosurgical patients or hypophysectomy Brain disorders: meningitis, trauma, bleeding, stroke, seizures, Parkinson, Dementia, disabled neuromuscular or severe psychiatric disorders Liver cirrhosis Terminal kidney failure Severe hypothyroidism Addison Alcohol withdrawal Macroprolactin
8 Brain dysfunction assessment Glasgow Coma Scale < 13 at admission Richmond Agitation Sedation Scale (RASS) score Confusion Assessment Method in the ICU (CAM-ICU) Ely W et al. JAMA hours after sedation withdrawal Delirium if RASS > -3 and CAM-ICU positive for at least 2 consecutive days Coma if RASS -4 or throughout ICU stay
9 Brain dysfunction after 24 H sedation withdrawal 127 patients with severe sepsis and septic shock Brain dysfunction 107 (84%) 85 delirium (80%) 22 coma (20%) 82/107 patients after first sepsis (77%) 62/82 documented nosocomial infection (76%)
10 RESULTS Characteristics at ICU admission and comorbidities n= 127 Age, years 65 ± 14 APACHE score 83 ± 30 SOFA score 8 ± 4 CRP (mg/dl) 208 ± 129 Males / females, n (%) 83/45 (65/35) Medical / surgical patients, n (%) 106/22 (83/17) Bronchopneumonia, n (%) 93 (73) Peritonitis, n (%) 22 (17) Gram negative / positive, n (%) 65/42 (51/49) Active smoking, n (%) 33 (26) Obesity (BMI > 30), n (%) 28 (22) Arterial hypertension, n (%) 53 (42) Diabetes, n (%) 24 (19) Alcohol abuse, n (%) 19 (15) History of brain disorder, n (%) 29 (23) History of Sepsis, n (%) 20 (16)
11 ICU evolution All patients (n= 127) No brain dysfunction (n=20) Brain dysfunction (n=107) p Cortisol admission (nmol/l) 413 ± ± ± Prolactin admission (pmol/l) 802 ± ± ± Mechanical ventilation, days 16 ± ± ± Inotropics length, days 6 ± 5 4 ± 2 6 ± Sedation, days 9 ± 7 8 ± 6 10 ± Midazolam, n (%) 80 (62) 12 (57) 68 (64) Fentanyl, n (%) 75 (59) 13 (62) 62 (58) Propofol, n (%) 48 (37) 9 (43) 41(38) Nosocomial infection, n (%) 67 (52) 5 (24) 62 (58) < 0.01 Shock recurrence, n (%) 37 (29) 1(5) 36(34) < 0.01 ICU mortality, n (%) 69 (54) 3 (14) 66 (62) < 0.01
12 Cortisol levels over the first four days after ICU admission Brain dysfunction p = 0, No brain dysfunction 150 day1 day2 day3 day4
13 Prolactin levels over the first four days after ICU admission p= Brain dysfunction No brain dysfunction 350 day1 day2 day3 day4
14 Cortisol prolactin ratio over the first four days after ICU admission day1 day2 day3 day4 p = 0,568 Brain dysfunction No brain dysfunction
15 Prolactin levels over the first four days after ICU admission p= 0,019
16 Cortisol prolactin ratio over the first four days after ICU admission p = No nosocomial infection Nosocomial infection 1 day1 day2 day3 day4
17 Cortisol prolactin ratio over the first four days after ICU admission p = 0,675 Males Females day1 day2 day3 day4
18 SOFA score over the first four days after ICU admission p = Brain dysfunction No brain dysfunction 4 day1 day2 day3 day4
19 Logistic regression results Covariates brain dysfunction OR 95% CI p-value SOFA score admission , Cortisol , Covariates nosocomial infection OR 95% CI p-value Prolactin/cortisol ratio ,
20 Cortisol and brain dysfunction cortisol Brain hippocampus frontal cortex Salpolsky, J Neurosci 1985 Salpolsky, J Neurosci 1986 Inhibition glucose uptake and utilisation ATP depletion Blood brain barrier leakage Accumulation toxic radicals, glutamate
21 Stress hormone and nosocomial infection Sepsis, inflammation stress prolactin cortisol Immunostimulating Stimulating T-lymphocytes function Bernton EW, Science 1988 Oberbeck R, J Surg Res 2003 Immunosuppressive Reduces T-lymphocytes function Chrousos GP, NEJM 1995 Webster JL, J Endocrinol 2004
22 Conclusions High cortisol levels are associated with the development of brain dysfunction in severe sepsis Low prolactin/cortisol ratio are associated with higher risk of development of nosocomial infection,
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