Impaired cerebral autoregulation and cerebral hypoperfusion may play a critical role in the high morbidity and mortality in patients with sepsis-associated encephalopathy (SAE). Bedside assessment of cerebral autoregulation may help individualize hemodynamic targets that optimize brain perfusion. We hypothesize that near-infrared spectroscopy (NIRS)–derived cerebral oximetry can identify blood pressure ranges that enhance autoregulation in patients with SAE and that disturbances in autoregulation are associated with severity of encephalopathy.
Methods:
Adult patients with acute encephalopathy directly attributable to sepsis were followed using NIRS-based multimodal monitoring for 12 consecutive hours. We used the correlation in time between regional cerebral oxygen saturation and mean arterial pressure (MAP) to determine the cerebral oximetry index (COx) as a measure of cerebral autoregulation. Autoregulation curves were constructed for each patient with averaged COx values sorted by MAP in 3 sequential 4-hour periods; the optimal pressure (MAPOPT), defined as the MAP associated with most robust autoregulation (lowest COx), was identified in each period. Severity of encephalopathy was measured with Glasgow coma scale (GCS).
Results:
Six patients with extracranial sepsis met the stringent criteria specified, including no pharmacological sedation or neurologic premorbidity. Optimal MAP was identified in all patients and ranged from 55 to 115 mmHg. Additionally, MAPOPT varied within individual patients over time during monitoring. Disturbed autoregulation, based on COx, was associated with worse neurologic status (GCS < 13) both with and without controlling for age and severity of sepsis (adjusted odds ratio [OR]: 2.11; 95% confidence interval [CI]: 1.77-2.52; P < .001; OR: 2.97; 95% CI: 1.63-5.43; P < .001).
Conclusions:
In this high-fidelity group of patients with SAE, continuous, NIRS-based monitoring can identify blood pressure ranges that improve autoregulation. This is important given the association between cerebral autoregulatory function and severity of encephalopathy. Individualizing blood pressure goals using bedside autoregulation monitoring may better preserve cerebral perfusion in SAE than current practice.
GaieskiDFEdwardsJMKallanMJCarrBG. Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med. 2013;41(5):1167–1174. doi:10.1097/CCM.0b013e31827c09f8.
2.
PaoliCJReynoldsMASinhaMGitlinMCrouserE. Epidemiology and costs of sepsis in the united states-an analysis based on timing of diagnosis and severity level. Crit Care Med. 2018;46(12):1889–1897. doi:10.1097/CCM.0000000000003342.
SonnevilleRVerdonkFRauturierC, et al.Understanding brain dysfunction in sepsis. Ann Intensive Care. 2013;3(1):15. doi:10.1186/2110-5820-3-15.
6.
EidelmanLAPuttermanDPuttermanCSprungCL. The spectrum of septic encephalopathy: definitions, etiologies, and mortalities. JAMA. 1996;275(6):470–473. doi:10.1001/jama.1996.03530300054040.
7.
IacoboneEBailly-SalinJPolitoAFriedmanDStevensRDSharsharT. Sepsis-associated encephalopathy and its differential diagnosis. Crit Care Med. 2009;37(suppl 10):S331–S336. doi:10.1097/CCM.0b013e3181b6ed58.
8.
KressJP. The complex interplay between delirium, sepsis and sedation. Crit Care. 2010;14(3):164. doi:10.1186/cc9038.
9.
MolnárLNémethNBerhésM, et al.Assessment of cerebral circulation in a porcine model of intravenously given E. coli induced fulminant sepsis. BMC Anesthesiol. 2017;17(1):98. doi:10.1186/s12871-017-0389-0.
10.
PfisterDSiegemundMDell-KusterS, et al.Cerebral perfusion in sepsis-associated delirium. Crit Care. 2008;12(3):R63. doi:10.1186/cc6891.
11.
JoshiBOnoMBrownC, et al.Predicting the limits of cerebral autoregulation during cardiopulmonary bypass. Anesth Analg. 2012;114(3):503–510. doi:10.1213/ANE.0b013e31823d292a.
12.
OnoMArnaoutakisGJFineDM, et al.Blood pressure excursions below the cerebral autoregulation threshold during cardiac surgery are associated with acute kidney injury*. Crit Care Med. 2013;41(2):464–471. doi:10.1097/CCM.0b013e31826ab3a1.
13.
SharsharTPolitoAChecinskiAStevensRD. Septic-associated encephalopathy-everything starts at a microlevel. Crit Care. 2010;14(5):199.
14.
JanzDRAbelTWJacksonJCGuntherMHeckersSElyEW. Brain autopsy findings in ICU patients previously suffering from delirium: a pilot study. J Crit Care. 2010;25(3):538. e7–e12. doi:10.1016/j.jcrc.2010.05.004.
15.
SingerMDeutschmanCSSeymourCW, et al.The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):801–810. doi:10.1001/jama.2016.0287.
16.
LassenNA. Cerebral blood flow and oxygen consumption in man. Physiol Rev. 1959;39(2):183–238.
17.
LeDouxDAstizMECarpatiCMRackowEC. Effects of perfusion pressure on tissue perfusion in septic shock. Crit Care Med. 2000;28(8):2729–2732.
18.
BourgoinALeoneMDelmasAGarnierFAlbanèseJMartinC. Increasing mean arterial pressure in patients with septic shock: effects on oxygen variables and renal function. Crit Care Med. 2005;33(4):780–786.
19.
SteinerLACzosnykaMPiechnikSK, et al.Continuous monitoring of cerebrovascular pressure reactivity allows determination of optimal cerebral perfusion pressure in patients with traumatic brain injury. Crit Care Med. 2002;30(4):733–738.
20.
HoriDOnoMRappoldTE, et al.Hypotension after cardiac operations based on autoregulation monitoring leads to brain cellular injury. Ann Thorac Surg. 2015;100(2):487–493. doi:10.1016/j.athoracsur.2015.03.036.
21.
HoriDHogueCAdachiH, et al.Perioperative optimal blood pressure as determined by ultrasound tagged near infrared spectroscopy and its association with postoperative acute kidney injury in cardiac surgery patients. Interact CardioVasc Thorac Surg. 2016;22(4):445–451. doi:10.1093/icvts/ivv371.
22.
AriesMJHCzosnykaMBudohoskiKP, et al.Continuous determination of optimal cerebral perfusion pressure in traumatic brain injury. Crit Care Med. 2012;40(8):2456–2463. doi:10.1097/CCM.0b013e3182514eb6.
23.
Le RouxPMenonDKCiterioG, et al.Consensus summary statement of the international multidisciplinary consensus conference on multimodality monitoring in neurocritical care: a statement for healthcare professionals from the neurocritical care society and the European society of intensive care medicine. Intensive Care Med. 2014;40(9):1189–1209. doi:10.1007/s00134-014-3369-6.
24.
OgawaYIwasakiKAokiK, et al.The different effects of midazolam and propofol sedation on dynamic cerebral autoregulation. Anesth Analg. 2010;111(5):1279–1284. doi:10.1213/ANE.0b013e3181f42fc0.
25.
SteinerLAJohnstonAJChatfieldDA, et al.The effects of large-dose propofol on cerebrovascular pressure autoregulation in head-injured patients. Anesth Analg. 2003;97(2):572–576. table of contents.
RikerRRShehabiYBokeschPM, et al.Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA. 2009;301(5):489–499. doi:10.1001/jama.2009.56.
28.
PisaniMAMurphyTENessPHVAraujoKLBInouyeSK. Characteristics associated with delirium in older patients in a medical intensive care unit. Arch Intern Med. 2007;167(15):1629–1634. doi:10.1001/archinte.167.15.1629.
29.
JormAFJacombPA. The Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE): socio-demographic correlates, reliability, validity and some norms. Psychol Med. 1989;19(4):1015–1022.
30.
TeasdaleGJennettB. Assessment of coma and impaired consciousness. A practical scale. Lancet. 1974;2(7872):81–84.
31.
HealyRJZorrilla-VacaAZiaiW, et al.Glasgow coma scale score fluctuations are inversely associated with a NIRS-based index of cerebral autoregulation in acutely comatose patients. J Neurosurg Anesthesiol. 2018. doi:10.1097/ANA.0000000000000513.
32.
KnausWADraperEAMWagnerDPZimmermanJE. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13(10):818–829.
33.
BradyKJoshiBZweifelC, et al.Real-time continuous monitoring of cerebral blood flow autoregulation using near-infrared spectroscopy in patients undergoing cardiopulmonary bypass. Stroke. 2010;41(9):1951–1956. doi:10.1161/STROKEAHA.109.575159.
34.
BradyKMMytarJOLeeJK, et al.Monitoring cerebral blood flow pressure autoregulation in pediatric patients during cardiac surgery. Stroke. 2010;41(9):1957–1962. doi:10.1161/STROKEAHA.109.575167.
35.
CzosnykaMSmielewskiPKirkpatrickPMenonDKPickardJD. Monitoring of cerebral autoregulation in head-injured patients. Stroke. 1996;27(10):1829–1834.
36.
BradyKMLeeJKKiblerKKEasleyRBKoehlerRCShaffnerDH. Continuous measurement of autoregulation by spontaneous fluctuations in cerebral perfusion pressure: comparison of 3 methods. Stroke. 2008;39(9):2531–2537. doi: 10.1161/STROKEAHA.108.514877.
37.
LundbergNKjallquistABienC. Reduction of increased intracranial pressure by hyperventilation. A therapeutic aid in neurological surgery. Acta Psychiatr Scand Suppl. 1959;34(139):1–64.
38.
MomjianSCzosnykaZCzosnykaMPickardJD. Link between vasogenic waves of intracranial pressure and cerebrospinal fluid outflow resistance in normal pressure hydrocephalus. Br J Neurosurg. 2004;18(1):56–61. doi:10.1080/02688690410001660481.
39.
WeerakkodyRACzosnykaMZweifelC, et al.Slow vasogenic fluctuations of intracranial pressure and cerebral near infrared spectroscopy—an observational study. Acta Neurochir. 2010;152(10):1763–1769. doi:10.1007/s00701-010-0748-9.
40.
SteinerLAPfisterDStrebelSPRadolovichDSmielewskiPCzosnykaM. Near-infrared spectroscopy can monitor dynamic cerebral autoregulation in adults. Neurocrit Care. 2008;10(1):122–128. doi:10.1007/s12028-008-9140-5.
41.
BradyKMLeeJKKiblerKK, et al.Continuous time-domain analysis of cerebrovascular autoregulation using near-infrared spectroscopy. Stroke. 2007;38(10):2818–2825. doi:10.1161/STROKEAHA.107.485706.
42.
MoermanATVanbiervlietVMVan WesemaelABouchezSMWoutersPFDe HertSG. Assessment of cerebral autoregulation patterns with near-infrared spectroscopy during pharmacological-induced pressure changes. Anesthesiology. 2015;123(2):327–335. doi:10.1097/ALN.0000000000000715.
43.
Rivera-LaraLZorrilla-VacaAGeocadinRGHealyRJZiaiWMirskiMA. Cerebral autoregulation-oriented therapy at the bedside: a comprehensive review. Anesthesiology. 2017;126(6):1187–1199. doi:10.1097/ALN.0000000000001625.
44.
BarbosaRRJawaRWattersJM, et al.Evaluation and management of mild traumatic brain injury: an Eastern Association for the Surgery of Trauma practice management guideline. J Trauma Acute Care Surg. 2012;73(5 suppl 4):S307–S314. doi:10.1097/TA.0b013e3182701885.
45.
TsurutaROdaY. A clinical perspective of sepsis-associated delirium. J Intensive Care. 2016;4:18. doi:10.1186/s40560-016-0145-4.
46.
EbersoldtMSharsharTAnnaneD. Sepsis-associated delirium. Intensive Care Med. 2007;33(6):941–950. doi:10.1007/s00134-007-0622-2.
47.
RosengartenBHechtMAuchD, et al.Microcirculatory dysfunction in the brain precedes changes in evoked potentials in endotoxin-induced sepsis syndrome in rats. Cerebrovasc Dis. 2007;23(2-3):140–147. doi:10.1159/000097051.
48.
MattaBFStowPJ. Sepsis-induced vasoparalysis does not involve the cerebral vasculature: indirect evidence from autoregulation and carbon dioxide reactivity studies. Br J Anaesth. 1996;76(6):790–794.
49.
SchrammPKleinKUFalkenbergL, et al.Impaired cerebrovascular autoregulation in patients with severe sepsis and sepsis-associated delirium. Crit Care. 2012;16(5):R181. doi:10.1186/cc11665.
50.
YoungGBBoltonCFArchibaldYMAustinTWWellsGA. The electroencephalogram in sepsis-associated encephalopathy. J Clin Neurophysiol. 1992;9(1):145–152.
51.
ZaunerCGendoAKramerL, et al.Impaired subcortical and cortical sensory evoked potential pathways in septic patients. Crit Care Med. 2002;30(5):1136–1139.
52.
ZaunerCGendoAKramerLKranzAGrimmGMadlC. Metabolic encephalopathy in critically ill patients suffering from septic or nonseptic multiple organ failure. Crit Care Med. 2000;28(5):1310–1315.
53.
StraverJSKeunenRWStamCJ, et al.Nonlinear analysis of EEG in septic encephalopathy. Neurol Res. 1998;20(2):100–106.
54.
GoodsonCMRosenblattKRivera-LaraLNyquistPHogueCW. Cerebral blood flow autoregulation in sepsis for the intensivist: why its monitoring may be the future of individualized care. J Intensive Care Med. 2018;33(2):63–73. doi:10.1177/0885066616673973.
55.
BowieRAO’ConnorPJMahajanRP. Cerebrovascular reactivity to carbon dioxide in sepsis syndrome. Anaesthesia. 2003;58(3):261–265.
56.
BergRMGPlovsingRRRonitABaileyDMHolstein-RathlouNHMøllerK. Disassociation of static and dynamic cerebral autoregulatory performance in healthy volunteers after lipopolysaccharide infusion and in patients with sepsis. Am J Physiol Regul Integr Comp Physiol. 2012;303(11):R1127–R1135. doi:10.1152/ajpregu.00242.2012.
57.
VaskóASiróPLászlóI, et al.Assessment of cerebral tissue oxygen saturation in septic patients during acetazolamide provocation - a near infrared spectroscopy study. Acta Physiol Hung. 2014;101(1):32–39. doi:10.1556/APhysiol.101.2014.1.4.
58.
BergRMGPlovsingRRBaileyDMHolstein-RathlouNHMøllerK. Dynamic cerebral autoregulation to induced blood pressure changes in human experimental and clinical sepsis. Clin Physiol Funct Imaging. 2016;36(6):490–496. doi:10.1111/cpf.12256.
59.
BindraJPhamPChuanAJaegerMAnemanA. Is impaired cerebrovascular autoregulation associated with outcome in patients admitted to the ICU with early septic shock?. Crit Care Resusc. 2016;18(2):95–101.
60.
PierrakosCAttouRDecorteL, et al.Cerebral perfusion alterations and cognitive decline in critically ill sepsis survivors. Acta Clinica Belgica. 2017;72(1):39–44. doi:10.1080/17843286.2016.1191851.
61.
De PaepePBelpaireFMVan HoeyGBoonPABuylaertWA. The influence of endotoxemia on the pharmacokinetics and the electroencephalographic effect of propofol in the rat. J Pharm Sci. 2003;92(1):104–114. doi:10.1002/jps.10275.
62.
ZamaconaMKSuárezEAguileraLRodríguez-Sasiaín, AguirreCCalvoR. Serum protein binding of propofol in critically ill patients. Acta Anaesthesiol Scand. 1997;41(10):1267–1272.
63.
AriesMJHWesselinkREltingJWJ, et al.Enhanced visualization of optimal cerebral perfusion pressure over time to support clinical decision making. Crit Care Med. 2016;44(10):e996–e999. doi:10.1097/CCM.0000000000001816.
64.
KorachMSharsharTJarrinI, et al.Cardiac variability in critically ill adults: influence of sepsis. Crit Care Med. 2001;29(7):1380–1385.
65.
BarnabyDFerrickKKaplanDTShahSBijurPGallagherEJ. Heart rate variability in emergency department patients with sepsis. Acad Emerg Med. 2002;9(7):661–670.
66.
de CastilhoFMRibeiroALPda SilvaJLPNobreVde SousaMR. Heart rate variability as predictor of mortality in sepsis: a prospective cohort study. Plos One. 2017;12(6):e0180060. doi:10.1371/journal.pone.0180060.
67.
PandeyNRBianYShouS. Significance of blood pressure variability in patients with sepsis. World J Emerg Med. 2014;5(1):42–47. doi:10.5847/wjem.j.issn.1920-8642.2014.01.007.
68.
TangYSorensonJLanspaMGrissomCKMathewsVJBrownSM. Systolic blood pressure variability in patients with early severe sepsis or septic shock: a prospective cohort study. BMC Anesthesiol. 2017;17(1):82. doi:10.1186/s12871-017-0377-4.
69.
WijdicksEFMKramerAARohsT, et al.Comparison of the full outline of unresponsiveness score and the Glasgow coma scale in predicting mortality in critically ill patients*. Crit Care Med. 2015;43(2):439–444. doi:10.1097/CCM.0000000000000707.
70.
LavinioATimofeevINortjeJ, et al.Cerebrovascular reactivity during hypothermia and rewarming. Br J Anaesth. 2007;99(2):237–244. doi:10.1093/bja/aem118.
71.
RaichleMEPosnerJBPlumF. Cerebral blood flow during and after hyperventilation. Arch Neurol. 1970;23(5):394–403.
72.
AdatiaKGeocadinRGHealyR, et al.Effect of body temperature on cerebral autoregulation in acutely comatose neurocritically ill patients. Crit Care Med. 2018;46(8):e733–e741. doi:10.1097/CCM.0000000000003181.
73.
PfisterDStrebelSPSteinerLA. Effects of catecholamines on cerebral blood vessels in patients with traumatic brain injury. Eur J Anaesthesiol. 2008;25(S42):98–103. doi:10.1017/S0265021507003407.
74.
SookplungPSiriussawakulAMalakoutiA, et al.Vasopressor use and effect on blood pressure after severe adult traumatic brain injury. Neurocrit Care. 2011;15(1):46–54. doi:10.1007/s12028-010-9448-9.
75.
EdvinssonLHardeboJEMacKenzieETOwmanC. Effect of exogenous noradrenaline on local cerebral blood flow after osmotic opening of the blood-brain barrier in the rat. J Physiol. 1978;274:149–156.
76.
MacKenzieETMcCullochJO’KeanMPickardJDHarperAM. Cerebral circulation and norepinephrine: relevance of the blood-brain barrier. Am J Physiol. 1976;231(2):483–488. doi:10.1152/ajplegacy.1976.231.2.483.
77.
BolaRAKiyatkinEA. Inflow of oxygen and glucose in brain tissue induced by intravenous norepinephrine: relationships with central metabolic and peripheral vascular responses. J Neurophysiol. 2018;119(2):499–508. doi:10.1152/jn.00692.2017.
78.
BurkhartCSSiegemundMSteinerLA. Cerebral perfusion in sepsis. Crit Care. 2010;14(2):215.
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