Courtie et al. Ann. Intensive Care (2020) 10:152 https://doi.org/10.1186/s13613-020-00768-3 REVIEW Open Access Retinal blood fow in critical illness and systemic disease: a review E. Courtie1,2,3, T. Veenith4,5, A. Logan6,7, A. K. Denniston1,2,8,9 and R. J. Blanch1,2,3,10* Abstract Background: Assessment and maintenance of end-organ perfusion are key to resuscitation in critical illness, although there are limited direct methods or proxy measures to assess cerebral perfusion. Novel non-invasive meth- ods of monitoring microcirculation in critically ill patients ofer the potential for real-time updates to improve patient outcomes. Main body: Parallel mechanisms autoregulate retinal and cerebral microcirculation to maintain blood fow to meet metabolic demands across a range of perfusion pressures. Cerebral blood fow (CBF) is reduced and autoregulation impaired in sepsis, but current methods to image CBF do not reproducibly assess the microcirculation. Peripheral microcirculatory blood fow may be imaged in sublingual and conjunctival mucosa and is impaired in sepsis. Retinal microcirculation can be directly imaged by optical coherence tomography angiography (OCTA) during perfusion- defcit states such as sepsis, and other systemic haemodynamic disturbances such as acute coronary syndrome, and systemic infammatory conditions such as infammatory bowel disease. Conclusion: Monitoring microcirculatory fow ofers the potential to enhance monitoring in the care of critically ill patients, and imaging retinal blood fow during critical illness ofers a potential biomarker for cerebral microcirculatory perfusion. Keywords: Critical illness, Retinal blood fow, Optical coherence tomography angiography Introduction including hypovolaemia and myocardial depression [4]. Critical illness with multiple organ dysfunction is charac- Early diagnosis of sepsis and prompt treatment to reduce terised by complex physiological and metabolic responses multiple organ failure reduces mortality [5], but survivors requiring support and optimisation of organ systems in often have physical and neurocognitive disability referred the intensive treatment unit (ITU) [1]. Common aetiolo- to as post-intensive care syndrome (PICS) [6]. Attempts gies include sepsis (60%), trauma, and perioperative care. to improve perfusion and end-organ microcirculation Sepsis is a systemic infammatory response to infection, using inotropes and fuids have produced variable results mediated by the pathogen and host factors, ultimately [7]. causing multiple organ failure [2], and is a growing global Microcirculation facilitates tissue oxygenation and concern with an estimated 48.9 million incident cases the exchange of substances between tissues and blood. recorded worldwide in 2017, 11 million of which were In septic shock, physiological haemodynamic param- fatal [3]. Septic shock describes a profound haemody- eters, such as mean arterial pressure (MAP), may not namic alteration associated with organ dysfunction, be indicative of microcirculatory perfusion [8]. Patients with sepsis often have microcirculatory alterations, such *Correspondence: [email protected] as reduced functional capillary density, which reduces 1 Neuroscience and Ophthalmology, Institute of Infammation oxygen delivery to vital organs and plays a key role in the and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK development of organ dysfunction [4, 9, 10]. While the Full list of author information is available at the end of the article extent of these microcirculatory alterations in the brain is © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. Courtie et al. Ann. Intensive Care (2020) 10:152 Page 2 of 18 less well characterised than in other organs, post-mortem by the penetrating arteriolar network from the brain sur- examination of septic patients demonstrated multiple face. Every neurone in the brain is within 20 µm of a cap- small ischaemic lesions, suggesting microvascular insuf- illary [24], receiving oxygen and nutrients yet remaining fciency [11]. Sepsis-associated brain dysfunction (SABD) protected from fuctuations in plasma composition, cir- is a common sepsis-related organ dysfunction [12], and culating proteins and immune cells by the blood–brain probably involves reduced cerebral blood fow (CBF) barrier (BBB). Endothelial cells (EC) and their tight cell causing cerebral ischaemia [12]. Compromised cerebral junctions are the fundamental constituents of the BBB blood supply often causes both immediate and delayed and regulate paracellular transport [24]. irreversible damage with associated neurocognitive Te neurovascular unit is in part responsible for the decline and poor outcome [13]. It is, therefore, essential coupling of blood fow with brain activity and is made up to be able to monitor CBF during critical illness. of EC, pericytes, astrocyte end-feet and vasoregulatory Te retina and brain share similar microvascular anat- nerve terminals [25]. Pericytes project stellate, fnger-like omy, and while direct visualisation of CBF is difcult, processes that ensheath the capillary wall [26] and con- retinal imaging is comparatively convenient [14]. Reti- tract or dilate in response to vasoactive mediators, such nal structural and blood fow changes associated with as nitric oxide (NO). NO is produced by neuronal nitric systemic and central nervous system illness are increas- oxide synthase (nNOS) or neural pathways [27] to alter ingly reported [15–17] with the use of ocular imaging to capillary diameter in autoregulation, shown in vivo in rat assess systemic disease termed “oculomics” [18]. Retinal retina and ex vivo in cerebellar slice cultures [28]. Tis changes may, therefore, associate with CBF in critically ill neurovascular coupling is impaired in the early stages of patients, ofering a novel biomarker to monitor in real- sepsis [29]. EC regulate CBF through the production of time and reduce cerebral hypoperfusion. vasodilatory factors, including NO and vasoconstrictors Tis review discusses the relationship between cerebral such as endothelins, which bind to ET A receptors in the and retinal blood fow, and the relevance of that relation- cerebrovascular smooth muscle, although endothelins ship to systemic pathology and monitoring microcir- also have vasodilatory efects when binding to ETB recep- culatory perfusion in critical illness, focussing more on tors on EC themselves [21]. sepsis. Retinal microcirculation Cerebral and retinal blood fow autoregulation Te retinal vascular beds, derived from the central Cerebral blood fow autoregulation retinal artery, include the radial peripapillary capil- Te human brain consumes 20% of the body’s energy at lary plexus (RPCP) in the nerve fbre layer, the super- rest, dependent on CBF to ensure the delivery of oxygen, fcial vascular plexus (SVP) spanning the ganglion cell nutrients and removal of metabolic waste products [19]. layer (GCL) and inner plexiform layer, the intermediate Global or focal hypoperfusion rapidly results in brain capillary plexus (ICP) sitting between the inner plexi- damage. form layer and inner nuclear layer, and the deep capil- Under normal physiological conditions, blood fow lary plexus (DCP) spanning the inner nuclear layer and to the brain remains constant, in part due to the contri- outer plexiform layer [30]. Tese supply the inner ret- bution of large arteries to vascular resistance, but also ina, including the retinal ganglion cells, while the outer because of autoregulation [20]. CBF autoregulation is retina derives oxygenation and nutrition from the cho- the ability of the brain to maintain relatively constant riocapillaris of the choroid (Fig. 1) [31]. Campbell et al. blood fow despite changes in perfusion pressure while propose OCTA nomenclature as the RPCP and SVP be matching fow to local metabolic demand [20]. Cerebral grouped into the superfcial vascular complex (SVC), perfusion pressure (CPP) is determined by MAP and with the ICP and DCP grouped into the deep vascular intracranial pressure (ICP), where autoregulation adjusts complex (DVC) to highlight anatomic location of the vascular resistance to maintain CBF. CBF autoregulation ICP at the inner plexiform/inner neuronal layer inter- is complex, with multiple proposed overlapping regula- face [30]. tory mechanisms, including myogenic, neurogenic, met- Te foveola centralis is a depressed, avascular area of abolic and endothelial regulation [21]. Most data suggest the macula, also referred to as the foveal avascular zone reduced CBF and impaired CBF autoregulation in sepsis (FAZ). It is this area which allows the most distinct vision [22]. because of the high cone density and absence of blood vessels [31]. Te circulation is particularly