Table 2.

Studies of retinal and cerebral blood flow changes in sepsis, other haemodynamic disturbances, and other inflammatory disorders

Sepsis studies	Species	Imaging modality	Pathology	Metrics measured	Findings
Taccone et al. [10]	Animal (ovine)	SDF videomicroscopy of the cerebral cortex—Microscan; MicroVision Medical	Septic model	Total perfused vessel density Functional capillary density Small perfused vessels Perfused capillaries	Septic animals showed progressive reduction in all metrics compared to control group, suggesting cerebral microcirculatory impairment
Crippa et al. [12]	Human	Transcranial Doppler of the middle cerebral artery—Compumedics DWL, Dresden, Germany	SABD	Cerebral autoregulation by blood flow velocity and mean flow index	Cerebral autoregulation impaired, cerebral blood flow increased and SABD in at least 50% of septic patients No difference in mean flow index between survivors and non-survivors
Simkiene et al. [34]	Human	Portable IDF of conjunctival microcirculation—Cytocam®, Braedius Medical, Huizen, The Netherlands Fundus imaging—Optomed Aurora (Optomed Oy, Oulu, Finland)	Sepsis or septic shock	MFI TVD PVD Retinal arteriolar and venular calibre	Lower MFI, TVD and PVD in all septic patients than healthy controls Lower MFI in non-survivors than survivors TVD and PVD and arteriolar calibre associated
De Backer and Creteur [107]	Human	OPS imaging of sublingual mucosa—Cytoscan ARII; Cytometrics	Sepsis, pre-cardiac surgery patients, ICU controls	Vascular density	Septic patients had decreased vascular density compared with all other groups
Kanoore Edul et al. [108]	Human	SDF microscopy imaging of sublingual mucosa—Microscan; MicroVision Medical	Septic shock	MFI Perfused capillary density	Hypoperfusion and microcirculatory abnormalities in septic patients compared with healthy controls, which were more severe in non-survivors
Hessler et al. [112]	Ovine	Portable IDF of sublingual and conjunctival microcirculation—Cytocam®, Braedius Medical, Huizen, The Netherlands	Sepsis and haemorrhagic shock	MFI TVD PVD PPV	Lower PVD, PPV and MFI in haemorrhagic and septic shock in mouth and conjunctiva than control group No change in TVD
Pranskunas et al. [113]	Pig	SDF videomicroscopy of sublingual, conjunctival, jejunal and rectal microcirculation—Microscan; Microvision Medical, Amsterdam, The Netherlands	Sepsis	MFI PPV PVD TVD	Lower MFI and PPV observed in all locations in the sepsis group than control group, with the lowest MFI in sublingual region No change in TVD Sublingual associates with conjunctival MFI
Taccone et al. [55]	Animal (ovine)	SDF videomicroscopy of cerebral cortex—MicroScan (MicroVisionMedical, Amsterdam, The Netherlands)	Sepsis	Mean flow index Proportion of small perfused vessels Functional capillary density Lactate/pyruvate ratio (tissue hypoxia)	Cerebral functional capillary density and proportion of small perfused vessels decreased significantly from baseline to shock onset, compared with control group Brain oxygen levels reduced while lactate/pyruvate ratio increased in septic animals Suggests impaired cerebral microcirculation in septic animals
Alnawaiseh et al. [123]	Animal (ovine)	OCTA—RTVue XR Avanti with Angiovue, Optovue Inc	Haemorrhagic shock	Flow density	Reduced flow density of the superficial retina after shock induction, which recovered after resuscitation
Park [124]	Animal (rat)	OCTA (manufacturer not specified)	Haemorrhagic shock and sepsis	BFI against MAP and lactate	As MAP decreased in the haemorrhagic shock model, BFI of the choroid but not retinal artery decreased and was associated with increased lactate concentration in sepsis
Erikson et al. [125]	Human	FFA—HRA 2–00153; Heidelberg Engineering, Heidelberg	Sepsis	RAFT Inflammatory markers	Retinal abnormalities observed in half of the patients with sepsis, being more common in those showing PRAFT Patients with PRAFT had lower levels of CRP and IL-6 compared with patients who had SRAFT, suggesting impaired inflammatory response
Simkiene et al. [126]	Human	Fundus imaging—Optomed Aurora (Optomed Oy, Finland)	Sepsis	Retinal arteriolar and venular calibre Retinal vascular length density	Retinal arteriolar calibre higher in septic than healthy control patients, but venular calibre did not differ Septic patients had lower retinal vascular length density

Other haemodynamic disturbances studies	Species	Imaging modality	Pathology	Metrics measured	Findings
Chua et al. [15]	Human	OCTA—AngioVue; Optovue, Inc	Systemic hypertension	Retinal vessel density	Vessel density was reduced in patients with poorly controlled blood pressure compared with those with well controlled blood pressure
Terheyden [114]	Human	OCTA—PLEX Elite 9000, Carl Zeiss Meditec Inc	Systemic hypertensive crisis	Retinal vessel density Skeletal density Vessel density index	Reduced skeletal density in the S-RL and D-RL and reduced vessel density in the D-RL in hypertensive patients compared with healthy controls
Alnawaiseh [115]	Human	OCTA—RTVue XR Avanti with AngioVue, Optovue, Inc	AF	FAZ area Flow density	No difference found in FAZ area between groups Flow density in the superficial retina and ONH were lower in the AF group
Arnould and Guenancia [116]	Human/	OCTA—Cirrus HD-OCT, model 5000, Carl Zeiss Meditec	ACS	Retinal vascular density of SCP	Vascular density of SCP negatively associated with cardiovascular risk factors and left ventricular ejection fraction at admission
Wang et al. [117]	Human	OCTA—AngioVue, Optovue, Inc	Coronary heart disease	Retinal vessel density Flow area	Some early stage coronary heart disease patients showed reduced vessel density, and reduced choroidal vessel density and blood flow
Lin [120]	Human	OCTA (manufacturer not specified)	High-risk pregnancies	Retinal vessel perfusion density/vessel length density of SVP, ICP and DCP	Reduced SVP perfusion density and vessel length density in high-risk pregnancy individuals compared with low-risk pregnancy individuals

Other inflammatory disorders studies	Species	Imaging modality	Pathology	Metrics measured	Findings
Kılınç Hekimsoy et al. [118]	Human	OCTA—XR Avanti AngioVue	Systemic sclerosis	FAZ area and perimeter Vessel density	Patients with systemic sclerosis showed significantly decreased vessel density compared with controls, but there was no difference in FAZ area or perimeter
Nakayama [16]	Human	OCT/OCTA—Topcon Triton, Topcon	IBD	FAZ area	Patients with active disease showed decreased FAZ area compared with patients in remission

Summary of studies investigating retinal and cerebral blood flow and microvascular changes in sepsis, other haemodynamic disturbances and other inflammatory disorders.

SDF, sidestream dark field; SABD, sepsis-associated brain dysfunction; ICU, intensive care unit; OPS, orthogonal polarisation spectral; ICU, intensive care unit; OCTA, optical coherence tomography angiography; S-RL, superficial retinal layer; D-RL, deep retinal layer; AF, atrial fibrillation; FAZ, foveal avascular zone; IDF, incident dark field; MFI, microvascular flow index; TVD, total vessel density; PVD, perfused vessel density; PPV, proportion of perfused vessels; ONH, optic nerve head; ACS, acute coronary syndrome; SCP, superficial capillary plexus; OCT, optical coherence tomography; IBD, inflammatory bowel disease; SVP, superficial vascular plexus; ICP, intermediate capillary plexus; DCP, deep capillary plexus; BFI, blood flow index; MAP, mean arterial pressure; FFA, fundus fluorescein angiography; RAFT, retinal arterial filling time; PRAFT, prolonged RAFT; SRAFT, short RAFT