Evaluating the relationship between ocular blood flow and systemic organ blood flow in hemorrhagic shock using a rabbit model

doi:10.21203/rs.3.rs-3347768/v1

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Evaluating the relationship between ocular blood flow and systemic organ blood flow in hemorrhagic shock using a rabbit model

https://doi.org/10.21203/rs.3.rs-3347768/v1

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published 14 Feb, 2024

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This study aimed to investigate the feasibility of utilizing noninvasive ocular blood flow measurements as a potential indicator of systemic circulation in rabbits experiencing hemorrhagic shock. Using Laser Speckle Flowgraphy, ocular blood flow indices, relative flow volume (RFV), and mean blur rate in the choroidal area (MBR-CH) were assessed in New Zealand White rabbits (n = 10) subjected to controlled blood removal and return. Hemodynamic parameters and biochemical markers were monitored alongside ocular circulation during blood removal and return phases. Additionally, correlations between ocular parameters and systemic indices were examined. The results indicated that RFV and MBR-CH exhibited significant correlations with renal and intestinal blood flows, with stronger correlations observed during blood removal. Additionally, ocular blood flow changes closely mirrored systemic dynamics, suggesting its potential as a real-time indicator of shock progression and recovery. These findings indicate that ocular blood flow measurements may serve as real-time indicators of systemic circulation status during hemorrhagic shock, offering potential insights into shock management and guiding tailored interventions. Thus, noninvasive ocular blood flow evaluation holds promise as an innovative tool for assessing systemic circulation dynamics during hemorrhagic shock.

Biological sciences/Physiology/Circulation/Blood flow

Biological sciences/Neuroscience/Visual system/Retina

Hemorrhagic shock is organ damage caused by inadequate blood flow in peripheral tissues resulting from decreased circulating plasma volume due to hemorrhage. Owing to the difficulty in direct observation of organ blood flow, although a comprehensive evaluation is conducted by combining vital signs, physical findings, and various examinations, no definitive conclusion has been reached regarding the appropriate index for circulatory resuscitation. In recent years, the evaluation of microcirculation in the sublingual^1–5 and body surface tissue^6–10 has attracted attention for shock management and is considered a better predictor of prognosis than macro-circulation indicators such as blood pressure.

Retinal vessels are the only vessels that allow direct observation of an organ’s blood supply and have been used for systemic evaluation such as arteriosclerosis for a long time^11–13. To date, studies have explored the relationship between the ocular blood flow index of fluorescent fundus angiography using contrast media and the APACHE II score and cardiac index in patients with sepsis who were hospitalized in the ICU¹⁴. Additionally, animal experiments investigating changes in structural ocular microcirculation during shock have been reported¹⁵. However, these previous reports had problems of invasiveness due to the contrast media and difficulty in quantification.

Laser Speckle Flowgraphy (LSFG, Softcare Ltd., Fukuoka, Japan) quantifies ocular blood flow non-invasively and in real-time^16,17, and can solve the problems encountered to date. The mechanism is based on changes in the speckle pattern of the laser light reflected from the fundus of the eye¹⁸. These changes in speckle pattern depend on the flow velocity of erythrocytes in the vessels and can be used to determine the mean blur rate (MBR), which is an indicator of ocular blood flow^19,20. MBR also correlates linearly with capillary blood flow volume^19,21. The relative flow volume (RFV) derived from the LSFG reflects blood flow velocity and volume in the retinal vessels^22,23.

We have reported that ocular blood flow measured non-invasively using LSFG reflects systemic circulation indices like blood pressure and cardiac output during the process of hemorrhagic shock progression and recovery using New Zealand White rabbits²⁴.

In this study, as a follow-up report, we comprehensively examined the relationship between ocular blood flow and organ blood flow in the kidneys and intestine using hemorrhagic shock rabbits in the progressive phase of shock due to blood loss and the recovery phase due to blood return. We aimed to investigate the extent to which ocular blood flow actually reflects organ blood flow, which is the essence of shock.

The amount of blood loss associated with the laparotomy was negligible in all cases. Following the commencement of the blood removal procedure, mean arterial blood pressure (MAP), renal blood flow (RBF), intestinal blood flow (IBF), central venous oxygen saturation (ScvO2), and LSFG parameters (%RFV and % MBR in the choroidal area [MBR-CH]) began to immediately decrease and showed a significant decrease at the end of blood removal. All parameters showed improvement to approximately the reference value by the blood return operation. Conversely, lactic acid (Lac) and creatinine began to increase with blood removal, with Lac peaking at the end of blood return and declining, whereas creatinine continued to increase thereafter.

The heart rate (HR) showed an increasing trend with blood removal and a decreasing trend with blood return, but none of the variations were significant. The time courses of the changes in the systemic circulation index and LSFG parameters (%RFV and %MBR-CH) are shown in Fig. 1. Figure 2 shows the actual LSFG measurement screens at baseline, at the end of blood removal, and at the end of blood return. The warm color represents high blood flow, and the cold color represents low blood flow. Figure 3 summarizes the time courses of CVP, RFV, RBF, MBR-CH, and IBF. The RFV, RBF, MBR-CH, and IBF showed similar changes. The change rate of RFV vs. RBF / MBR-CH vs. IBF at the end of blood loss, the beginning of blood return, and the end of blood return, respectively, was 39% vs. 44% / 55% vs. 55%, 42% vs. 50% / 58% vs. 63%, and 100% vs. 94% / 107% vs. 108%. Among them, the change rates in the MBR-CH and IBF at the end of blood removal were significantly equivalent (p = 0.049). The correlation coefficients between %RFV, %MBR-CH, %systemic hemodynamics, and laboratory parameters during the blood removal and return periods are presented in Tables 1 and 2. The %RFV and %MBR-CH showed significant positive correlations with %MAP, %RBF, %IBF, and %ScvO2. Moreover, %CVP showed a positive correlation with %RFV and %MBR-CH only during blood return. % hemoglobin (Hb) exhibited positive correlations with %RFV and %MBR-CH during blood removal and with %MBR-CH during blood return. %Lac showed a significant negative correlation with %MBR-CH during blood removal; however, no significant correlation showed during the blood return period. Similarly, % creatinine showed a significant negative correlation with %RFV and %MBR-CH only during blood removal.

During the stages of progression and recovery from hemorrhagic shock, changes in blood pressure, heart rate, ScvO2, Lac, and Hb were consistent with our previous report²¹. Ocular blood flow indices (RFV, MBR-CH) reflected blood pressure and other parameters and decreased and recovered with the progression and recovery process of shock. In this study, we compared the relationship between ocular, renal, and intestinal blood flow during the progression and recovery phases of shock.

The RFV and MBR-CH during the blood removal period exhibited a substantial positive correlation not only with blood pressure, Lac, and ScvO2, indicators of shock, but also with renal and intestinal blood flow. Moreover, the change rate in blood flow at the end of blood removal was RFV: 39% vs. RBF, 44%, MBR-CH: 55% vs. IBF, 55%, showing significant equivalence between MBR-CH and IBF. As shock prog, ocular blood flow correlates with Lac and creatinine levels, which are commonly used biochemical indicators of shock and renal dysfunction. Furthermore, the blood vessels of the eye, referred to as “strain vessels ²⁵” are believed to have the same structure and role as the kidneys and coronary arteries, which may allow us to predict the degree of renal and intestinal hypoperfusion by observing ocular blood flow during the progression of hemorrhagic shock. RFV and MBR-CH showed a linear decrease with the progression of shock due to the blood removal maneuver, similar to the RBV and IBF. Although the retinal vessels and kidneys are generally considered autoregulatory vessels and organs^26–28, their capacity is limited, and they are less active when blood pressure decreases than when it is elevating^29,30. Therefore, rapid hemorrhagic shock is thought to cause autoregulation failure and a decrease in ocular, renal, and intestinal blood flow. Additionally, retinal and renal blood flow were lower than choroidal and intestinal blood flow during de-bleeding, similar to previous reports^31,32. However, the retinal vessels and kidneys are considered ischemia-resistant organs compared to the intestinal tract^33–35. The reason for these two paradoxical facts is that the kidneys maintain glomerular blood flow through autoregulation in the more peripheral imported and exported arterioles³⁵ even when blood flow in the main trunk of the renal artery is reduced, as measured in this study. This suggests that, in the retina, future detailed blood flow observations at the lobule level, further peripherally, as in the kidney, may help elucidate the mechanisms of retinal autoregulation.

During the blood return period, RFV and MBR-CH showed a significant positive correlation with renal and intestinal blood flows; however, the degree of correlation was weaker with renal blood flow than during the blood removal period. This may be attributed to the difference in the degree of autoregulation by each organ and the intraocular region in response to increased blood flow. However, even during blood return, RFV showed a significant correlation with RBF (r = 0.5) and IBF (r = 0.84), suggesting that ocular blood flow measurement may be applied to evaluate the status of systemic organ blood flow, even during the shock recovery process. Additionally, ocular blood flow was negatively correlated with Lac and creatinine levels during shock progression but not with blood return. This was believed to be due to a time lag in the recovery of Lac and creatinie³⁶, which caused a gap in other circulatory and ocular blood flow indices. Therefore, using only biochemical data as indicators of infusion therapy may lead to excessive infusion³⁷. However, ocular blood flow measurements can reflect organ blood flow in real-time, and we believe that adding information on ocular blood flow to other circulatory indicators would allow for more appropriate infusion therapy without excess or deficiency.

Clinical studies have reported an association between ocular circulation and severity scores¹⁴ and mortality³⁸, which may support the application of the measurement of ocular blood flow, a peripheral organ, to the evaluation of systemic circulation in humans.

In addition, the treatment of hemorrhagic shock is centered on fluid and blood transfusion therapy. Although various evaluation methods have been proposed to date to determine the appropriate dosage, none of them directly observe organ blood flow, which is the true nature of hemorrhagic shock. In this study, ocular blood flow was shown to reflect blood flow to major organs throughout the body, and its measurement may be quantified non-invasively at the bedside in real-time. These findings suggest that the evaluation of ocular blood flow warrants future clinical research as a new method for evaluating circulation that may solve problems such as excessive transfusion.

This study had certain limitations. The blood pressure was low at 46.7 mmHg and Lac (3.8 mmol/L at the beginning of the experiment, and invasion by laparotomy could not be ruled out. However, 30 mL of blood removal operation, which is about 20% of the total blood volume, caused a 36% decrease in blood pressure and a significant increase in lactic acid level (from 3.8 mmol/L to 5.7 mmol/L, p = 0.043) and a significant decrease in ScvO2 (from 50.9–35.5%, p = 0.018), indicating that blood removal operation advanced shock state in this experiment. Generally, Hb concentration does not change immediately after the start of blood removal. However, in this case, Hb concentration was considered to have decreased immediately after the start of blood removal because of continuous saline infusion during the blood removal operation.

In conclusion, noninvasive ocular blood flow measurement using the LSFG reflects renal and intestinal blood flow in rabbits with hemorrhagic shock.

Animals and measurements

LSFG measurements were determined from fundus images as previously described^24,39.We used 10 male New Zealand White rabbits (16–18 weeks old, weight 2.90–3.40 kg, median 3.18 kg) housed in the same environment (Specific pathogen free). The experiments were performed under general anesthesia. Anesthesia was induced using ketamine (35 mg/kg, i.m., Daiichi Sankyo Propharma, Tokyo, Japan) and xylazine (5 mg/kg, i.m., Bayer Japan, Osaka, Japan) and maintained using isoflurane (end-tidal concentration of 1.5%, Pfizer Japan, Tokyo, Japan). After tracheostomy, the rabbits were mechanically ventilated (FiO2 = 1.0, tidal volume = 6 mL/kg, 40 strokes/min; SN-480-5®, Shinano, Tokyo, Japan). Saline (15 mL/h) and rocuronium (0.6 mg/kg/h; Fuji Pharma, Toyama, Japan) were continuously administered via a left ear vein. The rabbits’ body temperature was maintained at 37 ℃ with a heating pad.

All animal experiments were approved by Toho University Laboratory Animal Research (#19-53-358, #20-54-358) and performed in accordance with the Guiding Principles for the Care and Use of Laboratory Animals approved by The Japanese Pharmacological Society. This study also complies with the ARRIVE guidelines.

A heparinized catheter was inserted into the right brachial artery for the continuous measurement of blood pressure using transducers. For blood removal and central venous pressure measurement, a catheter was inserted into the femoral vein, and the tip of the catheter was placed in the inferior vena cava. The mean arterial blood pressure (MAP, mmHg), heart rate (HR, beats per minute [bpm]), and central venous pressure (CVP, mmHg) were recorded using a PowerLab system® (AD Instruments, Sydney, Australia). To measure IBF (mL/min) and RBF (mL/min), a blood flow meter was attached to the superior mesenteric artery exposed by laparotomy, and the renal artery was exposed from the retroperitoneum. The IBF and RBF were measured using an ultrasonic blood flowmeter (TS420®, Transonic Systems, Ithaca, NY, USA). The abdomen was closed with sutures to reduce insensible water loss. A plastic cover protected the blood flow meter from shifting. Figure 4 illustrates the apparatus used to measure systemic hemodynamics and ocular microcirculation in rabbits.

Experimental protocol

After confirming that the rabbits’ systemic hemodynamics and ocular circulation state were stable for approximately 30 min, the experiment was initiated. To induce hemorrhagic shock, blood was continuously removed from the central venous catheter (4-Fr. ga.) at the rate of 1 mL/min for 30 min. At the end of the 30-min blood removal period, an observation was conducted for 20 min, and heparinized blood (2 mL/min) was returned via the left auricular vein for 15 min. After returning 30 mL of blood, another observation was conducted for 15 min. After completing the experiment, the rabbits were sacrificed using a rapid intravenous injection of saturated potassium chloride. Systemic hemodynamic parameters were measured simultaneously every 2 min during the observation period and every 1 min during the blood removal and return periods. In addition, Hb (g/dL), lactic acid (Lac, mmol/l), central venous oxygen saturation (ScvO2, %), and creatinine (mg/dL) were measured using a blood analyzer (i-STAT 1 Analyzer®, Abbott, Chicago, IL). Blood samples (0.5 mL/time) for Hb, Lac, ScvO2, and creatinine were collected at six time points: at the beginning of blood removal, 15 min after the start of blood removal, the end of blood removal, the beginning of blood return, the end of blood return, and the end of the experiment.

Ocular blood flow evaluation

The MBR images were obtained using an LSFG-MRC® device (Softcare Ltd., Iizuka, Japan). Ocular blood flow was divided into retinal circulation from the central retinal artery and choroidal circulation from the posterior ciliary artery. The RFV in the retinal vessel and the mean MBR-CH were calculated using LSFG Analyzer software (ver. 3.8.04. Softcare, Co., Ltd). The LSFG can place a band in any region to obtain the RFV and MBR within that region. The principles and applications of this method have been previously described^16,19,40. RFV and MBR-CH were measured simultaneously as the systemic circulation index every 2 min during the observation period and every 1 min during the blood removal and blood return periods. To measure RFV, the band was placed in a straight section just outside the optic head and to measure MBR-CH, the band was placed in an area as far away from the retinal vessels as possible within the angle of view. In each experiment, rectangular bands were stored in the software program, and the same rectangular bands were used for all analyses. LSFG-MRC showed good reproducibility ⁴¹. Mydriasis was induced by eye drops tropicamide (Santen Pharmaceutical Co., Osaka, Japan). To prevent the corneal surface from drying, saline-containing hydroxyethyl cellulose gel (Senju Pharmaceutical Co. Ltd., Osaka, Japan) was dropped appropriately. Only the left eye was used in all experiments.

Statistical analyses

RFV and MBR-CH were evaluated based on the rate of change from the baseline value before blood removal (% RFV, % MBR-CH) because they are not established to compare absolute values between individuals due to differences in blood vessel diameter, blood vessel wall thickness, and pigment, among others⁴². The time courses of the changes in systematic and ocular hemodynamic parameters during the experiment were analyzed using repeated-measures ANOVA and Dunnett’s test as post hoc tests. To examine the equivalence between renal blood flow and RFV and intestinal blood flow and MBR-CH at the end of blood removal, we used two one-sided tests with a 10% margin of equivalence. Correlation coefficients between the change rate (%) of systemic hemodynamics (%MAP, %HR, %RBF, %IBF, %CVP), % laboratory parameters (%ScvO2, %Lac, %Hb, %creatinine), and LSFG parameters (%RFV and % MBR-CH) were analyzed using Pearson’s coefficient during blood removal and blood return. Correlations during the blood removal and return periods were analyzed using the rate of change, with the values at the beginning of the experiment and the beginning of the blood return operation as reference values. Continuous variables are presented as mean ± standard error. Statistical significance was set at P < 0.05. significant. The JMP-10.0 program® (SAS, Cary, NC, USA) was used for the statistical analyses.

Acknowledgments

This work was supported by a JSPS KAKENHI Grant-in-Aid for Scientific Research (C) (to T.S.; no. 16K11275), the Fund for the Memory of the 60th Anniversary of Toho University (to T.S.), and the Toho University Joint Research Fund (H30-4: to A.T., Y.H., T.S., Y.N., and M.A.).

Author contributions

W.K and S.T substantially contributed to study conceptualization.

W.K, S.T, and K.T significantly contributed to data analysis and interpretation.

W.K, S.T, H.H, and T.Y substantially contributed to preparing the manuscript draft.

T.A, N.Y, and A.M contributed to conducting the experiments.

H.Y supervised the study.

All authors critically reviewed and revised the manuscript draft and approved the final version for submission.

Competing Interests

The authors declare no competing interests.

Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Table 1 and 2 are available in the Supplementary Files section.

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You are reading this latest preprint version

Evaluating the relationship between ocular blood flow and systemic organ blood flow in hemorrhagic shock using a rabbit model

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Abstract

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Discussion

Methods

Animals and measurements

Experimental protocol

Ocular blood flow evaluation

Statistical analyses

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References

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