Continuous renal replacement therapy with cytokine-adsorbing hemofilter to control resuscitative endovascular balloon occlusion of the aorta-related ischemia-reperfusion injury in a swine hemorrhagic shock model

doi:10.21203/rs.3.rs-4437694/v1

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Continuous renal replacement therapy with cytokine-adsorbing hemofilter to control resuscitative endovascular balloon occlusion of the aorta-related ischemia-reperfusion injury in a swine hemorrhagic shock model

https://doi.org/10.21203/rs.3.rs-4437694/v1

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Purpose: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is beneficial for uncontrollable torso bleeding; however, prolonged REBOA causes ischemia-reperfusion injury. The purpose of this study is to examine the hypothesis that continuous renal replacement therapy (CRRT) with a cytokine-adsorbing hemofilter would improve mortality due to hemorrhagic shock with REBOA-reperfusion injury by controlling metabolic acidosis, hyperkalemia, and hypercytokinemia.

Methods: Hemorrhagic shock with 40% blood loss was induced by phlebotomy in eight female swine. CRRT was performed on four swine after 90 min of REBOA, and the remaining four swine (control group) underwent the same procedures except for CRRT. We evaluated the survival time and trends of pH, HCO^3-, potassium, lactate, circulatory inflammatory cytokines, and histopathology of the intestine for 180 min after REBOA deflation.

Results: Two swine in the CRRT group and one in the control group survived; no significant difference were observed in survival rates between the groups (p=0.45). Furthermore, no significant differences in the transition of biomarkers and histopathological grades were observed between the groups. The CRRT group showed a tendency of increasing pH and HCO^3-, decreasing lactate, lower elevation of potassium and cytokine levels (interleukin 6, CRRT: 1008.5 [770.4–1246.6], control; 1636.7 [1636.7–1636.7] pg/mL at t=270), and lower intestine histopathological grade (jejunum, CRRT; 1.5 [1.3–1.8], control; 4.0 [4.0–4.0], ileum, CRRT; 1.5 [1.3–1.8], control; 4.0 [4.0–4.0] at t=270) than the control group.

Conclusions: CRRT may mitigate acute-REBOA-related ischemia-reperfusion injury by controlling biomarkers. Further research is required to evaluate the impact on long-term mortality.

resuscitative endovascular balloon occlusion of the aorta

hemorrhagic shock

ischemia-reperfusion injury

continuous renal replacement therapy

cytokine-absorbing hemofilter

Hemorrhagic shock is a major cause of death in the acute phase of trauma injury, and controlling bleeding is essential for decreasing mortality [1, 2]. Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a beneficial bleeding-control device that is less invasive than aortic cross-clamping for use under emergency room thoracotomy for the resuscitation of torso hemorrhage [3–5]. However, prolonged REBOA can cause a problematic complication, which is ischemia-reperfusion injury (IRI); the resulting metabolic acidosis, hyperkalemia, and organ failure can lead to fatal conditions [6, 7].

Establishing treatment methods to control REBOA-related ischemia-reperfusion injury (R-IRI) not only improves poor prognosis caused by R-IRI but can also allow the use of REBOA to rescue more patients with uncontrollable bleeding. While various pharmacological therapies [8, 9] and targeted temperature management [10] for R-IRI have been reported, there is no established treatment strategy yet.

Some studies reported that continuous renal replacement therapy (CRRT) is effective in controlling metabolic acidosis and hyperkalemia associated with acute leg ischemia [11] and crush syndrome [12], which have similar pathophysiology to that of R-IRI; however, there are no reports on the effectiveness of CRRT for R-IRI. Notably, hypercytokinemia is considered to be a cause of cell death in IRI [13, 14], similar to that in sepsis [15]. Because CRRT with a cytokine-adsorbing hemofilter (CAH) controls hypercytokinemia [15], it may be effective in controlling hypercytokinemia in R-IRI.

We hypothesized that hemodialysis, particularly CRRT with CAH, will improve mortality due to hemorrhagic shock with R-IRI by controlling metabolic acidosis, hyperkalemia, and hypercytokinemia. In this study, we performed CRRT in a swine hemorrhagic shock model after inflating REBOA for 90 min, the longest REBOA inflation in previous reports in a swine model [16], and examined trends in blood gas analysis (BGA) data. We also evaluated the intestinal histopathological damage caused by R-IRI and differences in circulatory inflammatory cytokine levels.

Animals

To minimize variability due to age and sex differences, we used eight (four pigs each for the CRRT and control group) 3–4-month-old female non-pregnant domestic pigs weighing 35–45 kg (Landrace: purchased from Sanesu Breeding Co., Ltd. Chiba, Japan). This study was conducted in an accredited animal research laboratory (Centre for Development of Advanced Medical Technology, Jichi Medical University, Tochigi, Japan). All methods were performed in accordance with the relevant guidelines and regulations and were approved by the Institutional Animal Experiment Committee (authorization number: 21006-01). The ARRIVE guidelines (https://arriveguidelines.org) was used to ensure proper reporting of methods, results, and discussion.

Animal preparation

Anesthesia was induced and maintained as in a previous report [17]. After general anesthesia induction, an arterial line catheter was placed into the right carotid artery for proximal pressure monitoring and blood sampling. A triple-lumen catheter (Power-Trialysis®; Becton, Dickinson and Company, New Jersey, United States) was inserted into the right external jugular vein to connect the CRRT circuit. A 10-Fr sheath was placed into the right femoral artery to insert a 7-Fr REBOA catheter (Rescue Balloon®; Tokai Medical Products, Aichi, Japan). The side arm of the 10-Fr sheath was used for distal pressure monitoring. Acetated Ringer’s solution was infused, targeting a stroke volume variation between 10 and 15%, and a bolus injection was administered when the blood pressure dropped.

Induction of hemorrhagic shock and REBOA placement

As the hemorrhagic shock model, phlebotomy was performed using a 10-Fr arterial sheath in the right femoral artery, and 30 mL/kg of blood (approximately 40% blood loss) was withdrawn exponentially for 20 min to induce class IV shock. The first half of this blood volume was removed at 2.15 mL/kg/min for 7 min and the remainder at 1.15 mL/kg/min for 13 min [18].

The REBOA catheter was placed in the thoracic aorta to maintain the balloon position in zone 1 and fixed. The balloon was then gradually inflated with close distal pressure monitoring. Total REBOA (100% occlusion) inflation was defined as the complete cessation of distal pulse pressure and was performed on both the CRRT and control groups for 90 min after hemorrhagic shock induction.

T = 0 was defined as after phlebotomy and immediately before REBOA inflation, and t = 90 was defined as immediately before REBOA deflation.

CRRT setting

CRRT was performed using a JUN-55X-II (Toray Medical Co., Ltd., Japan) as a bedside monitoring console. CH-1.8W (Toray Medical Co., Ltd., Japan), made of a polymethyl methacrylate membrane, was used as the CRRT hemofilter to adsorb cytokines. Circuits and columns were primed with heparinized saline before treatment. CRRT treatment was performed immediately before REBOA deflation until 3 h later under the following conditions: Qb, 120 mL/min; Qd, 2000 mL/h; Qf, 2500 mL/h; and Qs, 500 mL/h. Heparin sodium (30 U/kg/h) was continuously administered as an anticoagulant.

Blood gas analysis and cytokine analysis

Arterial BGA was performed using a portable BGA measuring device, Epoc® (Siemens Healthineers, Bayern, Germany) before phlebotomy as the baseline values and at t = 0, 90, 150, 210, and 270. Serum cytokine assay was performed at t = 0, 90, 150, 210, and 270 and commissioned with Eurofins Clinical Testing Service Japan Co. (Tokyo, Japan) using Luminex® Multiplex Assays (ThermoFisher Scientific, Massachusetts, US).

Intestinal histopathology

To collect pathological specimens of the intestine, the jejunum (10 cm from the proximal) and ileum (10 cm from the distal) were resected. The specimen sections were then stained with hematoxylin and eosin (H&E), examined by three physicians and surgeons, and classified according to a grading system of tissue damage, as described in previous studies (details are shown in SI Methods) [19–21].

Statistical analysis

Data are expressed as median (interquartile range) for continuous values. Differences between the two groups were analyzed using the Mann–Whitney U test, and survival rate analysis was performed using the Kaplan–Meier method and log-rank test. Statistical significance was set at p < 0.05. significant. All statistical analyses were performed using the SPSS software version 26.0.0 (IBM Corporation, Armonk, NY, USA).

Baseline characteristics of a hemorrhagic shock model

Baseline characteristics of swine in the CCRT and control groups are shown in SI Table S1. The heights of swine in the CRRT and control groups were 106.0 (105.0–107.5) vs. 105.5 (104.8–106.3) cm (p = 0.49), respectively, and their weights were 37.7 (37.0–38.4) vs. 38.2 (37.2–39.0) kg (p = 0.89), respectively. No significant differences were observed in the total phlebotomy volume between the CRRT and control groups (1130.0 [1071.3–1180.0] vs. 1130.0 [1080.0–1180.0] mL; p = 0.89).

BGA results before and after phlebotomy revealed no significant differences in pH, HCO³⁻, base excess, potassium, hemoglobin, hematocrit, lactate, or creatinine in either group.

Effect of CRRT on survival

A comparison of survival rates between the CRRT and control groups is shown in Fig. 1. All swine survived during the hemorrhagic shock induction and REBOA phases; two swine in each group died immediately after REBOA deflation, and one in the control group died 1 h after REBOA deflation. Finally, two and one swine in the CRRT and control groups, respectively, survived; no significant differences were observed between the two groups (p = 0.45).

Effects of CRRT on the measurements of arterial blood gas analysis

The number of analyzed swine was decreased because of death (n = 4 at t = 0 and n = 2 at t = 150, 210, and 270 in the CRRT group; n = 4 at t = 0, n = 2 at t = 150, and n = 1 at t = 210 and 270 in the control group). No significant differences in pH, HCO³⁻, potassium, and lactate levels were observed between the CRRT and control groups, although the CRRT group showed a tendency toward increased pH and HCO³⁻, lower elevation of potassium, and decreased lactate levels (Fig. 2 and Table 1).

Table 1

Trend of blood gas analysis results in the CRRT and control groups
	CRRT	Control	p-value
pH
t = 90	7.27 (7.24–7.30)	7.30 (7.29–7.32)	0.34
t = 150	7.08 (7.07–7.10)	7.08 (7.06–7.10)	1.00
t = 210	7.27 (7.26–7.29)	7.08 (7.08–7.08)	0.67
t = 270	7.34 (7.32–7.35)	7.09 (7.09–7.09)	0.67
HCO³⁻, mmol/L
t = 90	15.2 (14.1–15.8)	14.8 (13.6–15.9)	1.00
t = 150	12.9 (12.1–13.6)	10.1 (9.9–10.2)	0.33
t = 210	14.8 (13.8–15.8)	8.6 (8.6–8.6)	0.67
t = 270	16.5 (15.3–17.8)	8.1 (8.1–8.1)	0.67
K⁺, mmol/L
t = 90	5.4 (5.0–5.6)	5.8 (5.6–6.0)	0.20
t = 150	5.1 (4.9–5.2)	8.1 (7.8–8.4)	0.33
t = 210	6.4 (6.1–6.6)	9.3 (9.3–9.3)	0.67
t = 270	7.0 (6.9–7.0)	9.4 (9.4–9.4)	0.67
Lactate, mmol/L
t = 90	15.4 (14.9–16.2)	16.3 (14.8–17.6)	0.89
t = 150	18.1 (17.6–18.7)	19.2 (18.8–19.6)	0.67
t = 210	18.3 (17.1–19.5)	17.2 (17.2–17.2)	1.00
t = 270	14.1 (12.7–15.5)	18.5 (18.5–18.5)	0.67
CRRT, continuous renal replacement therapy
Data are presented as a median and interquartile range for continuous variables; p-values were calculated using the Mann–Whitney U test.
The number of swine is decreased due to death (n = 4 at 0 min and n = 2 at 150, 210, and 270 min in the CRRT group; n = 4 at 0 min, n = 2 at 150 min, and n = 1 at 210 and 270 min in the control group).

In both groups, the pH was lower at t = 90 (CRRT, 7.27 [7.24–7.30]; control, 7.30 [7.29–7.32]) than that at t = 0 (CRRT, 7.44 [7.38–7.48]; control, 7.51 [7.51–7.52]). Further, the pH decreased in both groups at t = 150 (CRRT, 7.08 [7.07–7.10]; control, 7.08 [7.06–7.10]), although it should be noted that only data of surviving cases were analyzed. At t = 210 and 270, the CRRT group showed an increasing trend, whereas the trend for the control group remained low (t = 210: CRRT, 7.27 [7.26–7.29]; control, 7.08 [7.08–7.08]; t = 270: CRRT, 7.34 [7.32–7.35; control, 7.09 [7.09–7.09]; Fig. 2A). Similar to the trend for pH, HCO³⁻ tended to decrease in both groups at t = 90 (CRRT, 15.2 [14.1–15.8]; control, 14.8 [13.6–15.9] mmol/L) and t = 150 (CRRT, 12.9 [12.1–13.6]; control, 10.1 [9.9–10.2] mmol/L) and increase in the CRRT group only at t = 210 (CRRT, 14.8 [13.8–15.8]; control, 8.6 [8.6–8.6] mmol/L) and t = 270 (CRRT, 16.5 [15.3–17.8]; control, 8.1 [8.1–8.1] mmol/L) (Fig. 2B). In both groups, the potassium level was high at t = 90 (CRRT, 5.8 [5.0–6.4]; control, 6.0 [5.6–6.2] mmol/L), and only the potassium level in the control group was further elevated at t = 150 (CRRT, 5.1 [4.9–5.2]; control, 8.1 [7.8–8.4] mmol/L). The potassium level was elevated at t = 210 (CRRT, 6.4 [6.1–6.6]; control, 9.3 [9.3–9.3] mmol/L) and t = 270 (CRRT, 7.0 [6.9–7.0]; control, 9.4 [9.4–9.4] mmol/L) in both groups; however, the CRRT group exhibited a lower elevation than the control group (Fig. 2C). Lactate level was elevated at t = 90 (CRRT, 15.4 [14.9–16.2]; control, 16.3 [14.8–17.6] mmol/L), t = 150 (CRRT, 18.1 [17.6–18.7]; control, 18.3 [18.3–18.3] mmol/L), and t = 210 (CRRT, 18.3 [17.1–19.5]; control, 17.2 [17.2–17.2] mmol/L) in both groups and decreased at t = 270 (CRRT, 14.1 [12.7–15.5]; control; 18.5 [18.5–18.5] mmol/L) only in the CRRT group (Fig. 2D).

Effects of CRRT on intestinal histopathology

The number of analyzed was same as described above. No significant difference in the histopathological grade of the jejunum and ileum was observed between the CRRT and control groups at t = 90 (jejunum: CRRT, 3.0 [1.8–4.0]; control, 3.0 [3.0–3.0]; ileum: CRRT, 3.0 [1.8–4.0]; control, 3.0 [2.8–3.3]), t = 150 (jejunum: CRRT, 1.5 [1.3–1.8]; control, 3.0 [3.0–3.0]; ileum: CRRT, 1.5 [1.3–1.8]; control, 3.5 [3.3–3.8]), t = 210 (jejunum: CRRT, 1.5 [1.3–1.8]; control, 3.0 [3.0–3.0]; ileum: CRRT, 1.5 [1.3–1.8]; control, 4.0 [4.0–4.0]) and t = 270 (jejunum: CRRT, 1.5 [1.3–1.8]; control, 4.0 [4.0–4.0]; ileum: CRRT, 1.5 [1.3–1.8]; control, 4.0 [4.0–4.0]); nevertheless, the CRRT group tended to have a lower grade at t = 150, 210, and 270 (Fig. 3 and SI Fig S1, S2).

Effects of CRRT on serum cytokine levels

The number of analyzed was same as described above. The trends in serum cytokine levels are shown in SI Table S2. No significant difference in serum cytokine levels was observed between the CRRT and control groups; however, the CRRT group showed a tendency toward lower elevation of circulatory inflammatory cytokines such as interleukin (IL)-1b, IL-6, IL-12, and IL-18 (Fig. 4 and SI Table S2).

IL-6 levels increased in both groups, although, the increase was lower in the CRRT group (t = 0: CRRT, 39.6 [30.2–44.6]; control, 17.4 [8.1–37.3] pg/mL; t = 90: CRRT, 105.7 [80.0–151.8]; control, 323.5 [267.2–376.0] pg/mL; t = 150: CRRT, 302.4 [249.0–355.8]; control, 648.6 [577.9–719.3] pg/mL; t = 210: CRRT, 723.9 [560.2–887.5]; control, 1118.9 [1118.9–1118.9] pg/mL; t = 270: CRRT, 1008.5 [770.4–1246.6]; control, 1636.7 [1636.7–1636.7] pg/mL; Fig. 4B). IL-1b, IL-12, and IL-18 levels increased continuously in the control group but showed no increase in the CRRT group (Fig. 4A, 4C, and 4D).

This study represents one of the first attempts to examine the effectiveness of CRRT for R-IRI. We performed CRRT for 3 h in a swine hemorrhagic shock model and observed no apparent adverse events. No significant differences in the survival rate and transition of biomarkers and histopathological grades were observed between the CRRT and control groups. However, our study revealed that CRRT with CAH tended to improve metabolic acidosis, hyperkalemia, and hypercytokinemia associated with R-IRI and reduce damage to the intestine. This finding suggests that CRRT with CAH is effective in controlling R-IRI.

REBOA is an effective and less invasive aortic occlusion procedure for uncontrollable torso hemorrhage; however, recent randomized control trials and meta-analyses have not shown that REBOA resulted in any significant difference in mortality [22, 23]. Although bleeding control is the most important contributor to mortality in patients with severe trauma [1, 2], the control of subsequent complications is also important [14]. IRI is one of the most common and critical complications of REBOA, making establishing treatment strategies for IRI an important research topic [6, 7]. In the present study, survival tended to be longer in the CRRT group, although this difference was not statistically significant. Half of the swine in both groups died immediately after REBOA deflation, suggesting that overcoming this timing is the first step in improving the prognosis of R-IRI. Notably, only one swine in the control group died 1 h after REBOA deflation. Metabolic acidosis and hyperkalemia tended to improve only in the CRRT group, which may have contributed to lower mortality in this group. Although we investigated until up to 3 h after REBOA deflation in this study, this tendency of survival could be more pronounced with further observation, necessitating further research with longer observation times is needed.

In the pathophysiology of IRI, hypercytokinemia due to oxidative stress caused by mitochondrial dysfunction leads to cell death [13, 14]. A similar mechanism has been studied in sepsis, and modulating hypercytokinemia with CRRT and CAH is reported to improve patient’s outcome [15, 24]. We applied this to R-IRI and observed that CRRT with CAH modulated hypercytokinemia in R-IRI; furthermore, we demonstrated that CRRT with CAH modulated cytokines, including IL-1b, IL-6, IL-12, and IL-18. The improvement in mortality in the CRRT group may be attributable to the improvement of metabolic acidosis and hyperkinemia and the modulation of hypercytokinemia. The effect of CRRT on outcomes from this point could also be greater with longer observation period.

Various methods have been reported for controlling R-IRI. Partial REBOA minimizes distal organ ischemia by regulating the aortic flow via partial balloon inflation. Changes in distal organ blood flow following changes in balloon volume during partial REBOA have been previously reported [17, 25]. Partial REBOA has been applied clinically and is expected to improve mortality; however, its effectiveness has not been demonstrated in a recent clinical research [26]. While some studies have shown that target temperature management [10]; administration of a cocktail of adenosine, lidocaine, and magnesium [8]; and administration of elamipretide [9] were effective in reducing the R-IRI-induced damage, these approaches have yet to be applied in clinical trials. Our study demonstrates the effectiveness of CRRT as a novel treatment for R-IRI.

The strength of this study lies in the easily applicable results in clinical practice. CRRT is commonly performed in patients with acute kidney injury in the ICU and has already been clinically applied in conditions with similar a pathophysiology, such as acute leg ischemia [11] and crush syndrome [12]. Furthermore, intraoperative continuous hemofiltration has been reported in lower extremity ischemia surgery [27], cardiac surgery [28, 29], and liver transplantation [30]; hence, applying similar strategies, such as providing an extended time until damage control surgery using REBOA and deflating REBOA under CRRT intraoperatively, is feasible. Nevertheless, this study had several limitations. First, we observed a few cases of death-related interruptions, making the interpretation of some measurements difficult. The histopathological grade of the intestine at t = 90 tended to be higher than that at t = 150 in the jejunum and ileum in the CRRT group may be influenced by the poorly graded cases that died shortly thereafter. We inflated the REBOA for 90 min, the longest time for which survival has been reported in a previous swine study [16]. Observe more cases for a longer time may be possible by administering a vasopressor or bicarbonate, similar to the previous study. However, not administering these drugs allowed us to solely examine the effects of CRRT on R-IRI. Second, individual differences in the tolerance to metabolic acidosis and hyperkalemia could affect mortality. Survivors in the control group showed very low pH and very high potassium levels, suggesting that the swine had a high tolerance. Third, the effect of heparin administration may become an issue when applying the results of this study to clinical settings. Anticoagulants can worsen hemorrhage during massive bleeding events. In this study, heparin was administered to prevent thrombus formation in the aorta during REBOA and CRRT circuit. From the perspective of clinical applications, whether CRRT can be performed without anticoagulation should be further evaluated.

CRRT may mitigate acute-phase R-IRI by controlling biomarkers such as metabolic acidosis, hyperkalemia, and hypercytokinemia. Further research is required to evaluate its impact on long-term mortality. The establishment of treatment strategies for R-IRI, including CRRT with CAH, will improve the prognosis of patients with hemorrhagic shock.

Funding:

This study was funded by a Grant-in-Aid for Scientific Research (C) (Grant Number 21K09039, 2021-2024) from Japan Society for the Promotion of Science (JSPS).

Conflicts of interest/competing interests:

The authors have no conflicts of interest to declare that are relevant to the content of this article.

Ethics approval:

All methods were performed in accordance with the relevant guidelines and regulations and were approved by the Institutional Animal Experiment Committee (authorization number: 21006-01).

Data availability:

The datasets used and analyzed in the current study are available from the corresponding author upon reasonable request.

Authors’ contribution statements:

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Yosuke Hayashi, Yoshimitsu Izawa, Yasutaka Tanaka, Makoto Aoki and Yosuke Matsumura. The first draft of the manuscript was written by Yosuke Hayashi and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Acknowledgment

We thank all members of the Center for Development of Advanced Medical Technology, Jichi Medical University, and Honyaku Center Inc. for English language editing.

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Continuous renal replacement therapy with cytokine-adsorbing hemofilter to control resuscitative endovascular balloon occlusion of the aorta-related ischemia-reperfusion injury in a swine hemorrhagic shock model

Status:

Version 1

Abstract

Figures

Introduction

Methods

Animals

Animal preparation

Induction of hemorrhagic shock and REBOA placement

CRRT setting

Blood gas analysis and cytokine analysis

Intestinal histopathology

Statistical analysis

Results

Baseline characteristics of a hemorrhagic shock model

Effect of CRRT on survival

Effects of CRRT on the measurements of arterial blood gas analysis

Effects of CRRT on intestinal histopathology

Effects of CRRT on serum cytokine levels

Discussion

Conclusions

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1