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. 2022 Sep;10(17):e15451.
doi: 10.14814/phy2.15451.

Testing oxygenated microbubbles via intraperitoneal and intrathoracic routes on a large pig model of LPS-induced acute respiratory distress syndrome

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Testing oxygenated microbubbles via intraperitoneal and intrathoracic routes on a large pig model of LPS-induced acute respiratory distress syndrome

Riaz Ur Rehman Mohammed et al. Physiol Rep. 2022 Sep.

Abstract

With a mortality rate of 46% before the onset of COVID-19, acute respiratory distress syndrome (ARDS) affected 200,000 people in the US, causing 75,000 deaths. Mortality rates in COVID-19 ARDS patients are currently at 39%. Extrapulmonary support for ARDS aims to supplement mechanical ventilation by providing life-sustaining oxygen to the patient. A new rapid-onset, human-sized pig ARDS model in a porcine intensive care unit (ICU) was developed. The pigs were nebulized intratracheally with a high dose (4 mg/kg) of the endotoxin lipopolysaccharide (LPS) over a 2 h duration to induce rapid-onset moderate-to-severe ARDS. They were then catheterized to monitor vitals and to evaluate the therapeutic effect of oxygenated microbubble (OMB) therapy delivered by intrathoracic (IT) or intraperitoneal (IP) administration. Post-LPS administration, the PaO2 value dropped below 70 mmHg, the PaO2 /FiO2 ratio dropped below 200 mmHg, and the heart rate increased, indicating rapidly developing (within 4 h) moderate-to-severe ARDS with tachycardia. The SpO2 and PaO2 of these LPS-injured pigs did not show significant improvement after OMB administration, as they did in our previous studies of the therapy on small animal models of ARDS injury. Furthermore, pigs receiving OMB or saline infusions had slightly lower survival than their ARDS counterparts. The OMB administration did not induce a statistically significant or clinically relevant therapeutic effect in this model; instead, both saline and OMB infusion appeared to lower survival rates slightly. This result is significant because it contradicts positive results from our previous small animal studies and places a limit on the efficacy of such treatments for larger animals under more severe respiratory distress. While OMB did not prove efficacious in this rapid-onset ARDS pig model, it may retain potential as a novel therapy for the usual presentation of ARDS in humans, which develops and progresses over days to weeks.

Keywords: Berlin criteria; acute respiratory distress syndrome; intraperitoneal; intrathoracic; oxygenated microbubbles; peripheral oxygenation.

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Conflict of interest statement

None.

Figures

FIGURE 1
FIGURE 1
Study information. (a) Experimental timeline. (b) Grouping of pigs for the study
FIGURE 2
FIGURE 2
Schematic diagram depicting the porcine intensive care unit setup
FIGURE 3
FIGURE 3
PaO2 values of pigs in different groups. (a) The femoral artery PaO2 level was significantly greater in the control group than in the ARDS‐only group. The difference in PaO2 levels after oxygenated microbubble administration was not statistically significant (*p < 0.05). (b) The carotid artery PaO2 values were significantly greater in the control group compared with the lipopolysaccharide group (***p < 0.001). (c) The PmvO2 levels in the pulmonary artery did not show any significant difference between the groups (p > 0.05).
FIGURE 4
FIGURE 4
Pulse oximetry values. The % SpO2 values dropped starting at 2 h after lipopolysaccharide administration until the end of the experiment. The difference was statistically significant (***p < 0.001).
FIGURE 5
FIGURE 5
Heart rates pre‐ and postinfusions in subgroups of (a) intrathoracic catheter and (b) intraperitoneal administration catheter
FIGURE 6
FIGURE 6
Kaplan–Meier survival plot. Pigs in the control group showed a 100% survival rate after 7 h from the start of the study. Pigs in the ITAO group had a lower survival rate than their acute respiratory distress syndrome (ARDS)‐only and ITAS counterparts. However, the difference did not reach significance (p > 0.05). Pigs in the IAAO group had a lower survival rate than the pigs in the ARDS‐only group (*p < 0.05). The IAAS and ITAS groups showed similar survival rates after 3.5 h as seen from the overlapping curves. The differences between other groups were not significant.
FIGURE 7
FIGURE 7
Representative radiograph images (supine position) showing no significant signs of pulmonary edema. (a) Prestudy x‐ray of a control animal and (b) Postmortem x‐ray of the same control animal
FIGURE 8
FIGURE 8
Prestudy and poststudy radiograph scores. (a) The prestudy radiograph scores did not show a statistical difference between the groups. (b) The poststudy radiograph score was greater in the lipopolysaccharide group but the difference compared with controls was not statistically significant (p > 0.05). The radiograph score in the oxygenated microbubble group (IAAO) was significantly greater than controls (**p < 0.01)
FIGURE 9
FIGURE 9
Representative histological images for the control group with no statistically significant difference (each scale bar measures 65 μm). (a) Image with a score of 0 for inflammation and (b) Image with a score of 1 for inflammation
FIGURE 10
FIGURE 10
Representative histological images for the lipopolysaccharide group with a significantly greater incidence of inflammation (each scale bar measures 65 μm). (a) Image with a score of 2 for inflammation and (b) Image with a score of 3 for inflammation
FIGURE 11
FIGURE 11
Representative histological images for treatment groups (each scale bar measures 65 μm). (a) Image with a score of 1 for inflammation from ITAO group, (b) image with a score of 2 for inflammation from IAAO group, (c) image with a score of 1 for inflammation from ITAS group, and (d) image with a score of 2 for inflammation from IAAS group
FIGURE 12
FIGURE 12
Histology scores for edema, hemorrhage, and inflammation. (a) The histological score for edema was not significantly different among the groups, (b) the histological score for hemorrhage was not significantly different among the groups, and (c) the histological score for inflammation was significantly greater in the lipopolysaccharide group compared with controls (***p < 0.001).
FIGURE 13
FIGURE 13
Wet/dry lung ratios of pigs postmortem

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