Low-dose norepinephrine in combination with hypotensive resuscitation may prolong the golden window for uncontrolled hemorrhagic shock in rats

Abstract

Hypotension resuscitation is an important principle for the treatment after trauma. Current hypotensive resuscitation strategies cannot obtain an ideal outcome for remote regions. With the uncontrolled hemorrhagic shock (UHS) model in rats, the effects of norepinephrine (NE) on the tolerance time of hypotensive resuscitation, blood loss, vital organ functions, and animal survival were observed. Before bleeding was controlled, only the LR infusion could effectively maintain the MAP to 50-60 mmHg for 1 h, while the MAP gradually decreased with prolonging time, even with increasing infusion volume. Low-dose NE during hypotensive resuscitation prolonged the hypotensive tolerance time to 2-3 h, and the effect of 0.3 μg/kg/min NE was the best. Further studies showed that 0.3 μg/kg/min NE during hypotensive resuscitation significantly lightened the damage of organ function induced by UHS via protecting mitochondrial function, while the LR infusion did not. At the same time, NE administration improved Hb content, DO₂, and VO₂, and restored liver and kidney blood flow. The survival results showed that low-dose NE administration increased the survival rate and prolonged the survival time. Together, low-dose NE during hypotensive resuscitation was suitable for the early treatment of UHS, which can strive for the golden window of emergency treatment for serious trauma patients by reducing blood loss and protecting vital organ functions.

Keywords: golden treatment time; hypotension resuscitation; norepinephrine; organ function; uncontrolled hemorrhagic shock.

FIGURE 1

Timeline of the experimental phases. Phase I was the UHS period. Phase II was the permissive hypotensive resuscitation period. Phase III was the observation period. Part I: effects of NE administration on tolerance time during the permissive hypotensive resuscitation period before bleeding was controlled following UHS. Part II: the effects of NE on organ function and survival when the splenic artery was ligated after NE administration for 2 h during the hypotensive resuscitation period. Part III: the beneficial effects of NE on hemodynamics, organ function, and survival when the splenic artery was ligated after NE administration for 1 h.

FIGURE 2

NE prolonged the golden treatment time for UHS. (A) Mean arterial pressure (MAP). (B,C) Blood loss and infusion volume in permissive hypotensive maintenance period (Phase II). (D) The hypotensive maintenance time of NE or LR. (E) The hypotensive maintenance rate of rats with UHS at different times. ^* p < 0.05, ^** p < 0.01, ^*** p < 0.001 as compared with UHS. ^# p < 0.05, ^## p < 0.01, ^### p < 0.001 as compared with LR.

FIGURE 3

The effect of NE on survival time following prolonged golden treatment time for 2 h. (A,B) Blood loss and infusion volume in the permissive hypotensive maintenance period (Phase II). ^**, p < 0.01. (C) The average survival time. (D) 72-h survival rate. ^*, p < 0.05 as compared with UHS.

FIGURE 4

The effect of NE on vital organ functions following prolonged golden treatment time for 2 h. (A) ALT. (B) AST. (C) Scr. (D) BUN. (E) TnT. ^** p 0.01, ^*** p < 0.001 as compared with the sham group; ^# p < 0.05, ^## p < 0.01, ^### p < 0.001 as compared with the UHS group; ^@ p < 0.05 as compared with the 0.1 NE group.

FIGURE 5

The effect of NE on blood loss and infusion volume following 1 h of hypotensive resuscitation. (A,B) Blood loss and infusion volume in the permissive hypotensive maintenance period (Phase II). ^* p < 0.05, ^*** p < 0.001 as compared with the UHS group; ^## p < 0.01, ^### p < 0.001 as compared with the LR group.

FIGURE 6

The effect of NE on oxygen delivery and consumption following 1 h of hypotensive resuscitation. (A) Hb. (B) blood lactate. (C) TcPO₂. (D) DO₂. (E) VO₂. ^* p < 0.05, ^** p < 0.01 as compared with the LR group.

FIGURE 7

The effect of NE on vital organ functions following 1 h of hypotensive resuscitation. (A) CO. ^* p < 0.05 as compared with LR group. (B) CI. ^* p < 0.05 as compared with LR group. (C) TnT. ^*** p < 0.001 as compared with the Sham group. ^# p < 0.05 as compared with the LR group. (D,E) AST and ALT. ^*** p < 0.001 as compared with the Sham group. ^# p < 0.05, ^## p < 0.01 as compared with LR group. (F,G) Scr and BUN. ^*** p < 0.001 as compared with the Sham group. (H,I) Blood flow of liver and kidney. ^*** p < 0.001 as compared with the Sham group. ^# p < 0.05, ^## p < 0.01 as compared with LR group. (J,K) water content of the lung and brain.

FIGURE 8

The effect of NE on mitochondrial function of the vital organ following 1 h of hypotensive resuscitation. (A–C) The RCRs of mitochondria in heart, liver, and kidneys. ^*** p < 0.001 as compared with the Sham group. ^# p < 0.05, ^## p < 0.01 as compared with the LR group. (D) Mitochondrial morphology of heart by transmission electron microscope (TEM).

FIGURE 9

The effect of on survival outcome following 1 h of hypotensive resuscitation. (A) 72 h survival rate. ^* p < 0.05 as compared with the UHS group. ^## p < 0.01, ^### p < 0.001 as compared with the LR group. (B) the avrage survival time. ^* p < 0.05, ^*** p < 0.001 as compared with the LR group.