Development of a small-volume resuscitation fluid for trauma victims

Abstract

Objective: Traumatic haemorrhagic shock is a leading cause of mortality and morbidity on the battlefield and in civilian populations. In October 2016 the American College of Surgeons referred to it as 'a neglected public health emergency', highlighting the need for improved therapies in these environments. Small-volume 7.5% NaCl ALM had previously demonstrated some promising resuscitative capabilities in two rat models of haemorrhagic shock. The major aim of this thesis was to further investigate and develop this small-volume fluid following severe haemorrhagic shock in the rat and pig. Methods: Haemorrhagic shock was induced in the rat by 20 min phlebotomy to decrease mean arterial pressure (MAP) to 35-40 mmHg followed by 60 min hypovolaemic shock. Small-volume (~0.7-1.0 ml/kg) 7.5% NaCl ± ALM resuscitation bolus was administered IV after 60 min shock, and haemodynamics were monitored for 60 min. Coagulopathy was assessed with PT, aPTT, ROTEM, and ELISAs. In the pig, phlebotomy reduced MAP to 35-40 mmHg, and 4 ml/kg 7.5% NaCl ± ALM resuscitation bolus was administered after 90 min shock. After 60 min single bolus resuscitation, shed blood volume was reinfused and pigs were monitored for 180 min. Metrics included haemodynamics, cardiac function, oxygen consumption, metabolic status, and kidney function. Results: Small-volume 7.5% NaCl ALM induced and maintained a permissive hypotensive state (MAP 64-69 mmHg) with significantly higher pulse pressure in the rat after 41-42% blood loss and 60 min shock. ALM-treated animals also maintained significantly higher body temperature than saline controls (34ϒC vs. 32ϒC; p<0.05), and corrected haemorrhagic-shock induced hypocoagulopathy within 5 min of the single bolus administration with a reversal of PT and aPTT times to baseline, and restoration of ROTEM EXTEM, INTEM, and FIBTEM clots. ALM also reversed hyperfibrinolysis, and led to higher PAI-1 levels and lower D-dimers (8% of saline controls at 60 min) further supporting an ALM anti-fibrinolytic effect. Lower P-selectin in ALM-treated animals may indicate improved endothelial function, and reduced platelet dysfunction and inflammation, however this requires further investigation. In the pig model of 75% blood loss and 90 min shock, 4 ml/kg 7.5% NaCl ALM had significantly higher MAP (48 mmHg vs. 33 mmHg; p<0.0001), significantly higher cardiac index (76 ml/min/kg vs. 47 ml/min/kg; p<0.033), significantly lower arterial lactate (7.1 mM vs. 11.3 mM), and higher base excess, compared to 7.5% saline controls. Higher cardiac index was associated with two-fold higher stroke volume and significantly increased left ventricular systolic ejection times. After return of shed blood, whole body oxygen consumption decreased in ALM-treated pigs from 5.7 ml O₂/min/kg to 4.9 ml O₂/min/kg. After 180 min blood resuscitation, pigs that received 7.5% NaCl ALM had three-fold higher urinary output (2.1 ml/kg/hr vs. 0.7 ml/kg/hr; p=0.001), significantly lower plasma creatinine levels, and significantly higher creatinine clearance ratio, compared to saline controls. Conclusions: In the rat model of severe haemorrhagic shock, a single small-volume 7.5% NaCl ALM bolus rescued the heart, resuscitated into the permissive hypotensive range, protected against hypothermia, corrected trauma-induced hypocoagulopathy within 5 min, reversed hyperfibrinolysis, and possibly protected endothelial protection. In the pig model, ALM fluid also significantly improved left ventricular-arterial coupling, reduced whole body oxygen consumption, restored acid-base balance, and protected renal function. These multi-factorial restorative and protective effects may be explained by the ALM resynchronization hypothesis, and may involve nitric oxide as a possible mediator, as well as modulation of autonomic nervous system outputs. Further investigations are required to elucidate the underlying mechanisms of small-volume ALM resuscitation, as well as translational studies for possible human use.