Development of a small-volume resuscitation fluid for trauma victims

Letson, Hayley Louise (2016) Development of a small-volume resuscitation fluid for trauma victims. PhD thesis, James Cook University.

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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.

Item ID: 52101
Item Type: Thesis (PhD)
Keywords: adenocaine, adenosine, coagulopathy, endothelial, fibrinogen, fibrinolysis, haemorrhage, hemorrhage, hemorrhagic, hyperfibrinolysis, hypertonic saline, hypocoagulopathy, hypotensive resuscitation, inflammation, injury, lidocaine, magnesium, military, platelets, prehospital, resuscitation, ROTEM, shock, small volume, trauma
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This is a thesis by publication. Published articles included as chapters 2, 3, 4, 5, 7 and 8 have been redacted from the thesis due to copyright restrictions. The full thesis may either be requested via document delivery at your local library or viewed in the Eddie Koiki Mabo Library at JCU, Townsville.

Publications arising from this thesis are available from the Related URLs field. The publications are:

Chapter 2: Letson, Hayley L., Pecheniuk, Natalie M., Mhango, Lebo P., and Dobson, Geoffrey P. (2012) Reversal of acute coagulopathy during hypotensive resuscitation using small-volume 7.5% NaCl adenocaine and Mg2+ in the rat model of severe hemorrhagic shock. Critical Care Medicine, 40 (8). pp. 2417-2422.

Chapter 3: Granfeldt, Asger, Letson, Hayley L., Hyldebrandt, Janus A., Wang, Edward R., Salcedo, Pablo A., Nielsen, Torben K., Tønnesen, Else, Vinten-Johansen, Jakob, and Dobson, Geoffrey P. (2014) Small-volume 7.5% NaCI adenosine lidocaine, and Mg2+ has multiple benefits during hypotensive and blood resuscitation in the pig following severe blood loss: rat to pig translation. Critical Care Medicine, 42 (5). e329-e344.

Chapter 4: Letson, Hayley L., and Dobson, Geoffrey P. (2015) Correction of acute traumatic coagulopathy with small-volume 7.5% NaCl adenosine, lidocaine, and Mg2+ occurs within 5 minutes: a ROTEM analysis. Journal of trauma and acute care surgery, 78 (4). pp. 773-783.

Chapter 5: Letson, Hayley L., and Dobson, Geoffrey (2016) Differential contributions of platelets and fibrinogen to early coagulopathy in a rat model of hemorrhagic shock. Thrombosis Research, 141. pp. 58-65.

Chapter 7: Dobson, Geoffrey P., Letson, Hayley L., Sharma, Rajiv, Sheppard, Forest R., and Cap, Andrew P. (2015) Mechanisms of early trauma-induced coagulopathy: the clot thickens or not? Journal of Trauma and Acute Care Surgery, 79 (2). pp. 301-309.

Chapter 8: Dobson, Geoffrey Phillip, and Letson, Hayley Louise (2016) Adenosine, lidocaine, and Mg2+ (ALM): from cardiac surgery to combat casualty care - teaching old drugs new tricks. Journal of Trauma and Acute Care Surgery, 80 (1). pp. 135-145.

Date Deposited: 23 Jan 2018 02:29
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1102 Cardiovascular Medicine and Haematology > 110299 Cardiovascular Medicine and Haematology not elsewhere classified @ 60%
11 MEDICAL AND HEALTH SCIENCES > 1199 Other Medical and Health Sciences > 119999 Medical and Health Sciences not elsewhere classified @ 40%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920199 Clinical Health (Organs, Diseases and Abnormal Conditions) not elsewhere classified @ 85%
92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 15%
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