ROC trials update on prehospital hypertonic saline resuscitation in the aftermath of the US-Canadian trials

Dubick, Michael A.; Shek, I Pang; Wade, Charles E.

doi:10.6061/clinics/2013(06)25

Cited by 19 publications

(18 citation statements)

References 46 publications

(38 reference statements)

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“…Compared to conventional isotonic resuscitation fluids, significantly smaller volumes of hypertonic fluids are sufficient to restore circulation in hypotensive patients (21-22). The ease of transport of the small volumes of hypertonic fluids (250 ml per patient) has particular relevance in military applications.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Neutrophils by Hypertonic Saline Involves Pannexin-1, CD39, CD73, and Other Ectonucleotidases

Chen

Bao

Zhang³

et al. 2015

Shock

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Hypertonic saline (HS) resuscitation has been studied as a possible strategy to reduce PMN activation and tissue damage in trauma patients. HS blocks PMNs by ATP release and stimulation of A2a adenosine receptors. Here we studied the underlying mechanisms in search of possible reasons for the inconsistent results of recent clinical trials with HS resuscitation. Purified human PMNs or PMNs in whole blood were treated with HS to simulate hypertonicity levels found after HS resuscitation (40 mM beyond isotonic levels). ATP release was measured with a luciferase assay. PMN activation was assessed by measuring oxidative burst. The pannexin-1 (panx1) inhibitor 10panx1 and the gap junction inhibitor carbenoxolone (CBX) blocked ATP release from PMNs in purified and whole blood preparations, indicating that HS releases ATP via panx1 and gap junction channels. HS blocked fMLP-induced PMN activation by 40% in purified PMN preparations and by 60% in whole blood. These inhibitory effects were abolished by 10panx1 but only partially reduced by CBX, which indicates that panx1 has a central role in the immunomodulatory effects of HS. Inhibition of the ectonucleotidases CD39 and CD73 abolished the suppressive effect of HS on purified PMN cultures but only partially reduced the effect of HS in whole blood. These findings suggest redundant mechanisms in whole blood that may strengthen the immunomodulatory effect of HS in vivo. We conclude that HS resuscitation exerts anti-inflammatory effects that involve panx1, CD39, CD73, and other ectonucleotidases, which produce the adenosine that blocks PMNs by stimulating their A2a receptors. Our findings shed new light on the immunomodulatory mechanisms of HS and suggest possible new strategies to improve the clinical efficacy of hypertonic resuscitation.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Neutrophils by Hypertonic Saline Involves Pannexin-1, CD39, CD73, and Other Ectonucleotidases

Chen

Bao

Zhang³

et al. 2015

Shock

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“…In animal models, 7.5% NaCl has been shown to rapidly expand plasma volume but for longer term ‘pressor’ effect requires a suitable colloidal agent 37. Hypertonic saline also appears to have positive immunomodulatory properties, improve the microcirculation and oxygen delivery, and significantly reduce intracranial hypertension following traumatic brain injury (TBI) 48. Unfortunately, 7.5% NaCl solution, with or without a colloid, has not translated into clinical practice,35 although the small-volume hypothesis remains attractive for the concept of permissive hypotension, and with the overall scheme of damage control resuscitation in the pre-hospital setting 48…”

Section: Battlefield Resuscitation: What Are We Missing?mentioning

confidence: 99%

The Bellamy challenge: it's about time

2013

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In 1984, Col. Ronald Bellamy launched a worldwide challenge to develop a new resuscitation fluid to aid survival after catastrophic blood loss on the battlefield. In 1996, after careful compromise among need, cube weight and efficacy, the US military and later coalition forces adopted 6% hetastarch (HES) fluids for early resuscitation. In the intervening years, evidence has amassed indicating that the HES fluids may not be safe, and in June 2013 the US Food and Drug Administration issued a warning that HES solutions should not be used to treat patients with hypovolaemia or the critically ill. We review the unique challenges of early battlefield resuscitation, why the 'Bellamy challenge' remains open and discuss a number of forward-looking strategies that may help to solve the problem. The first two pillars of resuscitation that we believe have not been adequately addressed are rescuing and stabilising the heart (and brain) and the vascular system. The 'ideal' resuscitation fluid needs to nurture the heart and body slowly back to health, and not 'shock' it a second time with unnatural colloids or large volumes of unphysiological saline-based solutions.

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“…The recommendation for hemorrhagic shock in Fluid Resuscitation , a report published by the Committee on Fluid Resuscitation for Combat Causalities and Institute of Medicine in 1999, is a 250 ml bolus of 7.5% saline. However, a subsequent randomized, double-blinded study by the Resuscitation Outcomes Consortium did not show improved survival outcomes after treatment with hypertonic saline (5;6). In fact, hypertonic saline worsened hypo-coagulation and hyper-fibrinolysis (7).…”

Section: Introductionmentioning

confidence: 97%

Low-volume resuscitation using polyethylene glycol-20k in a preclinical porcine model of hemorrhagic shock

Plant

Limkemann

Liebrecht

et al. 2016

Journal of Trauma and Acute Care Surgery

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Introduction Polyethylene glycol-20k (PEG-20k) is highly effective for low volume resuscitation (LVR) by increasing tolerance to the low volume state. In our rodent shock model, PEG-20k increased survival and expanded the “golden hour” 16-fold compared to saline. The molecular mechanism is largely attributed to normalizations in cell and tissue fluid shifts after low flow ischemia resulting in efficient microvascular exchange. The objective of this study was to evaluate PEG-20k as a low volume resuscitation solution for hemorrhagic shock in a pre-clinical model. Methods Anesthetized male Yorkshire pigs (30–40 kg) were hemorrhaged to a MAP of 35–40 mmHg. Once lactate reached 7 mM/L, either saline (n = 5) or 10% PEG-20k (n = 5) was rapidly infused at 10% calculated blood volume. The primary outcome was LVR time, defined by the time from LVR administration to the time when lactate again reached 7 mM/L. Other outcomes measured included: MAP, heart rate (HR), cardiac output (CO), mixed venous oxygen saturation (SvO2), splanchnic blood flow, and hemoglobin. Results Relative to saline, PEG-20k given after controlled hemorrhage increased LVR time by 16-fold, a conservative estimate given that the lactate never rose after LVR in the PEG-20k group. Survival was 80% for PEG-20k LVR compared to 0% for the saline controls (P<0.05). PEG-20k also significantly decreased HR after hemorrhage and increased CO, MAP, splanchnic flow, and SvO2. Falling hemoglobin concentrations suggested sizable hemodilution from fluid shifts into the intravascular compartment. Conclusions In a pre-clinical model of controlled hemorrhagic shock, PEG-20k-based LVR solution increased tolerance to the shock state 16-fold compared to saline. PEG-20k is a superior crystalloid for low volume resuscitation that may increase safe transport times in the prehospital setting and find use in hospital emergency departments and operating rooms for patients awaiting volume replacement or normalization of cell, tissue, and compartment fluid volumes.

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ROC trials update on prehospital hypertonic saline resuscitation in the aftermath of the US-Canadian trials

Cited by 19 publications

References 46 publications

Inhibition of Neutrophils by Hypertonic Saline Involves Pannexin-1, CD39, CD73, and Other Ectonucleotidases

Inhibition of Neutrophils by Hypertonic Saline Involves Pannexin-1, CD39, CD73, and Other Ectonucleotidases

The Bellamy challenge: it's about time

Low-volume resuscitation using polyethylene glycol-20k in a preclinical porcine model of hemorrhagic shock

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