Blood pressure stabilising hormone cuts transfusion volumes by half

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Giving trauma patients with severe blood loss the hormone arginine vasopressin (AVP) cut the volume of blood products required to stabilise them by half, according to results of a first-of-its-kind clinical trial from Penn Medicine. The finding suggests that administering AVP to trauma patients with severe bleeding could become standard practice in trauma care, reducing the use of blood products and their adverse side effects. The authors say the study is particularly important for the treatment of patients with gun-related injuries. Each year, there are over 100,00 firearm-related injuries with over 36,000 deaths.

“Unintentional traumatic injuries are the leading cause of death in the US for people younger than 45, and the injuries often involve severe blood loss. We can replace a patient’s lost blood with blood products such as packed red blood cells, fresh frozen plasma, and platelets, but use of these options can lead to serious complications and they may not fully replace key molecules in blood that are needed to support blood pressure and the normal function of vital organs,” said Dr Carrie A Sims, an associate professor of surgery and laboratory director of the Penn Acute Research Collaboration. “The results of this trial suggest a promising way to reduce the amount of blood needed to save the lives of patients with life-threatening injuries.”

In the trial, 100 trauma patients were treated using low-dose AVP, a small protein produced in the hypothalamus and stored in the pituitary gland. AVP is secreted into the bloodstream when blood pressure is too low, and has the effect of constricting some blood vessels to bring blood pressure back up to the normal range. Treating trauma patients with AVP significantly decreased the need for blood products without increasing complications.

Prior studies have shown that patients with severe blood loss – a condition called haemorrhagic shock – may have lost most of their stores of AVP and/or their ability to secrete it into the circulation. For that reason, restoring an adequate blood pressure in these patients often requires the infusion of more blood products, involving more potential complications, than would otherwise be needed if AVP were present. Replacing AVP artificially in haemorrhagic shock patients may be a good way to reduce unnecessary blood product-use and improve patient outcomes. Experiments in animal models have suggested that is the case, but Sims and colleagues are the first to test the idea with a rigorous clinical trial design.

From May 2013 through May 2017 at a Penn Medicine trauma centre, they enrolled 100 trauma patients who had been brought in with haemorrhagic shock and otherwise met the study criteria. All but seven were male victims of gunshot or knife wounds. The researchers randomised 49 of the patients to receive AVP in an initial moderate dose plus a slow infusion – during the first 48 hours of care – and the other 51 to receive the placebo equivalent.

The researchers found that the patients treated with AVP for 48 hours ended up receiving an average of 1.4 litres of blood products – less than half the average amount given to those treated with the placebo (2.9 litres).

The AVP group also had a markedly lower rate (11% vs 34%) of deep-vein thrombosis- blood clot in a leg vein – which is a common complication in trauma patients. Rates of complications within 30 days for the AVP and placebo groups were otherwise similar (55% vs 64%), and the numbers of deaths in that period were the same (six in each group). Other findings showed that although the AVP group had shorter average stays in the hospital compared to the placebo group, the relatively small number of patients in the study meant that these length-of-stay differences were not statistically significant.

With the promising results from this initial study in hand, the researchers hope to initiate a larger study that would help determine whether AVP could save lives affected by severe trauma.

Abstract
Importance: Current therapies for traumatic blood loss focus on hemorrhage control and blood volume replacement. Severe hemorrhagic shock, however, is associated with a state of arginine vasopressin (AVP) deficiency, and supplementation of this hormone may decrease the need for blood products in resuscitation.
Objective: To determine whether low-dose supplementation of AVP in patients with trauma (hereinafter referred to as trauma patients) and with hemorrhagic shock decreases their need for transfused blood products during resuscitation.
Design, Setting, and Participants: This randomized, double-blind placebo-controlled clinical trial included adult trauma patients (aged 18-65 years) who received at least 6 U of any blood product within 12 hours of injury at a single urban level 1 trauma center from May 1, 2013, through May 31, 2017. Exclusion criteria consisted of prehospital cardiopulmonary resuscitation, emergency department thoracotomy, corticosteroid use, chronic renal insufficiency, coronary artery disease, traumatic brain injury requiring any neurosurgical intervention, pregnancy, prisoner status, or AVP administration before enrollment. Data were analyzed from May 1, 2013, through May 31, 2017, using intention to treat and per protocol.
Interventions: After administration of an AVP bolus (4 U) or placebo, participants received AVP (≤0.04 U/min) or placebo for 48 hours to maintain a mean arterial blood pressure of at least 65 mm Hg.
Main Outcomes: The primary outcome was total volume of blood product transfused. Secondary end points included total volume of crystalloid transfused, vasopressor requirements, secondary complications, and 30-day mortality.
Results: One hundred patients underwent randomization (49 to the AVP group and 51 to the placebo group). Patients were primarily young (median age, 27 years [interquartile range {IQR}, 22-25 years]) and male (n = 93) with penetrating trauma (n = 79). Cohort characteristics before randomization were well balanced. At 48 hours, patients who received AVP required significantly less blood products (median, 1.4 [IQR, 0.5-2.6] vs 2.9 [IQR, 1.1-4.8] L; P = .01) but did not differ in requirements for crystalloids (median, 9.9 [IQR, 7.9-13.0] vs 11.0 [8.9-15.0] L; P = .22) or vasopressors (median, 400 [IQR, 0-5900] vs 1400 [IQR, 200-7600] equivalent units; P = .22). Although the groups had similar rates of mortality (6 of 49 [12%] vs 6 of 51 [12%]; P = .94) and total complications (24 of 44 [55%] vs 30 of 47 [64%]; P = .37), the AVP group had less deep venous thrombosis (5 of 44 [11%] vs 16 of 47 [34%]; P = .02).
Conclusions and Relevance: Low-dose AVP during the resuscitation of trauma patients in hemorrhagic shock decreases blood product requirements. Additional research is necessary to determine whether including AVP improves morbidity or mortality.

Authors
Carrie A Sims, Daniel Holena, Patrick Kim, Jose Pascual, Brian Smith, Neils Martin, Mark Seamon, Adam Shiroff, Shariq Raza, Lewis Kaplan, Elena Grill, Nicole Zimmerman, Christopher Mason, Benjamin Abella, Patrick Reilly

University of Pennsylvania School of Medicine material
JAMA Surgery abstract


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