The effect HBOC-201 and sodium nitrite resuscitation after uncontrolled haemorrhagic shock in swine

Paula Moon-Massat; Anke Scultetus; Franoise Arnaud; Ammon Brown; Ashraful Haque; Biswajit Saha; Bobby Kim; Eileen Sagini; Gerald McGwin; Charles Auker; Richard McCarron; Daniel Freilich

doi:10.1016/j.injury.2010.10.013

The effect HBOC-201 and sodium nitrite resuscitation after uncontrolled haemorrhagic shock in swine

Paula Moon-Massat^*, Anke Scultetus, Franoise Arnaud, Ammon Brown, Ashraful Haque, Biswajit Saha, Bobby Kim, Eileen Sagini, Gerald McGwin, Charles Auker, Richard McCarron, Daniel Freilich

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

28 Scopus citations

Abstract

Background: Development of Haemoglobin-based oxygen carriers (HBOCs) as blood substitutes has reached an impasse due to clinically adverse outcomes attributed to vasoconstriction secondary to nitric oxide (NO) scavenging. Studies suggest haemoglobin exhibits nitrite reductase activity that generates NO and N ₂O ₃; harnessing this property may offset NO scavenging. Therefore, the effects of concomitantly infusing sodium nitrite (NaNO ₂) with HBOC-201 were investigated. Methods: Swine underwent uncontrolled liver haemorrhage before receiving up to three 10 min 10 ml/kg infusions of HBOC-201 (HBOC) with or without concurrent NaNO ₂ (5.4 μmol/kg [LD NaNO ₂] or 10.8 μmol/kg [HD NaNO ₂]) or 6% Hetastarch (HEX) with or without HD NaNO ₂ during "prehospital" resuscitation (15, 30 and 45 min after injury). Definitive surgical care occurred at 75 min; anaesthetic recovery at 120 min. Animals were euthanised at 72 h. Results: NaNO ₂ temporarily reduced systemic and pulmonary blood pressure increases from HBOC in a dose-dependent fashion. There was no significant effect between groups in indices of tissue oxygenation or survival. Adverse clinical signs requiring humane euthanasia occurred with highest frequency after HBOC + HD NaNO ₂ (3 of 4 pigs) and HBOC + LD NaNO ₂ (2 of 4 pigs). Gross evidence of pulmonary congestion was observed in 5 of 8 swine receiving a HBOC and NaNO ₂ combination compared to 1 of 16 swine receiving HBOC alone, HEX alone, or HEX + NaNO ₂. Gross lesions correlated with histological evidence of pulmonary oedema and congestion, and in 2 of 4 HBOC + HD NaNO ₂ pigs, pulmonary fibrin thrombi also were found. No other pig had similar evidence of thrombi. Asymmetric pre-resuscitation cardiac index was a potential confounder. Conclusions: A significant interaction between NaNO ₂ and HBOC-201 ameliorated HBOC-201 vasoconstrictive effects, consistent with HBOC possessing a nitrite reductase activity that generates vasodilator NO equivalents. Results were relatively equivalent in survival and markers of tissue oxygenation. The highest dose of NaNO ₂ was the most effective in reducing HBOC-associated pulmonary and systemic vasoactivity but also with the highest incidence of adverse events. In this model, the transient nature of NaNO ₂ in off-setting HBOC-201 vasoconstriction makes it less clinically promising than anticipated and the combination of NaNO ₂ and HBOC appear to increase the risk of pulmonary complications in a dose-dependent fashion independently of haemodilutional effects on haemostatic components.

Original language	English
Pages (from-to)	638-647
Number of pages	10
Journal	Injury
Volume	43
Issue number	5
DOIs	https://doi.org/10.1016/j.injury.2010.10.013
State	Published - May 2012
Externally published	Yes

Keywords

Blood substitute
Emergency medicine
HBOC
Haemorrhagic shock
Nitrite
Oxygen therapeutic
Resuscitation
Transfusion
Vasoactivity

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10.1016/j.injury.2010.10.013

Cite this

@article{6ce72415d9ec4db6bb10e59be3413958,

title = "The effect HBOC-201 and sodium nitrite resuscitation after uncontrolled haemorrhagic shock in swine",

abstract = "Background: Development of Haemoglobin-based oxygen carriers (HBOCs) as blood substitutes has reached an impasse due to clinically adverse outcomes attributed to vasoconstriction secondary to nitric oxide (NO) scavenging. Studies suggest haemoglobin exhibits nitrite reductase activity that generates NO and N 2O 3; harnessing this property may offset NO scavenging. Therefore, the effects of concomitantly infusing sodium nitrite (NaNO 2) with HBOC-201 were investigated. Methods: Swine underwent uncontrolled liver haemorrhage before receiving up to three 10 min 10 ml/kg infusions of HBOC-201 (HBOC) with or without concurrent NaNO 2 (5.4 μmol/kg [LD NaNO 2] or 10.8 μmol/kg [HD NaNO 2]) or 6% Hetastarch (HEX) with or without HD NaNO 2 during {"}prehospital{"} resuscitation (15, 30 and 45 min after injury). Definitive surgical care occurred at 75 min; anaesthetic recovery at 120 min. Animals were euthanised at 72 h. Results: NaNO 2 temporarily reduced systemic and pulmonary blood pressure increases from HBOC in a dose-dependent fashion. There was no significant effect between groups in indices of tissue oxygenation or survival. Adverse clinical signs requiring humane euthanasia occurred with highest frequency after HBOC + HD NaNO 2 (3 of 4 pigs) and HBOC + LD NaNO 2 (2 of 4 pigs). Gross evidence of pulmonary congestion was observed in 5 of 8 swine receiving a HBOC and NaNO 2 combination compared to 1 of 16 swine receiving HBOC alone, HEX alone, or HEX + NaNO 2. Gross lesions correlated with histological evidence of pulmonary oedema and congestion, and in 2 of 4 HBOC + HD NaNO 2 pigs, pulmonary fibrin thrombi also were found. No other pig had similar evidence of thrombi. Asymmetric pre-resuscitation cardiac index was a potential confounder. Conclusions: A significant interaction between NaNO 2 and HBOC-201 ameliorated HBOC-201 vasoconstrictive effects, consistent with HBOC possessing a nitrite reductase activity that generates vasodilator NO equivalents. Results were relatively equivalent in survival and markers of tissue oxygenation. The highest dose of NaNO 2 was the most effective in reducing HBOC-associated pulmonary and systemic vasoactivity but also with the highest incidence of adverse events. In this model, the transient nature of NaNO 2 in off-setting HBOC-201 vasoconstriction makes it less clinically promising than anticipated and the combination of NaNO 2 and HBOC appear to increase the risk of pulmonary complications in a dose-dependent fashion independently of haemodilutional effects on haemostatic components.",

keywords = "Blood substitute, Emergency medicine, HBOC, Haemorrhagic shock, Nitrite, Oxygen therapeutic, Resuscitation, Transfusion, Vasoactivity",

author = "Paula Moon-Massat and Anke Scultetus and Franoise Arnaud and Ammon Brown and Ashraful Haque and Biswajit Saha and Bobby Kim and Eileen Sagini and Gerald McGwin and Charles Auker and Richard McCarron and Daniel Freilich",

year = "2012",

month = may,

doi = "10.1016/j.injury.2010.10.013",

language = "English",

volume = "43",

pages = "638--647",

journal = "Injury",

issn = "0020-1383",

number = "5",

}

TY - JOUR

T1 - The effect HBOC-201 and sodium nitrite resuscitation after uncontrolled haemorrhagic shock in swine

AU - Moon-Massat, Paula

AU - Scultetus, Anke

AU - Arnaud, Franoise

AU - Brown, Ammon

AU - Haque, Ashraful

AU - Saha, Biswajit

AU - Kim, Bobby

AU - Sagini, Eileen

AU - McGwin, Gerald

AU - Auker, Charles

AU - McCarron, Richard

AU - Freilich, Daniel

PY - 2012/5

Y1 - 2012/5

N2 - Background: Development of Haemoglobin-based oxygen carriers (HBOCs) as blood substitutes has reached an impasse due to clinically adverse outcomes attributed to vasoconstriction secondary to nitric oxide (NO) scavenging. Studies suggest haemoglobin exhibits nitrite reductase activity that generates NO and N 2O 3; harnessing this property may offset NO scavenging. Therefore, the effects of concomitantly infusing sodium nitrite (NaNO 2) with HBOC-201 were investigated. Methods: Swine underwent uncontrolled liver haemorrhage before receiving up to three 10 min 10 ml/kg infusions of HBOC-201 (HBOC) with or without concurrent NaNO 2 (5.4 μmol/kg [LD NaNO 2] or 10.8 μmol/kg [HD NaNO 2]) or 6% Hetastarch (HEX) with or without HD NaNO 2 during "prehospital" resuscitation (15, 30 and 45 min after injury). Definitive surgical care occurred at 75 min; anaesthetic recovery at 120 min. Animals were euthanised at 72 h. Results: NaNO 2 temporarily reduced systemic and pulmonary blood pressure increases from HBOC in a dose-dependent fashion. There was no significant effect between groups in indices of tissue oxygenation or survival. Adverse clinical signs requiring humane euthanasia occurred with highest frequency after HBOC + HD NaNO 2 (3 of 4 pigs) and HBOC + LD NaNO 2 (2 of 4 pigs). Gross evidence of pulmonary congestion was observed in 5 of 8 swine receiving a HBOC and NaNO 2 combination compared to 1 of 16 swine receiving HBOC alone, HEX alone, or HEX + NaNO 2. Gross lesions correlated with histological evidence of pulmonary oedema and congestion, and in 2 of 4 HBOC + HD NaNO 2 pigs, pulmonary fibrin thrombi also were found. No other pig had similar evidence of thrombi. Asymmetric pre-resuscitation cardiac index was a potential confounder. Conclusions: A significant interaction between NaNO 2 and HBOC-201 ameliorated HBOC-201 vasoconstrictive effects, consistent with HBOC possessing a nitrite reductase activity that generates vasodilator NO equivalents. Results were relatively equivalent in survival and markers of tissue oxygenation. The highest dose of NaNO 2 was the most effective in reducing HBOC-associated pulmonary and systemic vasoactivity but also with the highest incidence of adverse events. In this model, the transient nature of NaNO 2 in off-setting HBOC-201 vasoconstriction makes it less clinically promising than anticipated and the combination of NaNO 2 and HBOC appear to increase the risk of pulmonary complications in a dose-dependent fashion independently of haemodilutional effects on haemostatic components.

AB - Background: Development of Haemoglobin-based oxygen carriers (HBOCs) as blood substitutes has reached an impasse due to clinically adverse outcomes attributed to vasoconstriction secondary to nitric oxide (NO) scavenging. Studies suggest haemoglobin exhibits nitrite reductase activity that generates NO and N 2O 3; harnessing this property may offset NO scavenging. Therefore, the effects of concomitantly infusing sodium nitrite (NaNO 2) with HBOC-201 were investigated. Methods: Swine underwent uncontrolled liver haemorrhage before receiving up to three 10 min 10 ml/kg infusions of HBOC-201 (HBOC) with or without concurrent NaNO 2 (5.4 μmol/kg [LD NaNO 2] or 10.8 μmol/kg [HD NaNO 2]) or 6% Hetastarch (HEX) with or without HD NaNO 2 during "prehospital" resuscitation (15, 30 and 45 min after injury). Definitive surgical care occurred at 75 min; anaesthetic recovery at 120 min. Animals were euthanised at 72 h. Results: NaNO 2 temporarily reduced systemic and pulmonary blood pressure increases from HBOC in a dose-dependent fashion. There was no significant effect between groups in indices of tissue oxygenation or survival. Adverse clinical signs requiring humane euthanasia occurred with highest frequency after HBOC + HD NaNO 2 (3 of 4 pigs) and HBOC + LD NaNO 2 (2 of 4 pigs). Gross evidence of pulmonary congestion was observed in 5 of 8 swine receiving a HBOC and NaNO 2 combination compared to 1 of 16 swine receiving HBOC alone, HEX alone, or HEX + NaNO 2. Gross lesions correlated with histological evidence of pulmonary oedema and congestion, and in 2 of 4 HBOC + HD NaNO 2 pigs, pulmonary fibrin thrombi also were found. No other pig had similar evidence of thrombi. Asymmetric pre-resuscitation cardiac index was a potential confounder. Conclusions: A significant interaction between NaNO 2 and HBOC-201 ameliorated HBOC-201 vasoconstrictive effects, consistent with HBOC possessing a nitrite reductase activity that generates vasodilator NO equivalents. Results were relatively equivalent in survival and markers of tissue oxygenation. The highest dose of NaNO 2 was the most effective in reducing HBOC-associated pulmonary and systemic vasoactivity but also with the highest incidence of adverse events. In this model, the transient nature of NaNO 2 in off-setting HBOC-201 vasoconstriction makes it less clinically promising than anticipated and the combination of NaNO 2 and HBOC appear to increase the risk of pulmonary complications in a dose-dependent fashion independently of haemodilutional effects on haemostatic components.

KW - Blood substitute

KW - Emergency medicine

KW - HBOC

KW - Haemorrhagic shock

KW - Nitrite

KW - Oxygen therapeutic

KW - Resuscitation

KW - Transfusion

KW - Vasoactivity

UR - http://www.scopus.com/inward/record.url?scp=84859428480&partnerID=8YFLogxK

U2 - 10.1016/j.injury.2010.10.013

DO - 10.1016/j.injury.2010.10.013

M3 - Article

C2 - 21094491

AN - SCOPUS:84859428480

SN - 0020-1383

VL - 43

SP - 638

EP - 647

JO - Injury

JF - Injury

IS - 5

ER -

The effect HBOC-201 and sodium nitrite resuscitation after uncontrolled haemorrhagic shock in swine

Abstract

Keywords

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