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Effects of terlipressin as early treatment for protection of brain in a model of haemorrhagic shock.

Ida KK, Otsuki DA, Sasaki AT, Borges ES, Castro LU, Sanches TR, Shimizu MH, Andrade LC, Auler JO, Dyson A, Smith KJ, Rocha Filho JA, Malbouisson LM - Crit Care (2015)

Bottom Line: Despite the HS-induced decrease in cardiac output (CO) and hyperlactataemia, resuscitation with terlipressin recovered MAP and resulted in restoration of CPP and in cerebral protection expressed by normalisation of AQP4, NKCC1, TBARS and MnSOD expression and Bcl-x/Bax ratio at T60 and T120 compared with sham animals.In the LR group, CO and blood lactate levels were recovered, but the CPP and MAP were significantly decreased and TBARS levels and AQP4, NKCC1 and MnSOD expression and Bcl-x/Bax ratio were significantly increased at T60 and T120 compared with the sham group.During recovery from HS-induced hypotension, terlipressin was effective in normalising CPP and cerebral markers of water balance, oxidative damage and apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Laboratório de Investigação Médica (LIM-08), Disciplina de Anestesiologia, Faculdade de Medicina, Universidade de São Paulo, Avenida Doutor Arnaldo, 455, 2° andar, sala 2120, Cerqueira César, São Paulo, SP, 01246-903, Brazil. keilaida@usp.br.

ABSTRACT

Introduction: We investigated whether treatment with terlipressin during recovery from hypotension due to haemorrhagic shock (HS) is effective in restoring cerebral perfusion pressure (CPP) and brain tissue markers of water balance, oxidative stress and apoptosis.

Methods: In this randomised controlled study, animals undergoing HS (target mean arterial pressure (MAP) 40 mmHg for 30 minutes) were randomised to receive lactated Ringer's solution (LR group; n =14; volume equal to three times the volume bled), terlipressin (TERLI group; n =14; 2-mg bolus), no treatment (HAEMO group; n =12) or sham (n =6). CPP, systemic haemodynamics (thermodilution technique) and blood gas analyses were registered at baseline, shock and 5, 30, 60 (T60), 90 and 120 minutes after treatment (T120). After the animals were killed, brain tissue samples were obtained to measure markers of water balance (aquaporin-4 (AQP4)), Na(+)-K(+)-2Cl(-) co-transporter (NKCC1)), oxidative stress (thiobarbituric acid reactive substances (TBARS) and manganese superoxide dismutase (MnSOD)) and apoptotic damage (Bcl-x and Bax).

Results: Despite the HS-induced decrease in cardiac output (CO) and hyperlactataemia, resuscitation with terlipressin recovered MAP and resulted in restoration of CPP and in cerebral protection expressed by normalisation of AQP4, NKCC1, TBARS and MnSOD expression and Bcl-x/Bax ratio at T60 and T120 compared with sham animals. In the LR group, CO and blood lactate levels were recovered, but the CPP and MAP were significantly decreased and TBARS levels and AQP4, NKCC1 and MnSOD expression and Bcl-x/Bax ratio were significantly increased at T60 and T120 compared with the sham group.

Conclusions: During recovery from HS-induced hypotension, terlipressin was effective in normalising CPP and cerebral markers of water balance, oxidative damage and apoptosis. The role of this pressor agent on brain perfusion in HS requires further investigation.

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Related in: MedlinePlus

Semiquantitative immunoblotting of membrane fractions prepared from cerebral samples. A densitometric analysis for the expression of aquaporin-4 (AQP4) and Na+-K+-2Cl− co-transporter (NKCC1) in samples from the sham, HAEMO, LR and TERLI groups is shown. Immunoblots reacted with anti-AQP4 revealed a 34 kDa band, and those reacted with anti-NKCC1 revealed a 135 to 170 kDa band. Data are expressed as mean ± standard error. *P <0.05 versus sham group. †P <0.05 versus HAEMO group. ‡P <0.05 versus LR group.
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Fig3: Semiquantitative immunoblotting of membrane fractions prepared from cerebral samples. A densitometric analysis for the expression of aquaporin-4 (AQP4) and Na+-K+-2Cl− co-transporter (NKCC1) in samples from the sham, HAEMO, LR and TERLI groups is shown. Immunoblots reacted with anti-AQP4 revealed a 34 kDa band, and those reacted with anti-NKCC1 revealed a 135 to 170 kDa band. Data are expressed as mean ± standard error. *P <0.05 versus sham group. †P <0.05 versus HAEMO group. ‡P <0.05 versus LR group.

Mentions: At 60 minutes after shock, semiquantitative immunoblot analysis revealed a significant increase in the expression of AQP4 in the HAEMO group (179 ± 12% of sham, P =0.0086), which was not reversed by treatment with LR (196 ± 8% of sham, P =0.0047), but was fully restored by TERLI (125 ± 6% of sham). In the TERLI group, the expression of AQP4 was significantly higher at 60 minutes compared with the HAEMO and LR groups (P =0.0071). At 120 minutes, a significant upregulation of AQP4 was observed only in the LR group (217 ± 37% of sham, P =0.0084), which was significantly higher than in TERLI group (117 ± 19% of sham, P =0.0169) (Figure 3). No significant increase in the expression of NKCC1 was observed in any group at 60 minutes after shock, but NKCC1 expression was significantly increased at 120 minutes in the HAEMO group (237 ± 47% of sham, P =0.0234), which was fully restored by treatment with terlipressin (100 ± 1% of sham, P =0.0270) (Figure 3).Figure 3


Effects of terlipressin as early treatment for protection of brain in a model of haemorrhagic shock.

Ida KK, Otsuki DA, Sasaki AT, Borges ES, Castro LU, Sanches TR, Shimizu MH, Andrade LC, Auler JO, Dyson A, Smith KJ, Rocha Filho JA, Malbouisson LM - Crit Care (2015)

Semiquantitative immunoblotting of membrane fractions prepared from cerebral samples. A densitometric analysis for the expression of aquaporin-4 (AQP4) and Na+-K+-2Cl− co-transporter (NKCC1) in samples from the sham, HAEMO, LR and TERLI groups is shown. Immunoblots reacted with anti-AQP4 revealed a 34 kDa band, and those reacted with anti-NKCC1 revealed a 135 to 170 kDa band. Data are expressed as mean ± standard error. *P <0.05 versus sham group. †P <0.05 versus HAEMO group. ‡P <0.05 versus LR group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4373118&req=5

Fig3: Semiquantitative immunoblotting of membrane fractions prepared from cerebral samples. A densitometric analysis for the expression of aquaporin-4 (AQP4) and Na+-K+-2Cl− co-transporter (NKCC1) in samples from the sham, HAEMO, LR and TERLI groups is shown. Immunoblots reacted with anti-AQP4 revealed a 34 kDa band, and those reacted with anti-NKCC1 revealed a 135 to 170 kDa band. Data are expressed as mean ± standard error. *P <0.05 versus sham group. †P <0.05 versus HAEMO group. ‡P <0.05 versus LR group.
Mentions: At 60 minutes after shock, semiquantitative immunoblot analysis revealed a significant increase in the expression of AQP4 in the HAEMO group (179 ± 12% of sham, P =0.0086), which was not reversed by treatment with LR (196 ± 8% of sham, P =0.0047), but was fully restored by TERLI (125 ± 6% of sham). In the TERLI group, the expression of AQP4 was significantly higher at 60 minutes compared with the HAEMO and LR groups (P =0.0071). At 120 minutes, a significant upregulation of AQP4 was observed only in the LR group (217 ± 37% of sham, P =0.0084), which was significantly higher than in TERLI group (117 ± 19% of sham, P =0.0169) (Figure 3). No significant increase in the expression of NKCC1 was observed in any group at 60 minutes after shock, but NKCC1 expression was significantly increased at 120 minutes in the HAEMO group (237 ± 47% of sham, P =0.0234), which was fully restored by treatment with terlipressin (100 ± 1% of sham, P =0.0270) (Figure 3).Figure 3

Bottom Line: Despite the HS-induced decrease in cardiac output (CO) and hyperlactataemia, resuscitation with terlipressin recovered MAP and resulted in restoration of CPP and in cerebral protection expressed by normalisation of AQP4, NKCC1, TBARS and MnSOD expression and Bcl-x/Bax ratio at T60 and T120 compared with sham animals.In the LR group, CO and blood lactate levels were recovered, but the CPP and MAP were significantly decreased and TBARS levels and AQP4, NKCC1 and MnSOD expression and Bcl-x/Bax ratio were significantly increased at T60 and T120 compared with the sham group.During recovery from HS-induced hypotension, terlipressin was effective in normalising CPP and cerebral markers of water balance, oxidative damage and apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Laboratório de Investigação Médica (LIM-08), Disciplina de Anestesiologia, Faculdade de Medicina, Universidade de São Paulo, Avenida Doutor Arnaldo, 455, 2° andar, sala 2120, Cerqueira César, São Paulo, SP, 01246-903, Brazil. keilaida@usp.br.

ABSTRACT

Introduction: We investigated whether treatment with terlipressin during recovery from hypotension due to haemorrhagic shock (HS) is effective in restoring cerebral perfusion pressure (CPP) and brain tissue markers of water balance, oxidative stress and apoptosis.

Methods: In this randomised controlled study, animals undergoing HS (target mean arterial pressure (MAP) 40 mmHg for 30 minutes) were randomised to receive lactated Ringer's solution (LR group; n =14; volume equal to three times the volume bled), terlipressin (TERLI group; n =14; 2-mg bolus), no treatment (HAEMO group; n =12) or sham (n =6). CPP, systemic haemodynamics (thermodilution technique) and blood gas analyses were registered at baseline, shock and 5, 30, 60 (T60), 90 and 120 minutes after treatment (T120). After the animals were killed, brain tissue samples were obtained to measure markers of water balance (aquaporin-4 (AQP4)), Na(+)-K(+)-2Cl(-) co-transporter (NKCC1)), oxidative stress (thiobarbituric acid reactive substances (TBARS) and manganese superoxide dismutase (MnSOD)) and apoptotic damage (Bcl-x and Bax).

Results: Despite the HS-induced decrease in cardiac output (CO) and hyperlactataemia, resuscitation with terlipressin recovered MAP and resulted in restoration of CPP and in cerebral protection expressed by normalisation of AQP4, NKCC1, TBARS and MnSOD expression and Bcl-x/Bax ratio at T60 and T120 compared with sham animals. In the LR group, CO and blood lactate levels were recovered, but the CPP and MAP were significantly decreased and TBARS levels and AQP4, NKCC1 and MnSOD expression and Bcl-x/Bax ratio were significantly increased at T60 and T120 compared with the sham group.

Conclusions: During recovery from HS-induced hypotension, terlipressin was effective in normalising CPP and cerebral markers of water balance, oxidative damage and apoptosis. The role of this pressor agent on brain perfusion in HS requires further investigation.

Show MeSH
Related in: MedlinePlus