The HCK/BTK inhibitor KIN-8194 is active in MYD88-driven lymphomas and overcomes mutated BTKCys481 ibrutinib resistance.

Activating mutations in MYD88 promote malignant cell growth and survival through hematopoietic cell kinase (HCK)-mediated activation of Bruton tyrosine kinase (BTK). Ibrutinib binds to BTKCys481 and is active in B-cell malignancies driven by mutated MYD88. Mutations in BTKCys481, particularly BTKCys481Ser, are common in patients with acquired ibrutinib resistance. We therefore performed an extensive medicinal chemistry campaign and identified KIN-8194 as a novel dual inhibitor of HCK and BTK. KIN-8194 showed potent and selective in vitro killing of MYD88-mutated lymphoma cells, including ibrutinib-resistant BTKCys481Ser-expressing cells. KIN-8194 demonstrated excellent bioavailability and pharmacokinetic parameters, with good tolerance in rodent models at pharmacologically achievable and active doses. Pharmacodynamic studies showed sustained inhibition of HCK and BTK for 24 hours after single oral administration of KIN-8194 in an MYD88-mutated TMD-8 activated B-cell diffuse large B-cell lymphoma (ABC DLBCL) and BCWM.1 Waldenström macroglobulinemia (WM) xenografted mice with wild-type BTK (BTKWT)- or BTKCys481Ser-expressing tumors. KIN-8194 showed superior survival benefit over ibrutinib in both BTKWT- and BTKCys481Ser-expressing TMD-8 DLBCL xenografted mice, including sustained complete responses of >12 weeks off treatment in mice with BTKWT-expressing TMD-8 tumors. The BCL_2 inhibitor venetoclax enhanced the antitumor activity of KIN-8194 in BTKWT- and BTKCys481Ser-expressing MYD88-mutated lymphoma cells and markedly reduced tumor growth and prolonged survival in mice with BTKCys481Ser-expressing TMD-8 tumors treated with both drugs. The findings highlight the feasibility of targeting HCK, a key driver of mutated MYD88 pro-survival signaling, and provide a framework for the advancement of KIN-8194 for human studies in B-cell malignancies driven by HCK and BTK.

Carbachol promotes gastrointestinal function during oral resuscitation of burn shock.

AIM: To investigate the effect of carbachol on gastrointestinal function in a dog model of oral resuscitation for burn shock. METHODS: Twenty Beagle dogs with intubation of the carotid artery, jugular vein and jejunum for 24 h were subjected to 35% total body surface area full-thickness burns, and were divided into three groups: no fluid resuscitation (NR, n = 10), in which animals did not receive fluid by any means in the first 24 h post-burn; oral fluid resuscitation (OR, n = 8), in which dogs were gavaged with glucose-electrolyte solution (GES) with volume and rate consistent with the Parkland formula; and oral fluid with carbachol group (OR/CAR, n = 8), in which dogs were gavaged with GES containing carbachol (20 µg/kg), with the same volume and rate as the OR group. Twenty-four hours after burns, all animals were given intravenous fluid replacement, and 72 h after injury, they received nutritional support. Hemodynamic and gastrointestinal parameters were measured serially with animals in conscious and cooperative state. RESULTS: The mean arterial pressure, cardiac output and plasma volume dropped markedly, and gastrointestinal tissue perfusion was reduced obviously after the burn injury in all the three groups. Hemodynamic parameters and gastrointestinal tissue perfusion in the OR and OR/CAR groups were promoted to pre-injury level at 48 and 72 h, respectively, while hemodynamic parameters in the NR group did not return to pre-injury level till 72 h, and gastrointestinal tissue perfusion remained lower than pre-injury level until 120 h post-burn. CO(2) of the gastric mucosa and intestinal mucosa blood flow of OR/CAR groups were 56.4 ± 4.7 mmHg and 157.7 ± 17.7 blood perfusion units (BPU) at 24 h post-burn, respectively, which were significantly superior to those in the OR group (65.8 ± 5.8 mmHg and 127.7 ± 11.9 BPU, respectively, all P < 0.05). Gastric emptying and intestinal absorption rates of GES were significantly reduced to the lowest level (52.8% and 23.7% of pre-injury levels) in the OR group at about 2 and 4 h post-burn, and did not return to 80% of pre-injury level until 24 h. In the first 24 h post-burn, the rate of gastric emptying and intestinal water absorption were elevated by a mean 15.7% and 11.5%, respectively, in the OR/CAR group compared with the OR group. At 5 days, the mortality in the NR group was 30% (3/10), 12.5% in the OR group (1/8), and none in the OR/CAR group. CONCLUSION: Carbachol had a beneficial effect on oral resuscitation of burn shock by promoting gastric emptying and intestinal absorption in our canine model.

[Carbachol improve oxygen dynamic parameters during orally fluid resuscitation of a 50% TBSA full-thickness burn in dogs].

OBJECTIVE: To investigate the effect of carbachol(CAR) on oxygen dynamic parameters and hyperlactacidemia during oral fluid resuscitation of burn shock. METHODS: Twelve male Beagle dogs were surgically prepared for cannulation of carotid and jugular vein, and enterostomy, 24 hours later they were subjected to a 50% (total body surface area, TBSA) full-thickness flame injury under a 10-15 minute anesthesia by IV injection of propofol. The dogs were randomized to gastric fluid infusion group (GI group)and gastric fluid infusion plus CAR group (GI + CAR). Either a glucose-electrolyte solution(GES) or GES containing CAR (20 microg/kg) were intragastricly given to animals in GI group or GI+ CAR groups. The delivery rate and volume of GES was in accordance with that of Parkland formula. Mean arterial pressure (MAP), intestinal mucosal blood flow (IMBF) and blood lactic acid were determined, and blood gas analysis evaluated for oxygen delivery (DO2), oxygen consumption (VO2) and oxygen uptake (O2ext) at 0, 2, 4, 8, 24, 48 and 72 hours after injury. RESULTS: The levels of MAP and IMBF markedly reduced, and LAC obviously increased in both groups after burn. MAP returned to 0 h level at 72 h post burn, while IMBF, and LAC were still higher or lower than 0 h levels. The level of MAP of GI + CAR group was significantly higher than that of GI group at 2 h, and those showed no significant differences between two groups after then. Carbochol administration led to a markedly higher levels of IMBF, and significant lower levels of LAC from 8 h after burn compared with those of GI group (P < 0.05 or P < 0.01). The levels of DO2 VO2 and Oext were reduced markedly after burn in both groups. At 72 h after burn, DOQ returned to 0 h level; while VO2 and Oext though still much lower than 0 h levels. The level of DO2. VO2 and Oext of GI + CAR group were significantly higher than those of GI group from 8 h after burn (P < 0.05 or P < 0.01). Three of six animals died in GI+ CAR group, which was lower than two of six in GI group. CONCLUSION: The results indicates that carbachol promotes intragastric fluid resuscitative effect of burn shock by increasing oxygen delivery and decreasing hyperlactacidemia.

[Influence of enteral administration of hypertonic electrolyte glucose solution on the intestinal barrier and organ functions in dogs with severe burn].

OBJECTIVE: To study the change in intestinal barrier and organ functions of burned dog after enteral administration of hypertonic electrolyte glucose solution (HEGS) in shock stage. METHODS: Twenty-four Beagle dogs inflicted with 35% TBSA full-thickness burn were divided into no-fluid group (NF), intravenous infusion with isotonic electrolyte glucose solution (IEGS) group (II group), enteral infusion with IEGS group (EI), and enteral infusion with HEGS group (EH) according to the random number table, with 6 dogs in each group. Saline, containing 50 g/L glucose, was intravenously or enterally infused into dogs in II group and EI group respectively 0.5 hour post injury (PIH) for resuscitation. Total infusion volume within PIH 24 was 4 mL x kg(-1) x %TBSA(-1) (half of the total volume was infused in the first 8 hours in a constant speed, the other half volume was infused in the rest 16 hours in a constant speed). HEGS, containing 18 g/L NaCl and 50 g/L glucose, was enterally infused into dogs in EH group. Total infusion volume within PIH 24 was 2 mL x kg(-1) x %TBSA(-1), with the same infusion speed as that in II and EI groups. Liver and kidney function indexes [activity of ALT and CK-MB, expression levels of creatinine and blood urea nitrogen (BUN) in serum], activity of diamine oxidase (DAO), and activity of Na(+)-K(+)-ATPase in intestinal mucosa at PIH 24 were determined. RESULTS: ALT activity in each group was close to one another. Serum levels of creatinine and BUN in II, EI, and EH groups were significantly lower than those in NF group. CK-MB activity obviously increased at PIH 2 in every group. CK-MB activity in EH group at PIH 2 to 8 was respectively lower than that in NF and II groups. DAO activity in serum in II, EI, and EH groups decreased since PIH 4 or PIH 6, respectively from (3.9 + or - 0.6) U/L to (3.6 + or - 0.5) U/L, (4.8 + or - 0.4) U/L to (2.8 + or - 0.8) U/L, (6.4 + or - 1.8) U/L to (3.5 + or - 0.8) U/L, all were significantly lower than those in NF group [from (12.5 + or - 0.4) U/L to (9.7 + or - 1.1) U/L, comparison between EH group and NF group, t value at PIH 4, 6, 8, 24 was respectively 10.25, 12.44, 17.99, 16.21, P values all below 0.05]. The order of Na(+)-k(+)-ATPase activity in intestinal mucosa at PIH 24 in each group from high to low was II group, EH group, EI group, and NF group (comparison between former 3 groups and NF group, t value was respectively 10.09, 4.96, 8.32, F value was 26.79, P values all below 0.05). CONCLUSIONS: HEGS does not cause significant harm to the barrier function of intestinal mucosa of shock dog after burn. Compared with NF, HEGS can significantly improve functions of heart, liver, and kidney, and it can achieve the same resuscitation effect as enteral or intravenous infusion of IEGS with only half of the solution volume.

[Effect of oral fluid resuscitation on pulmonary vascular permeability and lung water content in burn dogs in shock stage].

OBJECTIVE: To investigate the effect of oral fluid resuscitation on pulmonary vascular permeability and lung water content in burn dogs during shock stage. METHODS: Eighteen male Beagle dogs with catheterization of carotid artery and jugular vein for 24 hours were subjected to 50% TBSA full-thickness burn, then they were divided into non-fluid resuscitation (NR), oral fluid resuscitation (OR), intravenous fluid resuscitation (IR) groups, with 6 dogs in each group. Dogs in OR and IR groups were given glucose-electrolyte solution (GES) by gastric tube or intravenous infusion according to Parkland formula within 24 hours after burn, while those in NR group were not given any treatment. Dogs in each group were then given intravenous fluid for further resuscitation after 24 post burn hours (PBH). Deaths were recorded within 72 hours after burn. Mean arterial pressure (MAP), respiratory rate (RR), PaO2, extravascular lung water index (ELWI) and pulmonary vascular permeability index (PVPI) were determined before burn and at 30 mins and 4, 8, 24, 48, 72 PBH with the aid of PICCO. Dogs were sacrificed to collect lung tissue for determination of water content at 72 PBH or just before death. RESULTS: All dogs died during 9-22 PBH in NR group, 3 dogs died during 25-47 PBH in OR group, and all dogs survived within 72 PBH in IR groups. Compared with those before burn, RR (44.0 +/- 5.0) times/min, ELWI (10.3 +/- 0.6) mL/kg and PVPI (6.6 +/- 0.6) were markedly increased in NR group at 8 PBH, but PaO2 and MAP were obviously decreased (P < 0.05). In OR group, RR (33.0 +/- 4.0) times/min, ELWI (8.9 +/- 0.3) mL/kg and PVPI (5.7 +/- 0.4) were significantly lower than those of NR group (P < 0.05), but higher than those of IR group [RR (26.0 +/- 3.0) times/min, ELWI (8.2 +/-0.3) mL/kg, PVPI (4.2 +/- 0.4), P < 0.05] at 8 PBH. PaO2 and MAP in OR group were higher than that in NR group (P < 0.05). Lung water content showed no statistically significant difference between OR ang IR groups (P > 0.05), which were lower than that in NR group (P < 0.05). CONCLUSIONS: Although the protective effect of oral fluid resuscitation with GES on the lung of burn dog at shock stage was inferior to intravenous fluid, it still can decrease pulmonary vascular permeability, alleviate pulmonary edema, and reduce pulmonary complication compared with no resuscitation with fluids.

[Observation on the effect of vitamin C in alleviating peroxidative damage in gut of dogs during enteral fluid resuscitation of severe burn shock].

OBJECTIVE: To investigate the effect of vitamin C (VC) on alleviating peroxidative damage in gut of dogs during enteral fluid resuscitation of severe burn shock. METHODS: Eighteen male Beagle dogs were subjected to 50% total body surface area (TBSA) full-thickness burn 24 hours after duodenostomy and cannulation of cervical artery and vein. The dogs were divided into no resuscitation (NR) group (no treatment after burn), enteral resuscitation (ER) group, and ER+VC group according to the random number table, with 6 dogs in each group. Dogs in ER and ER+VC groups were respectively infused with glucose-electrolyte solution (GES) and GES containing 250 mg/kg VC through duodenostomy tube 30 minutes after burn. The infusion rate and volume of GES were in accordance with Parkland formula. Venous blood of dogs was drawn before (0) and at 2, 4, 6, and 8 post burn hours (PBH) to determine the activity of diamine oxidase (DAO) in plasma. Dogs were sacrificed at PBH 8 to collect specimens of jejunum tissue for determining the content of malondialdehyde (MDA), and activity of myeloperoxidase (MPO), xanthine oxidase (XOD) and superoxide dismutase (SOD), and assessment of the water ratio of intestinal tissue by dry-wet weight method. RESULTS: 50% TBSA burn injury resulted in significant elevation of DAO in every group. The activity of DAO in ER group was obviously higher than that in NR group at PBH 6 and 8 (P < 0.05), but DAO activity in ER+VC group was significantly lower than those in the other two groups after PBH 2 (P < 0.05 or P < 0.01). MDA content, MPO and XOD activity and the water ratio of intestinal tissue [(5.74 +/- 0.51) nmol/mg, (2.08 +/- 0.46) U/g, (58.4 +/- 3.8) U/mg, (81.5 +/- 1.8)%] in ER group at PBH 8 was respectively significantly higher than that in NR group [(5.43 +/- 0.25) nmol/mg, (1.55 +/- 0.21) U/g, (50.1 +/- 2.8) U/mg, (78.3 +/- 1.5)%, P < 0.05 or P < 0.01]. While the activity of SOD in ER group (72 +/- 12) U/mg was lower than that in NR group (97 +/- 20) U/mg. MDA content, MPO and XOD activity and water ratio of intestinal tissue in ER+VC group was respectively lower than that in ER group, with activity of SOD in the former group higher than that in the latter group (P < 0.01). CONCLUSIONS: Vitamin C can alleviate peroxidative damage and tissue edema in gut induced by ischemia and reperfusion, and intestinal complications during oral rehydration during burn shock can be reduced.

[The curative effect of 1.8% hypertonic electrolyte glucose solution in enteral resuscitation of burn shock].

OBJECTIVE: To study the resuscitative effect of hypertonic electrolyte glucose solution (HEGS) in enteral resuscitation of burn shock. METHODS: Eighteen Beagle dogs with 35% TBSA full-thickness flame injury were used in this study. They were randomized to a control group (no-fluid resuscitation, N group), a HEGS resuscitation group (H group) or an isotonic electrolyte glucose solution (IEGS) resuscitation group (I group). The solution enterally was given for resuscitation from half an hour after burn. The volumes and rates of fluid infusion in the H group were basically in accordance with 2 ml/(kg x 1%TBSA), those in the I group were basically in accordance with parkland formula [4 ml/(kg x 1%TBSA)]. The haemodynamic parameters, global end-diastolic volume index, plasma volume, osmotic pressure of plasma, intestinal absorptive rates of water and Na(+), and intestine mucosa blood flow were continuously assessed. RESULTS: The cardiac output index, global end-diastolic volume index, plasma volume and intestine blood mucosa flow reduced markedly after burn in the three groups, and then gradually returned from 2 h after burn in two resuscitation groups, which were higher than that in the N group (P < 0.05). The activities of diamine oxidase in plasma in the two resuscitation groups were higher than that in N group (P < 0.05). The intestinal absorption rates of water and Na(+) reduced markedly after burn in two resuscitation groups with the lowest levels, and then returned from 6 h after burn. The rates of water in H group were lower than that in I group (P < 0.05); the rates of Na(+) in H group were higher than in I group (P < 0.05). CONCLUSION: The results indicated that 35%TBSA III degrees burn-injury dogs be resuscitated effectively with 1.8% hypertonic electrolyte-glucose solution by enteral, which 1/2 volume of an isotonic electrolyte glucose solution.

[Effects of early oral fluid resuscitation on hemodynamic and tissue perfusion during shock stage in dogs with a 50% total body surface area full-thickness burn.].

OBJECTIVE: To investigate the effect of early oral fluid resuscitation on hemodynamic and tissue perfusion in dogs with severe burn shock. METHODS: Eighteen male Beagle dogs with intubation of carotid artery, jugular vein, stomach, jejunum and bladder for 24 h were subjected to a 50%TBSA full-thickness burn, then were equally divided into non fluid resuscitation (NR), oral resuscitation (OR) and intravenous resuscitation(IR) groups, (each n = 6). Dogs in IR and OR groups were given glucose-electrolyte solution (GES) by gastric tube or intravenous infusion according to Parkland formula within 24 h after burn, while those in NR group were not given any treatment. Dogs in each group were given intravenous fluid resuscitation from 24 h after burn. The mean arterial pressure (MAP), cardiac output (CO), systemic vascular resistance (SVR), dp/dt max of left ventricular contractility (dp/dt(max)), gastric carbon dioxide pressure (PgCO2), intestinal mucosal blood flow (IMBF), and urinary output were determined before burn (0 h) and 2, 4, 8, 24, 48 and 72 h after burn at no anaesthesia state. Mortality rate of 72 h after burn was also recorded. RESULTS: MAP, CO, dp/dt(max), IMBF greatly decreased, and SVR and PgCO2 obviously increased from 2 h after burn in each group (P < 0.01). The measurements except IMBF of IR group returned to pre-injury levels at 72 h after burn, while CO, SVR, PgCO2 and IMBF of OR group still worse compared with 0 h (P < 0.01). All measurements of NR group kept on worsen, and died with anuria within 24 h after burn. Parameters of hemodynamic and tissue perfusion of OR group were significantly superior to those of NR group, but it inferior to those of IR group. At 72 h after burn, 6 (6/6) survived in IR group, 3 (3/6) in OR group and 0 (0/6) in NR group. CONCLUSIONS: Although oral resuscitation with GES is not as efficient as intravenous resuscitation in a 50%TBSA burn injury, it still can promote hemodynamic, improve the tissue perfusion and reduce the mortality comparing to no resuscitation. Oral resuscitation might be an ideal alternative way of intravenous resuscitation, especially in wars or other site of mass casualties.

[Vitamin alleviates visceral lipid peroxidative injury in dogs during oral fluid resuscitation of burn shock].

OBJECTIVE: To investigate the effect of vitamin C (VC) on visceral lipid oxidative injury during oral fluid resuscitation of burn shock. METHODS: Twelve male Beagle dogs were surgically prepared for arterial and venous cannulation, and 24 hours later they were subjected to a 50% TBSA full-thickness flame injury. In the first 24 hours after burn dogs were resuscitated with gastric infusion of either glucose-electrolyte solution (GES group, n = 6) or GES containing 250 mg/kg of VC (GES/VC group, n = 6). The delivery rate and volume of GES was in accordance with that of Parkland formula (4 ml x kg(-1) x 1% TBSA(-1) in the first 24 hours). In the second 24 hours all animals received delayed i.v. fluid resuscitation. At end of 72 hours after injury, animals were sacrificed, and specimens of heart, lung, liver, kidney and jejunum were harvested for evaluation of xanthine oxidase (XOD), malondialdehyde (MDA) and assessment of the tissue water content (ratio of dry to wet weight) of organs. The plasma levels of alanine aminotransferase (ALT), creatinine (Cr), MB isoenzyme of creatine kinase (CK-MB) and diamine oxidase (DAO) were determined at same time. RESULTS: At 72 hours after burn it was showed significant higher activities of XOD in GES/CAR than GES group in heart, kidney and jejunum, and lower contents of MDA in heart, lung, liver, kidney and jejunum (P all < 0.01). Tissue water contents were significantly lower in GES/CAR than GES group in heart [(75.4 +/-1.1)% vs (78.5 +/- 0.8)%], lung [(68.1 +/- 0.9)% vs (73.9 +/- 1.0)%], liver [ (75.2 +/- 0.8)% vs (78.3 +/- 1.2)%], kidney [(73.8 +/- 1.1)% vs (78.1 +/- 0.8)%] and jejunum [(76.3 +/- 0.8)% vs ( 80.4 +/- 0.6)] respectively, all P < 0.01. The levels of ALT, CK-MB, Cr and DAO in GES/CAR group were (46.6 +/- 2.49) U/L, (43.4 +/- 7.05) mol/L, (7156 +/- 596) U/L and (1.86 +/- 0.45) U/L respectively, all significantly lower than those of the GES group [(86.9 +/- 7.89) U/L, (95.2 +/- 1.23) mol/L, (8023 +/- 384) U/L and (2.68 +/- 0.61) U/L respectively, all P < 0.05]. CONCLUSION: The results indicated that vitamin C alleviated visceral tissue edema and organ injury by inhibiting free radical production during oral fluid resuscitation of burn shock.

[Study on intestinal absorption rate of glucose electrolyte solution during enteral resuscitation of 35% total body surface area burn injury in dog].

OBJECTIVE: To investigate the intestinal absorption rate of glucose-electrolyte solution (GES) during enteral resuscitation of burn injury in Beagle dogs, and compare the effect of enteral intake with that of intravenous infusion resuscitation. METHODS: Twelve male Beagle dogs were subjected to a 35% total body surface area (TBSA) full-thickness flame III degree injury. Thirty minutes after burn, each dog was given either enteral resuscitation with a GES (EGES group) or intravenous resuscitation with lactated Ringer's solution (IVLR group), and the amount and speed of replenishment of fluid were in accordance with Parkland formula. In the first 8 hours post burn, intestinal absorption rates of water and Na+ were continuously assessed using phenol red as a nonabsorbable marker for water absorption rate. The plasma volume (PV) was measured by the dye (indocyanine green) dilution technique, and the plasma concentration of Na+, mean arterial pressure (MAP) cardiac output (CO), and urine volume were also determined in the first 8 hours. All above measurement were performed in animals without anesthesia. At the end of 8-hour-period of experiment, the remnant fluids in the intestine were collected to calculate the total volume of fluid absorbed in 8 hours. RESULTS: The intestinal absorption rates of water and Na+ reduced markedly down to lowest level (21% and 37% of pre-injury level) at 3.5 hours post burn, and then increased slowly. But the mean absorption rate of water was similar to infusing rate according to Parkland formula [(99+/-47) mlxh(-1)xm(-1) vs. (81+/-11) mlxh(-1)xm(-1), P>0.05]. The total fluid absorbed by intestine was (94.8+/-3.7)% of the total fluid infused within 8 hours post burn. There were no significant differences in plasma concentration of Na+, MAP and CO between two groups at 8 hours post burn. The urine volume and PV at 4 hours in EGES group were lower than those in IVLR group (both P<0.05), but those indexes at 8 hours showed no significant difference between two groups (both P>0.05). CONCLUSION: Intestinal absorption rate of fluid given according to Parkland formula after burn injury is sufficient to resuscitate shock in animals suffering from a 35%TBSA full-thickness burn. Enteral resuscitation with GES may attain a similar therapeutic effect in expanding PV and maintain hemodynamic parameters.

[Effect of carbachol on intestinal mucosa blood flow and absorption rate of glucose-electrolyte solution during enteral resuscitation for 50% total body surface area full-thickness burn injury in dog].

OBJECTIVE: To investigate the effect of carbachol (CAR) on blood flow of intestinal mucosa and absorption rate of glucose-electrolyte solution (GES) during enteral resuscitation of burn shock in dog. METHODS: Eighteen male Beagle dogs were subjected to a (51.2+/-2.6)% total body surface area (TBSA) full-thickness flame injury, and fluid resuscitation was given according to Parkland formula 0.5 hour after burn. Animals were randomly divided into intravenous infusion of GES group (VGES group, n=6), enteral infusion of GES group (EGES group, n=6) and EGES containing 0.25 microg/kg of CAR group (EGES/CAR group n=6). In the first 8 hours post burn, intestinal absorption rate of water and Na+, intestinal mucosa blood flow (IBF), the plasma volume (PV) and plasma concentration of Na+ were continuously determined without anesthesia. At the end of 8 hours animals were sacrificed, and specimens of gut tissue were taken to determine the activity of Na+-K+-ATPase. RESULTS: The intestinal absorption rate of water and Na+ was reduced markedly after burn in two enteral resuscitation groups and much lower than pre-injury levels and the expected infusing rate according to Parkland formula. It was found that the absorption rate of water and Na+ from 1.5 hours and 2.5 hours in EGES/CAR group were significantly higher compared with those in EGES group (all P<0.05). During 8 hours after burn, only 47.1% and 63.8% of fluids enterally infused in EGES and EGES/CAR groups were absorbed by the gut. The volume of fluid absorbed and the fluid absorption rate were significantly higher in EGES/CAR group than those in EGES group (P<0.05). Incidence of gut intolerance (diarrhea) was 83% in EGES group, which was higher than that of in EGES/CAR group (50%). IBF was significantly decreased compared with pre-injury levels in all groups. Enteral infusion of CAR led to a significant elevation of IBF in EGES/CAR compared with GES group from 4 hours after burn, but it was still lower than pre-injury levels and those in VGES group. The Na+-K+-ATPase activity between three groups ranked as follows: VGES group>EGES/CAR group>EGES group (P<0.05). Within 8 hours post injury, PV and plasma concentration of Na+ in two enteral resuscitation groups were much lower than those in VGES group, but from 4 hours after burn the values in EGES/CAR group were higher than those in EGES group (all P<0.05). CONCLUSION: 50%TBSA full-thickness flame injury led to a markedly decrease in intestinal absorption rate of water and Na+. The total volume of fluid absorbed by intestine in 8 hours was significantly lower in enteral resuscitation groups compared to the regime of the Parkland formula. CAR promoted intestinal absorption rate and PV by increasing the intestinal blood flow and Na+-K+-ATPase activity, and it seems to exert a helpful effect on the resuscitation of burn shock with electrolyte solution per oral route.

[Effect of carbachol on gastric emptying and gastric mucosa partial pressure of carbon dioxide in oral resuscitation of burn shock with a glucose-electrolyte solution in dogs].

OBJECTIVE: To investigate the effect of carbachol (CAR) on gastric emptying and gastric mucosa partial pressure of carbon dioxide (PgCO2) in the resuscitation of burn shock with oral administration of glucose-electrolyte solution (GES) in dogs. METHODS: Twenty-four adult male Beagle dogs were randomly divided into 4 groups: 35% total body surface area (TBSA) III degree burn resuscitated with oral GES (35% TBSA GES, n=6), 35% TBSA III degree burn with oral GES containing 20 microg/kg of CAR (35% TBSA GES/CAR, n=6), 50% TBSA III degree burn with oral GES (50% TBSA GES, n=6) and 50% TBSA III degree burn with oral GES containing 20 microg/kg of CAR (50% TBSA GES/CAR, n=6). Dogs were subjected to 35% TBSA or 50% TBSA full-thickness flame injury respectively. Thirty minutes after burn, dogs were given GES or GES containing CAR according to Parkland formula (1/2 of 4 mlxkg(-1)x1% TBSA(-1) within 8 hours post burn, and the remaining 1/2 within next 16 hours post burn) by gavage. The gastric emptying rate, PgCO2 and intolerance symptoms were determined at 2, 4, 8 and 24 hours post burn. RESULTS: The gastric emptying rate was significantly decreased in all groups after the burn (P<0.05), and it was 51.5% at 2 hours after burn in 35% TBSA GES group and 39.2% at 4 hours after burn in 50% TBSA GES group. It was gradually ameliorated, but still much lower than pre-injury levels (both P<0.05). The gastric emptying rate in GES/CAR group were significantly higher at all time points after injury than those in 35% GES group (P<0.05), and it was higher than that in 50% GES group at 8 hours and 24 hours (both P<0.05). The gastric emptying rate restored to pre-injury levels (P>0.05) in 35% GES/CAR group, and it was still lower than pre-injury level in 50% GES/CAR group (P<0.05). The PgCO2 were significantly elevated in all groups post burn (all P<0.05), and could not return to pre-injury levels. The PgCO2 in GES/CAR group were significantly higher at all time points after injury than those in 35% GES group (P<0.05), and it was higher than that in 50% GES group at 4 hours and 24 hours (P<0.05). The degree of gastric intolerance symptoms could be ranked as follows: 50%TBSA GES group (83.3%, 5/6)>50% TBSA GES/CAR group (50.0%, 3/6)>35%TBSA GES group (16.7%, 1/6)>35%TBSA GES/CAR group (0, 0/6). CONCLUSION: The results indicate that CAR has a significant effect in improving gastric emptying and gastric ischemia during oral resuscitation of burn shock with a glucose electrolyte solution.

[Effects of early oral fluid resuscitation on organ functions and survival during shock stage in dogs with a 50% total body surface area full-thickness burn].

OBJECTIVE: To investigate the effects of early oral fluid resuscitation on organ functions and survival in severe burn shock. METHODS: Eighteen male Beagle dogs were surgically prepared for measurement, subjected to 50% total body surface area (TBSA) full-thickness flame injury 24 hours later, and then randomly divided into 3 equal groups: oral fluid resuscitation group (OR group) undergoing gastric infusion of glucose-electrolyte solution(GES)according to Parkland formula 0.5 hour after burn with the dose of 4 ml x kg(-1).%TBSA(-1), 1/2 being given in the first 8 h and 1/2 in the latter 16 h. Intravenous (IV) resuscitation of GES group (VR group) undergoing IV infusion of GES with the same dose as mentioned above, and no fluid resuscitation (NR) group given with GES during the first 24 h. In the second 24 hours all dogs received IV fluid resuscitation. At the end of 72-hours-period experiment, the mortality was recorded. The mean arterial pressure (MAP), plasma blood volume (PV), hematocrit (HCT), urinary output, alanine aminotransferase (ALT), creatinine (Cr), and MB isoenzyme of creatine kinase (CK-MB) were examined before injury and at 2, 4, 8, 24, 48 and 72 hours after injury. RESULTS: At the end of 72-hours-period experiment, all dogs died in the NR group, 3 dogs died in the OR group, and no dog died in the VR group. The MAP and PV were significantly reduced after burn compared with those before-injury in the NR group, with the lowest levels of (34 +/- 9) mm Hg and (32.7 +/- 3.5) ml/kg (both P < 0.05) 8 h after burn, and the HCT, ALT, Cr, and CK-MB levels of the NR group peaked 8 h after burn to the levels of (61.7 +/- 2.7)%, (121.1 +/- 4.8) U/L, (91.0 +/- 6.1) micromol/L, and (13 891 +/- 297) U/L respectively. Eight hours after burn 4 dogs of the NR group showed anuria, and the rest two had the urine volume of 1.2 and 2.1 ml/kg respectively. Eight hours after burn the MAP, PV, and urinary output levels of the OR group were (84.3 +/- 17.1) mm Hg, (41.7 +/- 3.6) ml/kg, and (2.6 +/- 1.8) ml/kg respectively, all significantly higher than those of the NR group (all P < 0.05), but significantly lower than those of the VR group [(113.0 +/- 10.0) mm Hg, (50.3 +/- 5.2) ml/kg, and (7.0 +/- 1.9) ml/kg respectively, all P < 0.05]. The plasma ALT level of the OR group was (81.4 +/- 10.8) U/L, significantly lower than that of the NR group (P < 0.05), but significantly higher than that of the VR group [(66.3 +/- 7.6) U/L, P < 0.05]. The levels of plasma ALT at other time points, as well as the Cr and CK-MB levels at all time points of the OR group were all significantly higher than those of the VR group (all P < 0.05). The MAP, PV, HCT and urinary output levels of the two resuscitation groups returned to the pre-injury levels 72 h after burn, but the ALT, Cr, and CK-MB levels were still significantly higher than the pre-injury levels. CONCLUSIONS: Although oral resuscitation with GES is not as efficient as IV resuscitation in 50%TBSA burn, it still can maintain the MAP and PV, protect the organ functions and reduce the mortality comparing to no resuscitation. Oral resuscitation may be an ideal alternative way of IV resuscitation, especially in wars or other site of mass casualties.