Role of histamine in heartworm extract-induced shock in dogs

OBJECTIVE: To determine whether heartworm (HW) extract-induced shock in dogs is consistent with anaphylactic shock by examining the role of histamine. ANIMALS: 6 mixed-breed dogs (3 without and 3 with HW infections) and 4 specific pathogen-free (SPF) Beagles. PROCEDURE: Four experiments were performed as follows: 1) 6 mixed-breed dogs were treated IV with 2 ml of HW extract, and plasma histamine concentrations were determined; 2) 4 SPF dogs were treated IV with 2 ml of HW extract and examined for shock; 3) sera from 6 dogs of experiment 1 and from 4 SPF dogs of experiment 2 that were obtained before HW extract treatment were tested for heterologous passive cutaneous anaphylaxis (PCA), using rabbits during a sensitization period of 48 to 72 hours; and 4) mast cell degranulation by HW extract was tested, using rat mesentery and canine cultured mast cells. RESULTS: Experiment 1: 6 dogs developed shock, and plasma histamine concentrations increased significantly from 0.3 +/- 0.2 (mean +/- SD) ng/ml before HW extract treatment to 44.6 +/- 68.9 ng/ml at the onset of shock; experiment 2: all SPF dogs developed shock and had an increase in plasma histamine concentrations; experiment 3: sera from mixed-breed dogs without HW infection and from SPF dogs had negative PCA reactions; experiment 4: HW extract degranulated rat mesentery mast cells and released histamine directly from canine mast cells. CONCLUSIONS AND CLINICAL RELEVANCE: Results of our study indicate that an unknown mast cell-degranulating substances contained in HW extract may degranulate mast cells directly, consequently releasing histamine that may participate in the onset of shock in HW extract-induced shock in dogs.     

Hemodynamic alterations in dogs with shock induced by intravenous injection of heartworm extract

To elucidate one way of the shock mechanisms, the hemodynamic alterations were examined in 7 dogs with heartworm (HW) extract-induced shock. The first alteration observed after injection of HW extract was a decrease in right ventricular end-diastolic pressure (RVEDP). After that, left ventricular (LV) end-diastolic pressure, LV systolic pressure, and LV dp/dt fell significantly, followed by a decrease in the cardiac output of all dogs to below the detectable level (1.00 l/min). Since RVEDP depends on blood flow into the right ventricle, the decrease in RVEDP means a reduction in venous return. Therefore, this study showed that the first trigger of a decrease in blood pressure in HW extract-induced shock is the reduction in venous return.     

Tumor necrosis factor activity in the circulation of horses given endotoxin

Serum and plasma from horses injected with endotoxin was examined for cytotoxic activity. Each of the cell lines, L929 and WEHI 164 clone 13, was sensitive to the cytotoxic effects of equine serum; however, a precipitation artifact caused by the use of isopropanol in the WEHI assay limited the use of this assay to samples containing less than 2 mg of protein/ml. In foals treated with a sublethal IV bolus of 5 micrograms of lipopolysaccharide (LPS)/kg and in adult horses given a low-dose continuous infusion of LPS (30 ng/kg/h for 4 hours), cytotoxic activity was detected in all serum or plasma samples taken between 30 minutes and 4 hours after LPS infusion began. In horses given either continuous or bolus LPS infusions, circulating cytotoxic activity peaked at 1 to 2 hours before decreasing sharply. The onset of pyrexia after LPS infusion coincided with the appearance of circulating cytotoxic activity, but the temperature remained high, even after cytotoxic activity disappeared. Treatment of horses with flunixin meglumine (1 mg/kg) appeared to blunt the pyrexic effect of low-dose continuous LPS infusion, but had no significant effect on circulating cytotoxic activity. Incubation of serum samples with an antibody raised against a portion of human tumor necrosis factor (TNF) resulted in the removal of greater than 90% of serum cytotoxicity, suggesting strongly that the cytotoxic activity was attributable to TNF. These findings are consistent with the hypothesis that TNF is an early acting mediator of the effects of endotoxin in the horse.     

Effects of flunixin meglumine on selected clinicopathologic variables, and serum testosterone concentration in stallions after endotoxin administration

Four clinically normal stallions were infused intravenously with endotoxin (LPS) from Escherichia coli 055:B5 at a dose of 0.3 microg/kg b.w. and four stallions were treated with flunixin meglumine (FM) as a single intravenous injection at a dose of 1.1 mg/kg b.w., 5 min after the infusion of LPS. In response to endotoxin infusion, stallions' reaction was fever (increased rectal and scrotal skin temperature), increased heart rate (HR) and leucopenia. Administration of endotoxin also influenced the level of testosterone (decrease at 3-24 h and increase at 48-72 h after LPS administration) in the blood serum. FM treatment prevented an endotoxin-induced increase in rectal and scrotal skin temperature, HR, with no influence on the decrease of leucocytes. Administration of FM only had a significant effect on the latter changes (at 24-72 h) of serum testosterone concentration after addition of endotoxin.     

Endotoxn-induced nonthyroidal illness in dogs

OBJECTIVE: To determine the effects of endotoxin administration on thyroid function test results and serum tumor necrosis factor-alpha (TNF-alpha) activity in healthy dogs. ANIMALS: 6 healthy adult male dogs. PROCEDURES: Serum concentrations of thyroxine (T4), 3,5,3'-triiodothyronine (T3), 3,3'5'-triiodothyronine (rT3), free T4 (fT4), and endogenous canine thyroid stimulating hormone (TSH), and TNF-alpha activity were measured before (day-1; baseline), during (days 0 to 3), and after (days 4 to 24) IV administration of endotoxin every 12 hours for 84 hours. RESULTS: Compared with baseline values, serum T3 concentration decreased significantly, whereas rT3 concentration increased significantly 8 hours after initial endotoxin administration. Serum T4 concentration decreased significantly at 8 and 12 hours after initiating endotoxin administration. Serum T4 concentration returned to reference range limits, then decreased significantly on days 6 to 12 and 16 to 20. Serum fT4 concentration increased significantly at 12, 24, and 48 hours after cessation of endotoxin treatment, compared with baseline values. Serum rT3 concentration returned to reference range, then decreased significantly days 5 and 7 after stopping endotoxin treatment. Serum TNF-alpha activity was significantly increased only 4 hours after initial endotoxin treatment, compared with baseline activity. CONCLUSIONS AND CLINICAL RELEVANCE: Endotoxin administration modeled alterations in thyroid function test results found in dogs with spontaneous nonthyroidal illness syndrome. A decrease in serum T4 andT3 concentrations and increase in serum rT3 concentration indicate impaired secretion and metabolism of thyroid hormones. The persistent decrease in serum T4 concentration indicates that caution should be used in interpreting serum T4 concentrations after resolution of an illness in dogs.     

Effects of lactated Ringer solution and prednisolone sodium succinate on dogs with induced hemorrhagic shock.

Hemorrhagic shock was induced in nonsplenectomized dogs by removing 41% of their blood volume over a 15-minute period. Hemodynamic and metabolic variables were determined prior to and for 3 hours after completion of hemorrhage. One group of 5 dogs was not treated. After the 30-minute sample was collected, a second group of 5 dogs was given lactated Ringer solution (LRS) at 88 ml/kg of body weight, IV. A third group of 5 dogs was given LRS (88 ml/kg, IV) and prednisolone sodium succinate (11 mg/kg, IV) 30 minutes after hemorrhage. The IV administration of LRS was completed within 15 minutes. The glucocorticoid was administered as an IV bolus after 500 ml of LRS had been given. The large volume and administration of LRS significantly (P = 0.05) improved many of the hemodynamic and metabolic effects of acute hemorrhage and hemorrhagic shock. At one time or another during the 2.5-hour observation period after the initiation of treatment, mean arterial pressure, cardiac index, systemic vascular resistance, heart rate, respiratory rate, lactate, glucose, and arterial and venous blood gas values were significantly (P = 0.05) improved, compared with baseline values. The addition of prednisolone sodium succinate to the treatment regimen improved the effectiveness of LRS alone only in some dogs at random sampling times. Significant trends were not observed except, possibly, the improvement of venous pH and A-V pH and PCO2 differences.     

Effects of Lidocaine Infusion during Experimental Endotoxemia in Horses

Background: The clinical efficacy of IV infusion of lidocaine for treatment of equine endotoxemia has not been studied. Hypothesis: Lidocaine infusion after exposure to lipopolysaccharide (LPS) will inhibit the inflammatory response and have inhibitory effects on the hemodynamic and cytokine responses to endotoxemia. Animals: Twelve horses. Methods: Two equal groups (n = 6): saline (GI) and lidocaine (GII). In all animals, endotoxin (500 ng/kg body weight [BW]) was injected intraperitoneally over 5 minutes. Twenty minutes later, animals received a bolus of GI or GII (1.3 mg/kg BW) over 5 minutes, followed by a 6‐hour continuous rate infusion of GI or GII (0.05 mg/kg BW/min). Treatment efficacy was judged from change in arterial blood pressure, peripheral blood and peritoneal fluid (PF) variables (total and differential cell counts, enzyme activities, and cytokine concentrations), and clinical scores (CS) for behavioral evidence of abdominal pain or discomfort during the study. Results: Compared with the control group, horses treated with lidocaine had significantly lower CS and serum and PF tumor necrosis factor‐α (TNF‐α) activity. At several time points in both groups, total and differential cell counts, glucose, total protein and fibrinogen concentrations, and alkaline phosphatase, creatine kinase, and TNF‐α activities were significantly different from baseline values both in peripheral blood and in PF. Conclusions and Clinical Importance: Lidocaine significantly decreased severity of CS and inhibited TNF‐α activity in PF.     

Role of platelet activating factor in development of thrombocytopenia and neutropenia in dogs with endotoxemia

OBJECTIVE: To determine the role of platelet activating factor (PAF) in lipopolysaccharide (LPS)-induced thrombocytopenia and neutropenia in dogs. ANIMALS: 42 dogs. PROCEDURES: Blood samples were obtained from dogs given LPS (40 microg/kg of body weight; n = 16), PAF (1 microg/kg; 6), PAF (5 microg/kg/h for 90 minutes; 4), or physiologic saline (0.9% NaCl) solution (0.1 ml/kg/h for 90 minutes; 3) IV to monitor changes in blood cell counts, using automated counters and blood smears stained with Giemsa. Blood samples were also obtained from dogs given LPS (40 microg/kg) that had (n = 5) or had not (6) been treated beforehand with TCV-309, a potent PAF antagonist. Concentration of PAF in blood was determined by use of 125I-radioimmunoassay in dogs given LPS at 1 mg/kg (n = 3) and 40 microg/kg (9). RESULTS: Thrombocytopenia and neutropenia were found in all dogs except those given saline solution. The LPS-induced thrombocytopenia was significantly suppressed by prior treatment with TCV-309. The PAF concentrations increased markedly 1 hour after injection of 1 mg/kg of LPS and increased slightly but significantly 10 minutes after injection of 40 microg/kg of LPS. CONCLUSION AND CLINICAL RELEVANCE: PAF plays an important role in the development of LPS-induced thrombocytopenia and neutropenia in dogs. Control of PAF production, PAF-induced effects, or both may be important in the treatment of dogs with gram-negative bacterial infections and associated thrombocytopenia and neutropenia.     

Intramuscular administration of a low dose of ACTH for ACTH stimulation testing in dogs

OBJECTIVE: To compare adrenal gland stimulation achieved following administration of cosyntropin (5 microg/kg [2.3 microg/lb]) IM versus IV in healthy dogs and dogs with hyperadrenocorticism. DESIGN: Clinical trial. Animals-9 healthy dogs and 9 dogs with hyperadrenocorticism. PROCEDURES: In both groups, ACTH stimulation was performed twice. Healthy dogs were randomly assigned to receive cosyntropin IM or IV first, but all dogs with hyperadrenocorticism received cosyntropin IV first. In healthy dogs, serum cortisol concentration was measured before (baseline) and 30, 60, 90, and 120 minutes after cosyntropin administration. In dogs with hyperadrenocorticism, serum cortisol concentration was measured before and 60 minutes after cosyntropin administration. RESULTS: In the healthy dogs, serum cortisol concentration increased significantly after administration of cosyntropin, regardless of route of administration, and serum cortisol concentrations after IM administration were not significantly different from concentrations after IV administration. For both routes of administration, serum cortisol concentration peaked 60 or 90 minutes after cosyntropin administration. In dogs with hyperadrenocorticism, serum cortisol concentration was significantly increased 60 minutes after cosyntropin administration, compared with baseline concentration, and concentrations after IM administration were not significantly different from concentrations after IV administration. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that in healthy dogs and dogs with hyperadrenocorticism, administration of cosyntropin at a dose of 5 microg/kg, IV or IM, resulted in equivalent adrenal gland stimulation.     

Endotoxin-induced hematologic and blood chemical changes in ponies: effects of flunixin meglumine, dexamethasone, and prednisolone

To evaluate the effect of certain drugs on hematologic changes, blood chemical values, and survival in endotoxin shock, anesthetized ponies were given (IV) endotoxin (Escherichia coli O55:B5) and then treated as follows: Group A ponies--given a saline infusion at 5 minutes and at 3 hours after they were given endotoxin; group B ponies--given flunixin meglumine at 5 minutes and at 3, 6, 9, and 24 hours after they were given endotoxin; group C ponies--treated with dexamethasone; and group D ponies--treated with prednisolone at 5 minutes and at 3, 9, and 24 hours after they were given endotoxin. Anesthesia was maintained for 4 hours, after which time the ponies were allowed to recover. Throughout the experiment, samples of blood were collected for blood gas, hematologic, and blood chemical values. The endotoxin effects were seen in the 4 groups: lactic acidosis, prolonged coagulation times, leukopenia, hemoconcentration, and elevated blood chemical values. Although none of the treatments prevented the effects of endotoxin, changes were less severe and survival times were longer in ponies treated with flunixin meglumine.     

Endotoxin-induced hemodynamic changes in dogs: role of thromboxane and prostaglandin I2

Plasma concentrations of thromboxane and prostaglandin I2 (PGI2) before and after IV injection of endotoxin and resulting hemodynamic changes were evaluated. Effects of flunixin meglumine on plasma concentrations of these prostaglandins and the related hemodynamic changes were also determined. Shock was induced in 2 groups of anesthetized dogs. Four dogs were given endotoxin only and 4 dogs were given endotoxin and then were treated with flunixin meglumine. Arterial blood pressure (BP), cardiac output (CO), and heart rate were measured, and blood samples were collected at postendotoxin hours (PEH) 0, 0.1, 0.25, 0.5, 1, 2, 3, and 4. Plasma thromboxane and PGI2 concentrations were increased in canine endotoxic shock. Thromboxane concentration was highest early in shock, and appeared to be associated with an initial decrease in BP and CO. The increased concentration of PGI2 was associated with systemic hypotension at PEH 1 to 2. Treatment of dogs with flunixin meglumine at PEH 0.07 prevented further increase of thromboxane and blocked the release of PGI2, resulting in an increased CO, BP, and tissue aerobic metabolism.     

Effects of naloxone on endotoxin-induced changes in ponies

The value of naloxone (1 mg/kg of body weight/hr for 4 hrs), a beta-endorphin antagonist, was assessed in the management of endotoxin-induced shock in ponies. Three groups of 5 ponies each were used: controls, ponies given Escherichia coli endotoxin put untreated, and ponies given endotoxin and then treated with naloxone. Endotoxin-induced changes in hemodynamics, blood chemical values, regional blood flow, plasma enzymes, and energy supplies were measured at selected times during the first 6 hours after endotoxin was given. There was no evidence that beta-endorphins released during shock were responsible for the hemodynamic changes, blood flow changes, plasma enzyme changes, or energy deficits, because naloxone, at this dosage level, did not prevent these endotoxin-induced changes.     

Evaluation of polymyxin B in an ex vivo model of endotoxemia in horses

OBJECTIVE: To evaluate effects of polymyxin B sulfate (PMB) on response of horses to endotoxin, using an ex vivo model. ANIMALS: 8 healthy horses. PROCEDURE: In a crossover design, 3 doses of PMB (100, 1,000, and 10,000 U/kg of body weight) and physiologic saline solution (control) were evaluated. Prior to and for 24 hours after administration of PMB, blood samples were collected into heparinized tubes for use in 2 assays. For the endotoxin-induced tumor necrosis factor (TNF) assay, blood samples were incubated (37 C for 4 h) with 1 ng of Escherichia coli or Salmonella Typhimurium endotoxin/ml of blood. Plasma was harvested and assayed. For the residual endotoxin activity assay, plasma was collected into sterile endotoxin-free borosilicate tubes, diluted 1:10 with pyrogen-free water, and incubated for 10 minutes at 70 C. Escherichia coli endotoxin (0.1 or 1 ng/ml of plasma) was added to the thawed samples prior to performing the limulus ameobocyte lysate assay. Serum creatinine concentrations were monitored for 1 week. RESULTS: Compared with baseline values, PMB caused a significant dose- and time-dependent decrease in endotoxin-induced TNF activity. Compared with baseline values, residual endotoxin activity was significantly reduced after administration of 10,000 U of PMB/kg. Compared with baseline values, 1,000 and 5,000 U of PMB/kg should inhibit 75% of endotoxin-induced TNF activity for 3 and 12 hours, respectively. Serum creatinine concentrations remained within the reference range. CONCLUSION AND CLINICAL RELEVANCE: Results of the study suggest that PMB is a safe, effective inhibitor of endotoxin-induced inflammation in healthy horses.     

Yohimbine ameliorates the effects of endotoxin on gastric emptying of the liquid marker acetaminophen in horses.

The effect of yohimbine pretreatment on gastric emptying of a liquid marker in horses was evaluated by measuring serum concentrations of acetaminophen. Gastric emptying was determined in normal, fasted horses, in horses given endotoxin (E. coli 055 B5; 0.2 microg/kg) intravenously, and in horses given yohimbine (0.25 mg/kg, IV, over 30 minutes) plus endotoxin. Acetaminophen (20 mg/kg) was given by stomach tube 15 minutes after the endotoxin infusion. Blood samples for acetaminophen analysis were collected, and time to reach the peak serum concentration (Tmax), the maximum serum concentration (Cmax) and the area under the acetaminophen serum concentration versus time curve (AUC) were determined for each treatment group. Endotoxin significantly increased Tmax, indicating a profound delay in gastric emptying and yohimbine pretreatment significantly (P < or = 0.05) prevented this effect.     

Roles of thromboxane A2 and 5-hydroxytryptamine in endotoxin-induced digital vasoconstriction in horses

OBJECTIVE: To evaluate the roles of 5-hydroxytryptamine (5-HT), thromboxane A2 (TxA2), and platelet-activating factor (PAF) in endotoxin-induced digital hypoperfusion in horses. ANIMALS: 6 healthy adult Thoroughbreds. PROCEDURES: Horses were treated with IV administration of saline (0.9% NaCl) solution (control treatment) or the 5-HT 1B/D selective antagonist, GR55562 (0.3 mg/kg), prior to tryptamine infusion (1.6 microg/kg/min for 30 minutes) to establish an effective GR55562 dose. In a crossover study, horses were treated with IV administration of saline solution (control treatment), aspirin (4 mg/kg, 2 hours or 4 days before lipopolysaccharide [LPS] infusion), GR55562 (0.3 mg/kg), the PAF antagonist WEB2086 (3 mg/kg), or aspirin plus GR55562 prior to LPS infusion (30 ng/kg for 30 minutes). Digital blood flow was measured by use of Doppler ultrasonography. Concomitant measurements of hoof wall and coronary band surface temperatures were made. Serial blood samples were collected and plasma 5-HT and TxA2 concentrations determined. RESULTS: GR55562 abolished tryptamine-induced digital hypoperfusion. Neither WEB2086 nor GR55562 affected LPS-induced alterations in digital perfusion or plasma mediator concentrations. Aspirin given 2 hours before LPS administration abolished the increase in plasma TxA2 concentration and significantly attenuated LPS-induced digital hypoperfusion. Aspirin given 4 days before LPS significantly attenuated the increase in plasma TxA2 concentration and digital hypothermia. Aspirin plus GR55562 had a greater effect on LPS-induced digital hypothermia than aspirin alone. CONCLUSIONS AND CLINICAL RELEVANCE: Thromboxane A2 and 5-HT played a role in mediating LPS-induced digital hypoperfusion in horses. Platelet-activating factor appeared unimportant in mediating LPS-induced 5-HT or TxA2 release or digital hypoperfusion.     

Effect of administration of a phospholipid emulsion on the initial response of horses administered endotoxin

OBJECTIVE: To evaluate the effect of a phospholipid emulsion (PLE) on the initial response of horses to administration of endotoxin. ANIMALS: 12 healthy adult horses. PROCEDURES: Horses were assigned to 2 treatment groups (6 horses/group). The control group was administered 1 L of saline (0.9% NaCl) solution, and the treated group was administered PLE (200 mg/kg, IV); treatments were administered during a period of 120 minutes. An infusion of endotoxin was initiated in both groups starting 1 hour after initiation of the saline or PLE solutions. Physical examination and hemodynamic variables were recorded, and blood samples were analyzed for concentrations of tumor necrosis factor (TNF)-alpha, interleukin-6, thromboxane B2 (TxB2), 6 keto-prostaglandin F (PGF)1alpha, total leukocyte count, and PLE concentrations. An ANOVA was used to detect significant differences. RESULTS: Administration of PLE resulted in significantly lower rectal temperature, heart rate, cardiac output, right atrial pressure, and pulmonary artery pressure and higher total leukocyte counts in treated horses, compared with values for control horses. The TNF-alpha concentration was significantly less in treated horses than in control horses. The TxB2 and 6 keto-PGFF1alpha concentrations were significantly different between treated and control horses at 30 minutes (TxB2) and at 30 and 60 minutes (6 keto-PGF1alpha). CONCLUSIONS AND CLINICAL RELEVANCE: Prior infusion of PLE in horses administered a low dose of endotoxin decreased rectal temperature, heart rate, pulmonary artery pressure, and TNF-alpha concentrations. Results of this study support further evaluation of PLE for use in the treatment of horses with endotoxemia.     

Clinical efficacy of tirilazad mesylate for treatment of endotoxemia in neonatal calves.

The clinical efficacy of the lazaroid, tirilazad mesylate, a new therapeutic agent for prophylaxis and treatment of endotoxemia, was evaluated in 24 neonatal Holstein calves. Endotoxemia was induced by IV infusion of commercial Escherichia coli lipopolysaccharide (3.25 micrograms/kg of body weight) over 3 hours. Group-1 calves were given endotoxin alone; group-2 calves were given an infusion of 0.9% sterile saline solution, then were treated with tirilazad mesylate (1.5 mg/kg) 1 hour after the infusion was started. Group-3 calves were treated with tirilazad mesylate 1 hour after the start of the endotoxin infusion, and group-4 calves were given tirilazad mesylate 1 hour before the start of the endotoxin infusion. Clinical signs of endotoxemia were mitigated by tirilazad mesylate. In addition, tirilazad mesylate protected calves from endotoxin-induced hyperglycemia; treatment after endotoxin infusion decreased the severity of hypoglycemia and prevented lactic acidosis. Treatment with tirilazad mesylate after initiation of endotoxin infusion was as protective as was pretreatment.     

Correlation of clinical and laboratory data with serum tumor necrosis factor activity in horses with experimentally induced endotoxemia

Serum tumor necrosis factor (TNF) activity was quantitated in 8 horses given an IV infusion of endotoxin (0.03 micrograms of lipopolysaccharide/kg of body weight, from Escherichia coli 055:B5) in 0.9% NaCl solution over 1 hour. Serum TNF activity was likewise measured in 6 horses given only 0.9% sterile NaCl solution at the same rate. The duration of serum TNF activity was determined, and serum TNF activity was correlated with clinical and laboratory changes during the induced endotoxemia. Horses had no serum TNF activity prior to endotoxin administration, but geometric mean serum TNF activity was significantly higher from 1 to 4 hours after the start of the infusion. In response to endotoxin, horses seemed depressed, had signs of mild to moderate abdominal pain, developed tachycardia and fever, and had leukopenia followed by leukocytosis. Association between serum TNF activity and temperature, heart rate, attitude abnormality score, and WBC count of horses given endotoxin was significant. Serum TNF activity had a significant positive linear correlation with attitude abnormality and heart rate and a negative linear correlation with the WBC count during endotoxemia. Geometric mean serum TNF activity peaked approximately 1.5 hours prior to mean peak fever, and these data were significantly correlated. Results of this study suggest that TNF is an important mediator of endotoxemia in horses.     

Effects of naloxone in treating hemorrhagic shock in dogs with maintained baroreceptor responsiveness

The efficacy of treating hemorrhagic shock with naloxone in conjunction with fluids, compared with fluid therapy alone, was studied. Previously instrumented dogs were anesthetized with 0.04 mg of fentanyl/kg + 2.2 mg of droperidol/kg and pentobarbital sodium (to effect). Blood was withdrawn from each animal to achieve and maintain a mean arterial blood pressure of 40 to 50 mm of Hg for the first 2 hours of the experiment (t = 0 to 120 minutes). At t = 120 minutes, IV fluid administration was begun (all dogs) and continued for 1 hour (lactated Ringer's solution at a dosage of 70 ml/kg/hr). Hypothermia was corrected. Control dogs were given no other treatment. Dogs in the naloxone plus fluids group were given an IV bolus of naloxone (1 mg/kg) at t = 120 minutes and 1 mg of naloxone/kg/hr in the fluids from t = 120 to t = 180 minutes. Treatment (either naloxone plus fluids or fluids alone) was stopped at t = 180 minutes, and measuring of response was continued for an additional hour (posttherapeutic period). Significant differences were not seen in mean arterial pressures, left ventricular peak systolic pressures, dP/dt max, time constant T (a measure of left ventricular elasticity), and mean pulmonary arterial pressures between the dogs given naloxone and fluid therapy and those given fluid therapy alone. All dogs in both groups survived the procedure.     

Effects of subanesthetic doses of ketamine on hemodynamic and immunologic variables in dogs with experimentally induced endotoxemia

OBJECTIVE: To determine the effects of ketamine hydrochloride on hemodynamic and immunologic alterations associated with experimentally induced endotoxemia in dogs. ANIMALS: 9 mixed-breed dogs. PROCEDURES: In a crossover study, dogs were randomly allocated to receive ketamine (0.5 mg/kg, IV, followed by IV infusion at a rate of 0.12 mg/kg/h for 2.5 hours) or control solution (saline [0.9% NaCl] solution, 0.25 mL, IV, followed by IV infusion at a rate of 0.5 mL/h for 2.5 hours). Onset of infusion was time 0. At 30 minutes, lipopolysaccharide (LPS; 1 microg/kg, IV) was administered. Heart rate (HR), systolic arterial blood pressure (SAP), plasma tumor necrosis factor (TNF)-alpha activity, and a CBC were evaluated. RESULTS: Mean SAP was significantly reduced in dogs administered ketamine or saline solution at 2 and 2.5 hours, compared with values at time 0. However, there was no significant difference between treatments. At 1, 2, and 2.5 hours, dogs administered ketamine had a significantly lower HR than dogs administered saline solution. Although plasma TNF-alpha activity significantly increased, compared with values at time 0 for both groups, ketamine-treated dogs had significantly lower peak plasma TNF-alpha activity 1.5 hours after LPS administration. All dogs had significant leukopenia and neutropenia after LPS administration, with no differences detected between ketamine and saline solution treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of a subanesthetic dose of ketamine had immunomodulating effects in dogs with experimentally induced endotoxemia (namely, blunting of plasma TNF-alpha activity). However, it had little effect on hemodynamic stability and no effect on WBC counts.