A prospective, randomized trial of intravenous hydroxocobalamin versus noradrenaline or saline for treatment of lipopolysaccharide-induced hypotension in a swine model.

Early, non-clinical studies support the use of hydroxocobalamin to treat sepsis-induced hypotension, but there is no translational, large animal model. The objective of this study was to compare survival in a sepsis model where large swine had endotoxaemia induced with lipopolysaccharide (LPS) and were treated with intravenous hydroxocobalamin (HOC), noradrenaline (NA), or saline. Thirty swine (45-55 kg) were anaesthetized, intubated, and instrumented with continuous femoral and pulmonary artery pressure monitoring. Hypotension, predefined as 50% of baseline, was induced with LPS. Animals then received HOC, NA, or saline and monitored for 3 hours. The main outcome was survival to the conclusion of the study. Using a power of 80% and an alpha of 0.05, 10 animals were used per group. Secondary outcomes included: mean arterial pressure (MAP), systemic vascular resistance (SVR) and cardiac output (CO) along with several markers of sepsis. No differences were detected between groups at baseline or after hypotension. The survival distributions of the three groups were significantly different with more HOC animals surviving (10/10) compared with NA (8/10) or Saline (5/10) (log-rank P < 0.03). MAP was found to be higher in both the HOC and NA groups and HOC achieved the highest SVR. In this large animal, translational study of an endotoxaemic model of sepsis, hydroxocobalamin improved survival when compared with saline.

Intravenous Hydroxocobalamin Versus Hextend Versus Control for Class III Hemorrhage Resuscitation in a Prehospital Swine Model.

Background: Hydroxyethyl starch (Hextend) has been used for hemorrhagic shock resuscitation, however, hydroxyethyl starch may be associated with adverse outcomes. Objective: To compare systolic blood pressure (sBP) in animals that had 30% of their blood volume removed and treated with intravenous hydroxocobalamin, hydroxyethyl starch, or no fluid. Methods: Twenty-eight swine (45-55 kg) were anesthetized and instrumented with continuous femoral and pulmonary artery pressure monitoring. Animals were hemorrhaged 20 mL/kg over 20 minutes and then administered 150 mg/kg IV hydroxocobalamin in 180 mL saline, 500 mL hydroxyethyl starch, or no fluid and monitored for 60 minutes. Data were modeled using repeated measures multivariate analysis of variance. Results: There were no significant differences before treatment. At 20 minutes after hemorrhage, there was no significant difference in mean sBP between treated groups, however, control animals displayed significantly lower mean sBP (p < 0.001). Mean arterial pressure and heart rate improved in the treated groups but not in the control group (p < 0.02). Prothrombin time was longer and platelet counts were lower in the Hextend group (p < 0.05). Moreover, thromboelastography analysis showed longer clotting (K) times (p < 0.05) for the hydroxyethyl starch-treated group. Conclusion: Hydroxocobalamin restored blood pressure more effectively than no treatment and as effectively as hydroxyethyl starch but did not adversely affect coagulation.

Efficacy of Intravenous Cobinamide Versus Hydroxocobalamin or Saline for Treatment of Severe Hydrogen Sulfide Toxicity in a Swine (Sus scrofa) Model.

BACKGROUND: Hydrogen sulfide (H2 S) is a potentially deadly gas that naturally occurs in petroleum and natural gas. The Occupational Health and Safety Administration cites H2 S as a leading cause of workplace gas inhalation deaths. Mass casualties of H2 S toxicity may be caused by exposure from industrial accidents or release from oil field sites. H2 S is also an attractive terrorism tool because of its high toxicity and ease with which it can be produced. Several potential antidotes have been proposed for hydrogen sulfide poisoning but none have been completely successful. OBJECTIVE: The objective was to compare treatment response assessed by the time to spontaneous ventilation among groups of swine with acute H2 S-induced apnea treated with intravenous (IV) cobinamide (4 mg/kg in 0.8 mL of 225 mmol/L solution), IV hydroxocobalamin (4 mg/kg in 5 mL of saline), or saline alone. METHODS: Twenty-four swine (45-55 kg) were anesthetized, intubated, and instrumented with continuous femoral and pulmonary artery pressure monitoring. After stabilization, anesthesia was adjusted such that animals would spontaneously ventilate with an FiO2 of 0.21. Sodium hydrosulfide (NaHS; concentration of 8 mg/mL) was begun at 1 mg/kg/min until apnea was confirmed for 20 seconds by capnography. This infusion rate was sustained for 1.5 minutes postapnea and then decreased to a maintenance rate for the remainder of the study to replicate sustained clinical exposure. Animals were randomly assigned to receive cobinamide (4 mg/kg), hydroxocobalamin (4 mg/kg), or saline and monitored for 60 minutes beginning 1 minute postapnea. G* power analysis using the Z-test determined that equal group sizes of eight animals were needed to achieve a power of 80% in detecting a 50% difference in return to spontaneous ventilations at α = 0.05. RESULTS: There were no significant differences in baseline variables. Moreover, there were no significant differences in the mg/kg dose of NaHS (5.6 mg/kg; p = 0.45) required to produce apnea. Whereas all of the cobinamide-treated animals survived (8/8), none of the control (0/8) or hydroxocobalamin (0/8)-treated animals survived. Mean (±SD) time to spontaneous ventilation in the cobinamide-treated animals was 3.2 (±1.1) minutes. CONCLUSIONS: Cobinamide successfully rescued the severely NaHS-poisoned swine from apnea in the absence of assisted ventilation.

Intraosseous hydroxocobalamin versus intravenous hydroxocobalamin compared to intraosseous whole blood or no treatment for hemorrhagic shock in a swine model.

OBJECTIVE: To determine if intraosseous (IO) hydroxocobalamin can improve systolic blood pressure (SBP) in a swine model after severe hemorrhagic shock. METHODS: Thirty six swine (45-55 kg) were anesthetized, intubated, and instrumented with continuous femoral and pulmonary artery pressure monitoring and then hemorrhaged such that 30 percent of their blood volume was extracted over 20 minutes. Five minutes later, animals were randomly assigned to receive 500 mL IO whole blood, 150 mg/kg IO or intravenous (IV) hydroxocobalamin in 180 mL of saline, or no treatment and then monitored for 60 minutes. A sample size of eight animals per group was based on a power of 80 percent, an alpha of 0.05, and a small effect size to detect a difference in SBP between groups. Outcome data were analyzed using repeated measures analysis of variance (RMANOVA). RESULTS: RMANOVA outcome analysis detected a significant difference between groups (p < 0.05). IO whole blood, IO hydroxocobalamin, and IV hydroxocobalamin groups were similar to each other, but significantly different compared to controls regarding SBP, mean arterial pressure (MAP), systemic vascular resistance, and heart rate. Differences in SBP and MAP were sustained throughout the experiment. At 60 minutes, the comparison among the groups, IO whole blood, IO hydroxocobalamin, IV hydroxocobalamin, and control, was the following: SBP 78.2 versus 83.7 versus 75.1 versus 55.3 mm Hg; MAP 62.7 versus 65 versus 60 versus 43 mm Hg. There was a significant interaction by time in lactate values (p < 0.01) such that control animal lactate values increased over time (3.3 mmol/L) compared to IO whole blood, IO or IV hydroxocobalamin treated animals (1.1, 1.6, 1.3 mmol/L). CONCLUSIONS: IO hydroxocobalamin improved SBP, MAP, compared to no treatment and was similar to IO whole blood and IV hydroxocobalamin in this animal model of severe hemorrhage. Moreover, whereas serum lactate was improving in all treated groups, it was deteriorating in the control group.

A prospective, randomized trial of intravenous hydroxocobalamin versus whole blood transfusion compared to no treatment for Class III hemorrhagic shock resuscitation in a prehospital swine model.

OBJECTIVES: The objective was to compare systolic blood pressure (sBP) over time in swine that have had 30% of their blood volume removed (Class III shock) and treated with intravenous (IV) whole blood or IV hydroxocobalamin, compared to nontreated control animals. METHODS: Thirty swine (45 to 55 kg) were anesthetized, intubated, and instrumented with continuous femoral and pulmonary artery pressure monitoring. Animals were hemorrhaged a total of 20 mL/kg over a 20-minute period. Five minutes after hemorrhage, animals were randomly assigned to receive 150 mg/kg IV hydroxocobalamin solubilized in 180 mL of saline, 500 mL of whole blood, or no treatment. Animals were monitored for 60 minutes thereafter. A sample size of 10 animals per group was determined based on a power of 80% and an alpha of 0.05 to detect an effect size of at least a 0.25 difference (>1 standard deviation) in mean sBP between groups. sBP values were analyzed using repeated-measures analysis of variance (RANOVA). Secondary outcome data were analyzed using repeated-measures multivariate analysis of variance (RMANOVA). RESULTS: There were no significant differences between hemodynamic parameters of IV hydroxocobalamin versus whole blood versus control group at baseline (MANOVA; Wilks' lambda; p = 0.868) or immediately posthemorrhage (mean sBP = 47 mm Hg vs. 41 mm Hg vs. 37 mm Hg; mean arterial pressure = 39 mm Hg vs. 28 mm Hg vs. 34 mm Hg; mean serum lactate = 1.2 mmol/L vs. 1.4 mmol/L vs. 1.4 mmol/L; MANOVA; Wilks' lambda; p = 0.348). The outcome RANOVA model detected a significant difference by time between groups (p < 0.001). Specifically, 10 minutes after treatment, treated animals showed a significant increase in mean sBP compared to nontreated animals (mean sBP = 76.3 mm Hg vs. 85.7 mm Hg vs. 51.1 mm Hg; p < 0.001). RMANOVA modeling of the secondary data detected a significant difference in mean arterial pressure, heart rate, and serum lactate (p < 0.001). Similar to sBP, 10 minutes after treatment, treated animals showed a significant increase in mean arterial pressure compared to nontreated animals (mean arterial pressure = 67.7 mm Hg vs. 61.4 mm Hg vs. 40.5 mm Hg). By 10 minutes, mean heart rate was significantly slower in treated animals compared to nontreated animals (mean heart rate = 97.3 beats/min vs. 95.2 beats/min vs. 129.5 beats/min; p < 0.05). Serum lactate, an early predictor of shock, continued to rise in the control group, whereas it did not in treated animals. Thirty minutes after treatment, serum lactate values of treated animals were significantly lower compared to nontreated animals (p < 0.05). This trend continued throughout the 60-minute observation period such that 60-minute values for lactate were 1.4 mmol/L versus 1.1 mmol/L versus 3.8 mmol/L. IV hydroxocobalamin produced a statistically significant increase in systemic vascular resistance compared to control, but not whole blood, with a concomitant decrease in cardiac output. CONCLUSIONS: Intravenous hydroxocobalamin was more effective than no treatment and as effective as whole blood transfusion, in reversing hypotension and inhibiting rises in serum lactate in this prehospital, controlled, Class III swine hemorrhage model.

Investigation of the anti-inflammatory, antinociceptive effect of ellagic acid as measured by digital paw pressure via the Randall-Selitto meter in male Sprague-Dawley rats.

Ellagic acid (EA), a dietary supplement, is purported to have anti-inflammatory, antinociceptive properties via cyclooxygenase (COX) inhibition. We measured the antinociceptive efficacy of EA alone and in combination with a nonselective COX inhibitor and a selective COX-2 inhibitor. We assigned 54 male Sprague-Dawley rats to 1 of 6 groups to be given the following compounds: (1) vehicle, (2) ketorolac (nonselective COX inhibitor), (3) meloxicam (selective COX-2 inhibitor), (4) EA, (5) EA plus ketorolac, and (6) EA plus meloxicam. Inflammatory pain was induced in the right hind paw by injecting carrageenan. Rats were given study compounds via intraperitoneal injection 30 minutes after paw injections. Pain tolerance was assessed using the Randall-Selitto instrument at 30 minutes and 4, 8, 12, and 24 hours. The highest pressure tolerated was recorded in grams. The analysis of variance suggested a significant difference (F = 2.44; P = .048). The least significant difference post hoc analysis suggested that at 8 hours, EA plus ketorolac provided greater antinociception than all other compounds (P = .04). Furthermore the combination of EA plus ketorolac provided longer antinociception than all other compounds (P = .03) such that EA plus ketorolac was effective at 24 hours.

Evaluation of the anti-inflammatory effects of ellagic acid.

Few studies have investigated the anti-inflammatory properties of ellagic acid and no published studies have examined the effects of ellagic acid in combination with anesthetic adjuvants. In this study, 54 Sprague-Dawley rats were assigned to one of six groups: (1) vehicle; (2) ketorolac and vehicle; (3) meloxicam and vehicle; (4) ellagic acid and vehicle; (5) ellagic acid, ketorolac, and vehicle; and (6) ellagic acid, meloxicam, and vehicle. Groups 5 and 6 investigated interactions between ellagic acid and cyclooxygenase inhibitors. Paw inflammation was induced with 3% carrageenan and was measured with a plethysmometer at 30 minutes and 4, 8, and 24 hours after intraperitoneal injection. All rats received one intraperitoneal injection of equivalent volumes according to group assignment. Analysis of covariance followed by post hoc analysis determined that ketorolac was the only compound to significantly reduce paw edema at 4 hours (P = .019); ellagic acid alone (P = .038) and the combination of ellagic acid and ketorolac (P = .038) were the only compounds to significantly reduce paw edema at 8 hours. At 24 hours, only ellagic acid was effective (P = .01). Our findings suggest that ellagic acid may be effective against inflammation, may have a prolonged onset and duration of action, and may interact with known cyclooxygenase inhibitors.

Effects of anesthetics and analgesics on natural killer cell activity.

Surgical excision of cancerous tumors and the human stress response can lead to metastasis of tumor cells. Furthermore, the medications used during the perioperative period (eg, opioids and anesthetic agents) have been shown to inhibit or suppress natural killer (NK) cell activity, one of the body's main defenses against spread of cancer. There are currently no anesthetic regimens that have been shown to completely reverse surgical stress-induced suppression of NK cell activity. However, there may be anesthetic techniques that attenuate surgical suppression of NK cell activity. This article reviews the effects of various anesthetics and analgesics on NK cell activity and suggests techniques to attenuate the suppressive effects of these compounds.

A brief report of basic science: the effects of preincisional low-dose ketamine on natural killer cell activity in male Fischer 344 rats after intra-abdominal surgery.

Although the first line of defense in cancer treatment often is surgery, studies suggest that postoperative pain and anesthetic drugs suppress the activity of cells that lyse metastatic cells, that is, natural killer cells. We assessed the affect of low-dose ketamine on natural killer cell activity. The findings are presented in this brief report.

Investigation of modulation of the alpha-2 receptor in tetrahydropalmatine (THP) analgesia in male Sprague-Dawley rats.

The increased use of nutraceuticals over the past 20 years makes it essential to know the effects these may have with anesthetics and analgesics (Kaye et al., 2000). Tetrahydropalmatine (THP), a derivative of the herb corydalis, may have analgesic properties (Hu & Jin, 2000a; Wei, Zou, Young, Dubner, & Ren, 1999); however, the mechanism of action is unclear. We proposed that THP may modulate alpha-2 receptors and interact with dexmedetomidine, a known alpha-2-receptor agonist, used for sedation. Fifty-five male Sprague-Dawley rats, divided into five groups, were administered the following by intraperitoneal injection: (1) vehicle, (2) dexmedetomidine, (3) THP, (4) THP and yohimbine, and (5) THP and dexmedetomidine. A baseline measurement of hot-plate latency was recorded, followed by an injection of appropriate compound(s). Testing occurred at 5, 10, 30, and 60 min after injections. Repeated measures ANOVA suggested a significant difference among groups (f = 8.09; p = 0.00). Post hoc Bonferroni suggested that THP significantly prolonged reaction time on the hot plate compared to vehicle (p =. 037). Rats injected with THP and yohimbine did not have significantly shorter latency times compared to those injected with THP alone suggesting that THP does not modulate alpha-2 receptors. Finally, rats injected with THP and dexmedetomidine did not demonstrate a significantly increased latency time compared to THP alone, suggesting no additive effect of THP.

Menstrual cycle-related variations in postoperative analgesia with the preemptive use of N-methyl D-aspartate antagonist ketamine: a pilot study.

Several studies have supported that N-methyl-D-aspartate receptor antagonist can reduce the perception of postoperative pain. Hormonal fluctuations throughout the human menstrual cycle can influence pain pathways. In this pilot study, we evaluated postoperative pain in 22 female participants between the ages of 20 and 56 years undergoing laparoscopic abdominal procedures. Participants were randomly assigned to receive either placebo or ketamine at the induction of anesthesia. Progesterone levels were measured to determine menstrual phase. Visual analog scale scores were obtained at arrival into and discharge from the post anesthesia care unit. Total equipotent analgesic administration was also recorded. We found trends suggesting that women receiving ketamine and women in the luteal phase of their menstrual cycle had lower visual analog scale scores upon arrival to the unit. Ketamine recipients also received less rescue analgesic medication in the unit.

The effects of chrysin, a Passiflora incarnata extract, on natural killer cell activity in male Sprague-Dawley rats undergoing abdominal surgery.

Chrysin, a passion flower extract, may be beneficial because of its potential to attenuate surgical suppression of natural killer (NK) cell activity. We divided 37 male Sprague-Dawley rats into 3 treatment groups: (1) rats undergoing abdominal surgery and administered isoflurane and a 5% solution of dimethyl sulfoxide in saline (vehicle), (2) rats undergoing abdominal surgery and administered isoflurane and chrysin solubilized in 5% dimethyl sulfoxide, and (3) rats not undergoing surgery but administered isoflurane and chrysin. Natural killer cell activity was measured before and 24 hours after the experiment. Analysis of covariance, with preoperative NK cell activity as the covariate, was used to compare differences in NK cell activity among groups. The Scheffe procedure was used to make post hoc comparisons. Analysis revealed a significant difference (P = .006) such that group 2 had significantly less NK cell suppression compared with groups 1 and 3. These findings suggest that chrysin may attenuate surgical suppression of NK cell activity, thereby minimizing metastatic spread of cancer.

Predictors of student success in the US Army Graduate Program In Anesthesia Nursing.

The primary objective of this research was to identify cognitive and noncognitive factors that may predict student success in the US Army Graduate Program in Anesthesia Nursing. Second, the results of this study will help identify students possibly at risk for failure so that interventional measures can be developed and implemented to promote success and reduce attrition. Participants in this 3-year longitudinal, nonexperimental, prospective, descriptive study were 42 students. Cognitive and noncognitive assessment tools were used to identify predictors of success. The measure of success was defined as graduation from the program and withdrawal or relief as nonsuccess. All data were analyzed using logistic regression. Results were considered statistically significant at a P value of .05 or less. Only 2 noncognitive factors, locus of control and trait anxiety, were statistically significant such that students with a more external locus of control and lower trait anxiety were more likely to succeed (-2 log likelihood of 33.83; overall P = .012). The findings suggest that locus of control and trait anxiety may be the most predictive indicators of success in the program. Furthermore, our findings support that noncognitive factors may be as vital as cognitive factors in predicting academic success.

The effects of valerian on the time course of emergence from general anesthesia in Sprague-Dawley rats (Rattus norvegicus).

Herbal use may be associated with increased morbidity and mortality as a consequence of interactions with anesthetic agents. The purpose of this study was to investigate the effects on emergence from isoflurane anesthesia using a combination of the herb valerian and midazolam compared with valerian alone, midazolam alone, and no additional drug-herb treatment in Sprague-Dawley rats. We assigned 32 male Sprague-Dawley rats to 1 of 4 groups: (1) isoflurane alone, (2) isoflurane plus valerian, (3) isoflurane plus midazolam, and (4) isoflurane plus a combination of valerian and midazolam. Thirty minutes after treatment, animals underwent a standard laparotomy. The time in seconds from discontinuation of isoflurane to the time the animal righted itself and took I step was recorded as emergence time. A 1-way analysis of variance with a post hoc Scheffe procedure revealed that animals given a combination of midazolam and valerian took significantly longer to emerge from anesthesia (F = 58.21; P < .00) compared with all other groups. Awareness of possible interactions of herbals with conventional anesthetics is important so that potential problems may be recognized and treated. These data demonstrate the need for continued research concerning the effects of herbals and their potential for interaction with anesthetics.

Effects of preincisional ketamine treatment on natural killer cell activity and postoperative pain management after oral maxillofacial surgery.

Poorly controlled pain may lead to increased risk of cancer metastasis by suppressing natural killer (NK) cell activity. Ketamine may be beneficial by potentiating opioid-induced analgesia. We enrolled 59 participants in a randomized double-blind, placebo-controlled clinical trial and assigned them to receive propofol plus (1) saline, 2 mL; (2) ketamine, 0.5 mg/kg; or (3) ketamine, 1.2 mg/kg, followed by a standardized anesthesia protocol. The visual analogue scale (VAS) and 24-hour opioid consumption measured postoperative pain perception. NK cell activity was measured before and 24 hours after ketamine administration using the chromium 51 release assay. Nonparametric analysis of VAS data revealed that women receiving 0.5 mg/kg of ketamine reported less pain (P <.05) compared with the saline 1.2 mg/kg-ketamine groups. This finding was not evident in men. Comparing opioid consumption among the 3 groups (using analysis of variance) revealed a drug-gender interaction (P < .05): 0.5 mg/kg of ketamine decreased postoperative opioid consumption for women more than for men. Although not statistically significant, women receiving 0.5 mg/kg of ketamine had the least NK cell suppression compared with preoperative values (repeated analysis of variance). These findings suggest that for women, low-dose ketamine may be beneficial.

Description of the oxygen concentration delivered using different combinations of oxygen reservoir volumes and supplemental oxygen flow rates with the Ohmeda Universal Portable Anesthesia Complete draw-over vaporizer system.

The Ohmeda Universal Portable Anesthesia Complete system is used in austere conditions where oxygen resources are limited and must be conserved. The purpose of this study was to describe the concentration of oxygen delivered with different combinations of seven oxygen reservoir volumes and four oxygen flow rates. The Medical Education Technologies Incorporated Human Patient Simulator reproduced human physiological tidal volumes of four simulated patients of different weights based upon a typical soldier's weight. Using least squares multiple nonlinear regression, a formula for the curves of the oxygen concentrations was developed. The analysis, across the different patient weights, showed no appreciable increase in oxygen concentration beyond a reservoir volume of 260 mL. Our findings suggest the current standard universal portable anesthesia complete reservoir may not provide optimal oxygen delivery, therefore, we recommend the current reservoir volume be increased from 130 to 260 mL.