Juan Carlos Puyana

Methylene blue reverses endotoxin-induced hypotension.

Hypotension in septic shock is a reflection of unregulated nitric oxide (NO) production and vascular smooth muscle guanylyl cyclase activation. We examined the effect of methylene blue on lipopolysaccharide (LPS)-induced shock in anesthetized rabbits. Shock was induced with 150 micrograms/kg LPS after measurement of mean arterial pressure, platelet cGMP, and total plasma NO (nitrogen monoxide+S-nitrosothiol) content. Measurements were repeated before and after the intravenous administration of 1, 5, and 10 mg/kg methylene blue in response to a 55% reduction in mean arterial pressure. At baseline, mean +/- SEM arterial pressure was 88 +/- 3 mm Hg, which fell to 51 +/- 3 mm Hg after LPS (P < .05). Methylene blue at doses of 1, 5, and 10 mg/kg produced a prompt dose-dependent increase in mean arterial pressure to 69 +/- 2, 77 +/- 3, and 81 +/- 2 mm Hg, respectively (P < .05 versus mean arterial pressure after LPS) in association with normalization of plasma total NO content (P < .05); however, methylene blue did not significantly affect intraplatelet cGMP levels. Thus, methylene blue restores normal arterial pressure in rabbits with septic shock. This effect is associated with persistent elevation of intraplatelet cGMP levels and normalization of total plasma NO content. These data are consistent with methylene blue-mediated inhibition of NO synthase and/or degradation of NO in this model and suggest a novel therapeutic approach to the treatment of septic shock.

Continuous Measurement of Gut ph with Near-infrared Spectroscopy during Hemorrhagic Shock

BACKGROUND The rate and magnitude of pH changes in the bowel during hemorrhagic shock are greater than those in the stomach, implying that gastric intramucosal pH may not be a reliable indicator of gut perfusion. Here, we evaluate near-infrared spectroscopy (NIRS) to assess bowel pH in a swine shock model. METHODS Laparotomy was performed to place flow probes, pH microelectrodes, and NIRS probes. Shock was maintained for 45 minutes at a blood pressure of 45 mm Hg, and resuscitation was achieved with shed blood and lactated Ringers solution to baseline over 60 minutes. RESULTS Hemodynamic measurements were significantly reduced during shock. Lactic acid peaked during resuscitation and remained elevated. NIRS-measured pH was correlated to electrode-measured pH (R2 = 0.903 [ischemia] and R2 = 0.889 [reperfusion]). Estimated measurement accuracy after subject-specific offset correction was 0.083 pH units during ischemia and 0.076 pH units during reperfusion. CONCLUSION NIRS determination of small-bowel pH may be a good tool to monitor the adequacy of resuscitation.

Application of fiberoptic sensors for the study of hepatic dysoxia in swine hemorrhagic shock.

ObjectivesTo determine whether the simultaneous measurement of tissue pH, Pco2, and Po2 with a multiple-parameter fiberoptic sensor can be used to indicate the onset of hepatic dysoxia, to determine critical values, and to assess their use in predicting negative outcomes. DesignProspective animal study. SettingUniversity research laboratory. SubjectsFourteen Yorkshire swine. InterventionsHemorrhagic shock (n = 11) was induced over 15 mins to lower systolic blood pressure to 40 mm Hg and was maintained for 30, 60, or 90 mins. Resuscitation was achieved with shed blood and warm saline to maintain mean pressure >60 mm Hg for 120 mins. Sham animals (n = 3) were subjected to 90 mins of sham shock, followed by a 120-min recovery period. Measurements and Main Results The multiple-parameter sensor continuously measured tissue pH, Pco2, and Po2. pH and Pco2, indicators of anaerobic metabolism, were plotted against tissue Po2. All shocked animals, but no sham animals, showed a biphasic relationship between Po2 and both pH and Pco2. Curves were fit to both an exponential and a dual-line linear function to determine critical values for Po2, pH, and Pco2. The length of time the animal was dysoxic was evaluated as a predictor of negative outcome. Critical values determined from the exponential models were more sensitive indicators of negative outcome than values determined from the linear model and more sensitive than arterial lactate and tonometric intramucosal pH and Pco2. ConclusionsThe multiple-parameter sensor offers the unique opportunity to study solid as well as hollow organ dysoxia through the simultaneous measurement of interstitial pH, Pco2, and Po2 in a small tissue region. The gradual transition from sufficient oxygen availability to dysoxia as a result of hemorrhage was better described by an exponential equation. The length of time that pH was below or Pco2 was above the critical value determined from the exponential model was predictive of a negative outcome.

Effect of the Modified Glasgow Coma Scale Score Criteria for Mild Traumatic Brain Injury on Mortality Prediction: Comparing Classic and Modified Glasgow Coma Scale Score Model Scores of 13

BACKGROUND The Glasgow Coma Scale (GCS) classifies traumatic brain injuries (TBIs) as mild (14-15), moderate (9-13), or severe (3-8). The Advanced Trauma Life Support modified this classification so that a GCS score of 13 is categorized as mild TBI. We investigated the effect of this modification on mortality prediction, comparing patients with a GCS score of 13 classified as moderate TBI (classic model) to patients with GCS score of 13 classified as mild TBI (modified model). METHODS We selected adult TBI patients from the Pennsylvania Outcome Study database. Logistic regressions adjusting for age, sex, cause, severity, trauma center level, comorbidities, and isolated TBI were performed. A second evaluation included the time trend of mortality. A third evaluation also included hypothermia, hypotension, mechanical ventilation, screening for drugs, and severity of TBI. Discrimination of the models was evaluated using the area under receiver operating characteristic curve (AUC). Calibration was evaluated using the Hosmer-Lemershow goodness of fit test. RESULTS In the first evaluation, the AUCs were 0.922 (95% CI, 0.917-0.926) and 0.908 (95% CI, 0.903-0.912) for classic and modified models, respectively. Both models showed poor calibration (p < 0.001). In the third evaluation, the AUCs were 0.946 (95% CI, 0.943-0.949) and 0.938 (95% CI, 0.934-0.940) for the classic and modified models, respectively, with improvements in calibration (p = 0.30 and p = 0.02 for the classic and modified models, respectively). CONCLUSION The lack of overlap between receiver operating characteristic curves of both models reveals a statistically significant difference in their ability to predict mortality. The classic model demonstrated better goodness of fit than the modified model. A GCS score of 13 classified as moderate TBI in a multivariate logistic regression model performed better than a GCS score of 13 classified as mild.

Skeletal muscle acidosis correlates with the severity of blood volume loss during shock and resuscitation.

BACKGROUND Continuous assessment of tissue perfusion and oxygen utilization may allow for early recognition and correction of hemorrhagic shock. We hypothesized that continuously monitoring skeletal muscle (SM) PO2, PCO2, and pH during shock would provide an easily accessible method for assessing the severity of blood loss and the efficacy of resuscitation. METHODS Thirteen anesthetized pigs (25-35 kg) underwent laparotomy and femoral vessel cannulation. Multiparameter fiberoptic sensors were placed in the deltoid (SM) and femoral artery. Ventilation was maintained at a PaCO2 of 40-45 mm Hg. Total blood volume (TBV) was measured using an Evans blue dye technique. Animals were bled for 15 minutes, maintained at a mean arterial pressure (MAP) of 40 mm Hg for 1 hour, resuscitated (shed blood + 2 times shed volume in normal saline) and observed for 1 hour. Four animals served as controls (sham hemorrhage). Blood and tissue samples were taken at each time point. RESULTS Blood loss ranged from 28.5-56% of TBV. SM pH and SM PO2 levels fell rapidly with shock. SM PO2 returned to normal with resuscitation; however, SM pH did not return to baseline. SM PCO2 significantly rose with shock, but returned to baseline promptly with resuscitation. There was a significant correlation between SM pH and blood volume loss at end shock (r2 = 0.73, p < 0.001) and recovery (r2 = 0.84, p < 0.001). Animals (n = 2) whose SM pH did not recover to 7.2 were found to have ongoing blood loss from biopsy sites and persistent tissue hypercarbia despite normal MAP. CONCLUSION Continuous multiparameter monitoring of SM provides a minimally invasive method for assessing severity of shock and efficacy of resuscitation. Both PCO2 and PO2 levels change rapidly with shock and resuscitation. SM pH is directly proportional to lost blood volume. Persistent SM acidosis (pH < 7.2) and elevated PCO2 levels suggest incomplete resuscitation despite normalized hemodynamics.

Mathematical modeling of posthemorrhage inflammation in mice: studies using a novel, computer-controlled, closed-loop hemorrhage apparatus.

Hemorrhagic shock (HS) elicits a global acute inflammatory response, organ dysfunction, and death. We have used mathematical modeling of inflammation and tissue damage/dysfunction to gain insight into this complex response in mice. We sought to increase the fidelity of our mathematical model and to establish a platform for testing predictions of this model. Accordingly, we constructed a computerized, closed-loop system for mouse HS. The intensity, duration, and time to achieve target MAP could all be controlled using a software. Fifty-four male C57/black mice either were untreated or underwent surgical cannulation. The cannulated mice were divided into 8 groups: (a) 1, 2, 3, or 4 h of surgical cannulation alone and b) 1, 2, 3, or 4 h of cannulation + HS (25 mmHg). MAP was sustained by the computer-controlled reinfusion and withdrawal of shed blood within ±2 mmHg. Plasma was assayed for the cytokines TNF, IL-6, and IL-10 as well as the NO reaction products NO2−/NO3−. The cytokine and NO2−/NO3− data were compared with predictions from a mathematical model of post-hemorrhage inflammation, which was calibrated on different data. To varying degrees, the levels of TNF, IL-6, IL-10, and NO2−/NO3− predicted by the mathematical model matched these data closely. In conclusion, we have established a hardware/software platform that allows for highly accurate, reproducible, and mathematically predictable HS in mice.ABBREVIATIONS-HS-hemorrhagic shock; HR-heart rate

Safety of Performing a Delayed Anastomosis During Damage Control Laparotomy in Patients with Destructive Colon Injuries

BACKGROUND Recent studies report the safety and feasibility of performing delayed anastomosis (DA) in patients undergoing damage control laparotomy (DCL) for destructive colon injuries (DCIs). Despite accumulating experience in both civilian and military trauma, questions regarding how to best identify high-risk patients and minimize the number of anastomosis-associated complications remain. Our current practice is to perform a definitive closure of the colon during DCL, unless there is persistent acidosis, bowel wall edema, or evidence of intra-abdominal abscess. In this study, we evaluated the safety of this approach by comparing outcomes of patients with DCI who underwent definitive closure of the colon during DCL versus patients managed with colostomy with or without DCL. METHODS We performed a retrospective chart review of patients with penetrating DCI during 2003 to 2009. Severity of injury, surgical management, and clinical outcome were assessed. RESULTS Sixty patients with severe gunshot wounds and three patients with stab wounds were included in the analysis. DCL was required in 30 patients, all with gunshot wounds. Three patients died within the first 48 hours, three underwent colostomy, and 24 were managed with DA. Thirty-three patients were managed with standard laparotomy: 26 patients with primary anastomosis and 7 with colostomy. Overall mortality rate was 9.5%. Three late deaths occurred in the DCL group, and only one death was associated with an anastomotic leak. CONCLUSIONS Performing a DA in DCI during DCL is a reliable and feasible approach as long as severe acidosis, bowel wall edema, and/or persistent intra-abdominal infections are not present.

Simultaneous Measurement Of Hepatic Tissue ph, Venous Oxygen Saturation And Hemoglobin By Near Infrared Spectroscopy

The purpose of this study was to investigate the feasibility of using near infrared (NIR) spectroscopy of the liver to simultaneously assess oxygen content in combination with tissue pH, an indicator of anaerobic metabolism. Six anesthetized swine were subjected to 45 min of hemorrhagic shock followed by resuscitation with blood and crystalloid. Calibration models between NIR spectra and reference measurements of tissue pH, hepatic venous oxygen saturation (S(V)O2), and blood hemoglobin concentration (Hb) were developed using partial least-squares regression. Model accuracy was assessed using cross validation. The average correlation (R2) between NIR and reference measurements was 0.87, 0.68, and 0.93, respectively for pH, Hb, and S(V)O2. Estimated accuracy, the root mean squared deviation between spectral, and reference measurements was 0.03 pH units, 0.3 g/dL, and 6%. NIR determination of hepatic oxygen content and tissue pH during shock and resuscitation demonstrated that there can be a variance between hepatic venous oxygenation and regional tissue acidosis. NIR spectroscopy provides a technique to explore the implications of post-shock depression of tissue pH and evaluate new methods of resuscitation.

Monitoring skeletal muscle and subcutaneous tissue acid-base status and oxygenation during hemorrhagic shock and resuscitation.

Gastric tonometry correlates with the severity of blood loss during shock. However, tonometry is cumbersome, has a slow response time, and is not practical to apply in the acute resuscitation setting. We hypothesized that subcutaneous tissue (SC) and skeletal muscle (SM) pH, pCO2, and pO2 changes are comparable with changes seen in bowel tonometry during shock and resuscitation. Thirteen male mini-swine (25-35 kg; n = 4 control, n = 9 shock) underwent laparotomy and jejunal tonometry. A multisensor probe (Diametrics Medical, Roseville, MN) was placed in the carotid artery, the chest SC, and the adductor muscle of the leg (SM). PaCO2 was maintained between 40 and 45 mmHg. Shocked animals were hemorrhaged and kept at mean arterial pressure of 40 mmHg. Animals were bled until a reinfusion of >10% of the total shed blood was needed to maintain the mean arterial pressure at 40 mmHg. Animals were resuscitated with shed blood plus 2x shed volume in lactated Ringers solution (20 min) and were observed for 3 h. The average blood loss was 47.2% ± 8.7% of calculated blood volume. During the hemorrhagic phase, SM and SC displayed tissue acidosis (r2 = 0.951), tissue hypercapnea (r2 = 0.931), and tissue hypoxia (r2 = 0.748). Overall, pH displayed the best correlation between SM and SC during shock and resuscitation. PCO2 in the jejunum (tonometry), SM, and SC increased during decompensation. However, during resuscitation as tonometric pCO2 normalized, only SC pCO2 decreased to its baseline value, whereas the SM pCO2 decrease tended to lag behind. Bland-Altman analyses demonstrated that the variability of the tissue pH changes in SM and SC are predictable according to the phases of hemorrhage and resuscitation. Changes in tissue pH correlated during bleeding and during resuscitation among SC and SM, and these changes followed the trends in gut tonometry as well. Continuous pCO2 and pO2 monitoring in the SM and SC tissues had significant correlations during the induction of shock only. SM and SC continuous pH and pCO2 monitoring reflect bowel pCO2 values during hemorrhagic shock. The response of these indicators as potential surrogates of impaired tissue metabolism varies among tissues and according to the phases of hemorrhage or resuscitation.

Directly measured tissue pH is an earlier indicator of splanchnic acidosis than tonometric parameters during hemorrhagic shock in swine

Objective To compare tissue pH in the stomach, bowel, and abdominal wall muscle during hemorrhagic shock and recovery using tissue electrodes; also, to compare tissue electrode pH measurements to gastric intramucosal pH (pHi), gastric luminal Pco2, and Pco2 gap (gastric luminal CO2 − arterial CO2) measured with an air-equilibrated tonometer. Design Prospective animal study. Setting University animal research laboratory. Subjects Eight anesthetized, mechanically ventilated Yorkshire swine. Interventions Hemorrhagic shock was initiated by withdrawing blood over a 15-min period to lower systolic blood pressure to 45 mm Hg. Shock was maintained for 45 mins and was followed by a 5-min resuscitation to normal blood pressure with a blood/lactated Ringer’s (1:2) mixture. Recovery was monitored for 60 mins. Measurements and Main Results pH was measured with electrodes in the submucosa of the stomach, the submucosa of the small bowel, and the abdominal wall muscle. Gastric luminal Pco2 was measured with an air-equilibrated tonometer and pHi and Pco2 gap were calculated. Each organ showed a different sensitivity to shock and resuscitation. The bowel pH responded most rapidly to the onset of hemorrhagic shock and had the largest change in tissue pH. The bowel also showed the most rapid recovery during resuscitation. The submucosal pH of the stomach responded more slowly than the bowel, but faster than the abdominal wall muscle pH, gastric Pco2 gap, or pHi. The smallest changes in organ pH as a result of hemorrhagic shock were seen in the abdominal wall muscle and the stomach as assessed by gastric tonometry. Conclusions Direct measurement of tissue pH indicates that intra-abdominal organ pH varies during hemorrhagic shock. The small bowel pH changes the most in magnitude and rapidity compared with stomach pH or abdominal wall muscle pH. Tonometrically derived parameters were not as sensitive in the detection of tissue acidosis during shock and resuscitation as pH measured directly in the submucosa of the stomach or small bowel.