Pyrrolidine dithiocarbamate improves mortality in a rat model of severe hemorrhage

BackgroundHemorrhagic shock is a life threatening condition characterized by diminishing organ function. The aim of this study was to determine whether an effective pyrrolidine dithiocarbamate (PDTC) treatment protocol could be established to decrease organ dysfunction and mortality in a lethal hemorrhagic shock-resuscitation (HSR) model.Materials and methodsSprague-Dawley rats were randomized into three experimental groups; HSR alone (HSR), PDTC (100 mg/kg) administered 12 h pre-HSR (PDTC-12), and PDTC administered 1 h post-shock prior to resuscitation (PDTC+1). Hemorrhage was induced by arterial blood withdrawal to a mean arterial pressure (MAP) of 25 ± 5 mmHg for 1 h. Resuscitation was performed until pre-HSR MAP was attained. Blood was collected immediately prior to HSR, 1 h post-shock, and at protocol end. Measurements of base excess, lactate, arterial partial pressure of carbon dioxide (PaCO₂) and oxygen (PaO₂), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, blood urea nitrogen (BUN), and lipase were performed.ResultsIn PDTC+1 animals, PDTC was ineffective in improving survival. In contrast, survival was significantly increased in the PDTC-12 animals versus PDTC+1 and HSR groups. Analysis of physiologic parameters demonstrated that elevations in base deficit and lactate levels following hemorrhage were blunted by PDTC administration in the PDTC-12 group. At time of death, creatinine, ALT, and AST levels were significantly higher in HSR versus PDTC-12 animals.ConclusionsAdministration of PDTC 12 h prior to HSR significantly improves survival through preservation of organ function.     

RhBMP-7 improves survival and eruption in a growing tooth avulsion trauma model

Long-term loss of avulsed and replanted teeth is a frequent clinical problem. Bone morphogenetic protein-7 (BMP 7) induces cementogenesis in periodontitis-associated periodontal ligament (PDL) defects. This study's aim was to assess the utility of rhBMP 7 in a tooth avulsion trauma model in growing individuals. Immature primary incisors of 12 minipigs were extracted. PDL and cementum were removed either partially (group 1: 4 mm2 [n=28 teeth]; group 2: 16 mm2 [n=26 teeth]) or totally (group 3 [n=26 teeth]). 500 microg rhBMP 7/g collagen matrix was applied to the teeth from one side while the corresponding teeth on the contralateral side served as controls (split mouth model). After an experimental period of 4 months, microradiography, fluorescence and light microscopy of nondecalcified sections were performed. All teeth of group 1 survived and all teeth of group 3 were lost, whether rhBMP-7 was applied or not. In group 2, nine out of ten teeth survived when rhBMP-7 was applied and four out of ten teeth were lost when rhBMP-7 was not applied. In the presence of rhBMP-7, eruption of teeth in group 2 was significantly improved (difference [median]: 5 mm, P<0.05, n=6). Even though there was a tendency towards increased deposition rates of cementum under rhBMP-7, this difference was not significant (Wilcoxon: P>0.05, ANOVA: P=0.002; n=6/group). In conclusion, rhBMP-7 improved survival rates and eruption of replanted teeth in growing individuals. No adverse effects were seen. Based on the present results, future clinical trials appear to be warranted.     

Transient receptor potential vanilloid 1 antagonist, capsazepine, improves survival in a rat hemorrhagic shock model

OBJECTIVE: To evaluate the role of transient receptor potential vanilloid 1 (TRPV1) in a rat hemorrhagic shock (HS) model using the TRPV1 antagonist, capsazepine (CPZ). SUMMARY BACKGROUND DATA: TRPV1, distributed within the sensory nerve, plays a role in the regulation of cardiovascular functions. TRPV1 may be involved in the cardiovascular responses to HS. METHODS: Male rats were anesthetized and HS was induced with the mean arterial pressure (MAP) at 30 mm Hg for 90 minutes. CPZ (5.0 micromol/kg) was administered at 30 minutes after the shock induction, and the 24-hour survival rates were assessed. The MAP, heart rate, and shed blood volume (SBV) were recorded throughout the experiment. Arterial blood gas analysis and the plasma catecholamines levels were measured before and after HS. Double-immunohistochemistry for Fos and tyrosine hydroxylase (TH) was performed in the rostral ventrolateral medulla (RVLM) of the brain. RESULTS: CPZ significantly improved the 24-hour survival rates, which was accompanied by the increase in the MAP and the SBV, a decrease of the plasma catecholamines levels, and attenuation of the severe metabolic acidosis. Furthermore, CPZ reduced the percentage of double-labeled neurons for Fos and TH in the RVLM of the rat brain. CONCLUSIONS: TRPV1 may be involved in the regulation of the cardiovascular responses to HS, at least in part, by recruiting catecholaminergic neurons in the RVLM. CPZ appears to induce metabolic compensations, which may be potentially useful in HS.     

Aggressive treatment of acute kidney injury and hyperkalemia improves survival in a combat relevant trauma model in swine

IntroductionOur swine model of pulmonary contusion (PC) and hemorrhagic shock (HS) was initially complicated by renal failure, hyperkalemia, and premature death. To study the effects of novel therapies on organ failure, improved survival was necessary requiring the design of an aggressive treatment regimen.MethodsAnesthetized swine sustained either PC or PC with grade V liver injury to induce HS (PC + HS). After injury, animals were resuscitated followed by either standard care (SC) with maintenance intravenous fluids (IVF) and treatment at potassium level of 6.0 mmol/L (n = 7; 3 PC, 4 PC + HS) or aggressive care (AC) with increased initial IVF, early and frequent potassium monitoring, and treatment at potassium level of 5.0 mmol/L (n = 15, 8 PC, 7 PC + HS). Hyperkalemia was treated with calcium, insulin, and glucose in both groups.ResultsSurvival to 48 h was achieved in 13/15 (87%) in the AC group and 2/7 (29%) in the SC group (p = 0.014). Compared to SC, AC improved median survival (48 vs. 18 h, p = 0.008) and lowered potassium (5.0 vs. 7.5 mmol/L), creatinine (2.4 vs. 4.0 mg/dL), BUN (27.5 vs. 39.0 mg/dL), and lactate (0.97 vs. 3.57 mmol/L) at the last observed time-point prior to death. For PC + HS animals, survival to 48 h was achieved in 6/7 in the AC group and 0/4 in the SC group with an improved median survival in the AC group (48 vs. 18 h, p = 0.011)DiscussionAggressive and early hyperkalemia treatment prolongs survival while reducing kidney injury and potassium levels in a combat relevant injury model in swine.     

Haemorrhagic shock after severe blunt shoulder trauma

The management of severe injured patients requires life-threatening lesions research, especially potential haemorrhagic lesions. The haemorrhagic shock is a rare but serious complication of shoulder girdle traumas. We report in this study the clinical and paraclinical signs that lead us to take care from such evolution.     

Exsanguination protocol improves survival after major hepatic trauma

Background

Hepatic injury remains an important cause of exsanguination after major trauma. Recent studies have noted a dramatic reduction in mortality amongst severely injured patients when trauma exsanguinations protocols (TEP) are employed. We hypothesised that utilisation of our institution's TEP at the initiation of hospital resuscitation would improve survival in patients with significant hepatic trauma.

Patients and methods

All patients who (1) sustained intra-abdominal haemorrhage with Grades III-V hepatic injury and (2) underwent immediate operative intervention between February 2004 and January 2008 were included in the study. TEP was instituted in February 2006, and all subsequent patients who met inclusion criteria and were treated with TEP constituted the study group. Patients who met inclusion criteria, were treated before introduction of TEP, and received at least 10 units packed red blood cells in the first 24 h constituted pre-TEP comparison group. Univariate and multivariate analyses evaluated the effects of TEP on the study population.

Results

Seventy-five patients were included in the study: 39 in the pre-TEP cohort (31% 30-day survival) and 36 in the TEP cohort (53% 30-day survival). There were no differences in demographics, extent of hepatic injury, or operative approach between the patient groups (all p ≥ 0.27). Injury Severity Scores were significantly higher in the TEP group (41 ± 18 vs. 28 ± 15, p < 0.01). TEP patients received more plasma and platelets during operative intervention and significantly less crystalloid (all p < 0.01). Occurrence of cardiac dysfunction and abdominal compartment syndrome was significantly lower in TEP patients who survived 24-h post-injury (both p ≤ 0.04). After adjusting for the significant negative effects of Grade V injury and involvement of major hepatic vasculature (both p ≤ 0.02), TEP significantly improved 30-day survival: OR = 0.22, 95% CI: 0.06-0.81, p = 0.02.

Conclusions

TEP allows for an effective use of plasma and platelets during intra-operative management of severe hepatic injury. Utilisation of TEP is associated with significant reductions of cardiac dysfunction and development of abdominal compartment syndrome, as well as, significant improvement in 30-day survival.     

Vasopressin improves survival after cardiac arrest in hypovolemic shock

Survival after hypovolemic shock and cardiac arrest is dismal with current therapies. We evaluated the potential benefits of vasopressin versus large-dose epinephrine in hemorrhagic shock and cardiac arrest on vital organ perfusion, and the likelihood of resuscitation. In 18 pigs, 35% of the estimated blood volume was withdrawn over 15 min and ventricular fibrillation was induced 5 min later. After 4 min of cardiac arrest and 4 min of standard cardiopulmonary resuscitation, a bolus dose of either 200 microg/kg epinephrine (n = 7), 0.8 unit/kg vasopressin (n = 7), or saline placebo (n = 4) was administered in a blinded, randomized manner. Defibrillation was attempted 2.5 min after drug administration, and all animals were subsequently observed for 1 h without further intervention. Spontaneous circulation was restored in 7 of 7 vasopressin animals, in 6 of 7 epinephrine pigs, and in 0 of 4 placebo swine. At 5 and 30 min after return of spontaneous circulation, median (minimum and maximum) renal blood flow after epinephrine was 2 (0-31), and 2 (0-48) mL. 100 g(-1). min(-1), respectively; and after vasopressin 96 (12-161), and 44 (16-105) mL. 100 g(-1). min(-1), respectively (P: <.01 between groups). Epinephrine animals developed a profound metabolic acidosis by 15 min after return of spontaneous circulation (mean arterial pH, 7.11 +/- 0.01), and by 60 min all epinephrine-treated animals had died. The vasopressin pigs had (P: = 0.015) less acidosis (pH = 7.26+/-0. 04) at corresponding time points, and all survived > or =55 min (P: < 0. 01). In conclusion, treatment of hypovolemic cardiac arrest with vasopressin, but not with large-dose epinephrine or saline placebo, resulted in sustained vital organ perfusion, less metabolic acidosis, and prolonged survival. Based on these findings, clinical evaluation of vasopressin during hypovolemic cardiac arrest may be warranted. IMPLICATIONS: The chances of surviving cardiac arrest in hemorrhagic shock are considered dismal without adequate fluid replacement. However, treatment of hypovolemic cardiac arrest with vasopressin, but not with large-dose epinephrine or saline placebo, resulted in sustained vital organ perfusion and prolonged survival in an animal model of suspended infusion therapy.     

Increased survival among severe trauma patients: the impact of a national trauma system

HYPOTHESIS: The survival of severe trauma patients is affected by the implementation of a national trauma system, which brought about developments both at the hospital and prehospital levels during the past decade. DESIGN: A retrospective cohort study of all severely injured patients (Injury Severity Score >16) recorded in the Israeli National Trauma Registry at all level I trauma centers in Israel from January 1, 1997, to December 31, 2001. Inpatient death rates were examined overall and by subgroups. SETTING: The National Trauma Registry includes trauma (International Statistical Classification of Diseases, 9th Revision, Clinical Modification diagnosis codes 800-959) hospitalizations, patients who were transferred to or from other hospitals, and those who died in the emergency department. It excludes patients who were dead on arrival, discharged following treatment in the emergency department, and patients who do not fall into the definition of trauma.Main Outcome Measure Inpatient death. RESULTS: Seven thousand four hundred twenty-three severe trauma patients were recorded. Inpatient death rates decreased significantly from 21.6% in 1997 to 14.7% in 2001. The odds ratios of mortality in 1998 through 2001 vs 1997, adjusted for year, age, sex, penetrating injury, and severity of injury (Injury Severity Score >25), were 0.92, 0.89, 0.70, and 0.65, respectively, confirming the downward trend. CONCLUSIONS: A steady significant reduction in the inpatient death rate of severe trauma patients hospitalized at all level I trauma centers in Israel between 1997 and 2001 was observed. Although a single factor that explains the reduction was not identified, it is evident that the establishment of the trauma system brought about a significant decrease in mortality. We believe that integrated cooperation of various components of the national trauma system in Israel across the years may explain the reduction.     

Cysteine-rich matricellular protein improves callus regenerate in a rabbit trauma model

Purpose

Open fractures with severe soft-tissue trauma are predisposed to poor bone healing. The vital coupling between osteo- and angiogenesis is disturbed. Cysteine-rich protein 61 (CYR61) is an angiogenic inducer promoting vascularisation. However, little is known about the effect of CYR61 on the callus regenerate after acute musculoskeletal trauma. Therefore, our aim was to determine whether local administration of CYR61: (1) has an influence on callus formation and remodelling, (2) increases bone volume and (3) partially restores callus stability.

Methods

A musculoskeletal trauma was created in 20 rabbits. To simulate fracture-site debridement, the limb was shortened. In the test group, a CYR61-coated collagen matrix was locally applied around the osteotomy. After ten days, gradual distraction was commenced (0.5 mm/12 h) to restore the original length. New bone formation was evaluated histomorphometrically, radiographically and biomechanically.

Results

Osseus consolidation occured in all animals. Average maximum callus diameter was higher in the test group [1.39 mm; standard deviation (SD) = 0.078 vs 1.26 mm (SD = 0.14); p = 0.096]. In addition, bone volume was higher (p = 0.11) in the test group, with a mean value of 49.73 % (SD = 13.68) compared with 37.6 % (SD = 5.91). Torsional strength was significantly higher (p = 0.005) in the test group [105.43 % (SD = 31.68 %) vs. 52.57 % (SD = 24.39)]. Instead, stiffness of the newly reconstructed callus decreased (64.21 % (SD = 11.52) vs. 71.30 % (SD = 32.25) (p = 0.81)).

Conclusions

CYR61 positively influences callus regenerate after acute trauma, not only histologically and radiographically but also biomechanically, most probably by a CYR61-associated pathway.     

The pineal gland hormone melatonin improves survival in a rat model of sepsis/shock induced by zymosan A

BACKGROUND: Melatonin has demonstrated protective effects in severe sepsis/shock in the animal model. Zymosan A causes inflammation and shock leading to death in rats. We hypothesized that daily afternoon melatonin administration would improve rat survival after an intraperitoneal (IP) zymosan injection. METHODS: Adult male rats, maintained on a 12L:12D photoperiod, received a single IP injection of either zymosan (500 mg/kg) or paraffin vehicle at 1200 hours. At 1700 hours and daily thereafter, zymosan-injected rats received subcutaneous injections of either melatonin (0.8 mg/kg) or saline (SAL). Any surviving animals were killed on day 10 to obtain wet organ weights. RESULTS: Three independent experiments produced similar results. In each zymosan+SAL group, all animals died by day 4. In the melatonin-treated groups combined, 33/45 rats survived (73.33%, P<.00002). Posthumous body weight was greater in melatonin-treated animals compared with the zymosan+SAL groups (P<.001). Mean splenic weight in the melatonin-treated groups was twice that of the control groups (P<.001). CONCLUSION: Melatonin administered in the late afternoon after a lethal dose of zymosan significantly improved animal survival. Melatonin has no known adverse effects in humans and may represent a novel treatment for sepsis/shock.     

Superoxide dismutase polyethylene glycol improves survival in hemorrhagic shock.

Oxygen free radicals are known to form after reperfusion of ischemic tissue. To test the role and importance of oxygen free radicals in hemorrhagic shock, an animal model of hemorrhagic shock and resuscitation was utilized. Sprague-Dawley rats were anesthetized with halothane and then subjected to approximately 50 per cent blood volume hemorrhage (30 cc/kg), followed by a 60 min shock period. Resuscitation was performed over 1 hour with lactated ringers (LR) at a volume of two times blood loss (60 cc/kg). This model results in a survival rate of 25 per cent over 72 hrs. Using this model, animals were randomized to receive either LR, Superoxide Dismutase-Polyethylene Glycol (SOD-PEG) (15,000 units/kg) with LR or Catalase-Polyethylene Glycol (CAT-PEG) (175,000 units/kg) with LR. The group treated with SOD-PEG demonstrated significantly increased survival rates vs the group treated with LR (67% vs 25%, P = 0.02). The group treated with CAT-PEG demonstrated no significant improvement in survival when compared to the LR-treated group (20% vs 24%). These data suggest that treatment directed toward oxygen free radicals and reperfusion injury may play an important role in hemorrhagic shock resuscitation.     

Non-cavitary hemorrhage producing shock in trauma patients: incidence and severity

Intraperitoneal and intrathoracic bleeding, cavitary hemorrhage (CH), are recognized as major causes of hypovolemic shock in trauma patients. Blood loss from fractures and lacerations, non-cavitary hemorrhage (NCH), is not considered a common cause of shock. Of 466 trauma patients admitted during a 12-month period without spinal cord injury, burns, or ongoing CPR, 13.1% were admitted in hypovolemic shock. Of these 466 patients 55.7% had strictly non-cavitary sources of blood loss, most commonly long bone fractures and skin lacerations. There was no significant difference in the resuscitative fluid requirements, morbidity, or mortality between patients presenting in hypovolemic shock due to CH and NCH. Blood loss from NCH must be recognized as a significant source of hypovolemic shock in trauma patients.