Effects of hemodilution on coagulation function during prolonged hypotensive resuscitation in a porcine model of severe hemorrhagic shock.

Background: Although hemorrhage remains the leading cause of survivable death in casualties, modern conflicts are becoming more austere limiting available resources to include resuscitation products. With limited resources also comes prolonged evacuation time, leaving suboptimal prehospital field care conditions. When blood products are limited or unavailable, crystalloid becomes the resuscitation fluid of choice. However, there is concern of continuous crystalloid infusion during a prolonged period to achieve hemodynamic stability for a patient. This study evaluates the effect of hemodilution from a 6-hour prehospital hypotensive phase on coagulation in a porcine model of severe hemorrhagic shock. Methods: Adult male swine (n=5/group) were randomized into three experimental groups. Non-shock (NS)/normotensive did not undergo injury and were controls. NS/permissive hypotensive (PH) was bled to the PH target of systolic blood pressure (SBP) 85±5 mm Hg for 6 hours of prolonged field care (PFC) with SBP maintained via crystalloid, then recovered. Experimental group underwent controlled hemorrhage to mean arterial pressure 30 mm Hg until decompensation (Decomp/PH), followed by PH resuscitation with crystalloid for 6 hours. Hemorrhaged animals were then resuscitated with whole blood and recovered. Blood samples were collected at certain time points for analysis of complete blood counts, coagulation function, and inflammation. Results: Throughout the 6-hour PFC, hematocrit, hemoglobin, and platelets showed significant decreases over time in the Decomp/PH group, indicating hemodilution, compared with the other groups. However, this was corrected with whole blood resuscitation. Despite the appearance of hemodilution, coagulation and perfusion parameters were not severely compromised. Conclusions: Although significant hemodilution occurred, there was minimal impact on coagulation and endothelial function. This suggests that it is possible to maintain the SBP target to preserve perfusion of vital organs at a hemodilution threshold in resource-constrained environments. Future studies should address therapeutics that can mitigate potential hemodilutional effects such as lack of fibrinogen or platelets. Level of evidence: Not applicable-Basic Animal Research.

Cerebral Regional Tissue Oxygenation as Surrogate for Blood Loss in Nonhuman Primate Models of Shock.

INTRODUCTION: Hemorrhage is the leading cause of preventable death, with a majority of mortalities in the prehospital setting. Current hemorrhage resuscitation guidelines cannot predict the critical point of intervention to activate massive transfusion (MT) and prevent cardiovascular decompensation. We hypothesized that cerebral regional tissue oxygenation (CrSO2) would indicate MT need in nonhuman primate models of hemorrhagic shock. METHODS: Nineteen anesthetized male rhesus macaques underwent hemorrhage via a volume-targeted (VT) or pressure-targeted (PT) method. VT animals were monitored for 30 min following 30% blood volume hemorrhage. PT animals were hemorrhaged to mean arterial pressure (MAP) of 20 mmHg and maintained for at least 60 min until decompensation. Statistics for MAP, heart rate (HR), end tidal carbon dioxide (EtCO2), and CrSO2 were analyzed via one- or two-way repeated-measures analysis of variance, Pearson's R, and receiver-operator curve. A P < 0.05 is considered significant. RESULTS: Following initial hemorrhage (S0), there were no significant differences between groups. After cessation of hemorrhage in the VT group, MAP and EtCO2 returned to baseline while CrSO2 plateaued. The PT group maintained model-defined low MAP, suppressing EtCO2, and significantly decreased CrSO2 compared to the VT group by S25. Linear regression of CrSO2versus shed blood volume demonstrated R2 = 0.7539. CrSO2 of 47% was able to detect >40% blood loss with an area under the curve of 0.9834 at 92.3% (66.7%-99.6%) sensitivity and 95.5% (84.9%-99.2%) specificity. CONCLUSIONS: Regardless of hemorrhage modality and compensatory response, CrSO2 correlated strongly with shed blood volume. Analysis demonstrated that CrSO2 values below 49% indicate Advanced Trauma Life Support class IV shock (blood loss>40%). CrSO2 at the point of care may help indicate MT need earlier and more accurately than traditional markers.

Therapeutic cardiac arrest as an adjunct to resuscitative endovascular balloon occlusion of the aorta: Bridging the gap from fatal hemorrhage to definitive surgical control in swine.

BACKGROUND: Uncontrolled hemorrhage is the leading cause of potentially survivable combat casualty mortality, with 86.5% of cases resulting from noncompressible torso hemorrhage. Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a minimally invasive technique used to stabilize patients with noncompressible torso hemorrhage; however, its application can take an average of 8 minutes to place. One therapeutic capable of bridging this gap is adenosine-lidocaine-magnesium (ALM), which at high doses induces a reversible cardioplegia. We hypothesize by using ALM as an adjunct to REBOA, the ALM-induced cardiac arrest will temporarily halt exsanguination and reduce blood loss, allowing for REBOA placement and control of bleeding. METHODS: Male Yorkshire swine (60-80 kg) were randomly assigned to REBOA only or ALM-REBOA (n = 8/group). At baseline, uncontrolled hemorrhage was induced via a 1.5-cm right femoral arteriotomy, and hemorrhaged blood was quantified. One minute after injury (S1), ALM was administered, and 7 minutes later (T0), zone 1 REBOA inflation occurred. If cardiac arrest ensued, cardiac function either recovered spontaneously or advanced life support was initiated. At T30, surgical hemostasis was obtained, and REBOA was deflated. Animals were resuscitated until they were humanely euthanized at T90. RESULTS: During field care phase, heart rate and end-tidal CO2 of the ALM-REBOA group were significantly lower than the REBOA only group. While mean arterial pressure significantly decreased from baseline, no significant differences between groups were observed throughout the field care phase. There was no significant difference in survival between the two groups (ALM-REBOA = 89% vs. REBOA only = 100%). Total blood loss was significantly decreased in the ALM-REBOA group (REBOA only = 24.32 ± 1.89 mL/kg vs. ALM-REBOA = 17.75 ± 2.04 mL/kg, p = 0.0499). CONCLUSION: Adenosine-lidocaine-magnesium is a novel therapeutic, which, when used with REBOA, can significantly decrease the amount of blood loss at initial presentation, without compromising survival. This study provides proof of concept for ALM and its ability to bridge the gap between patient presentation and REBOA placement.

Evaluation of prolonged 'Permissive Hypotension': results from a 6-hour hemorrhage protocol in swine.

BACKGROUND: Tactical Combat Casualty Care guidelines for hemorrhage recommend resuscitation to systolic blood pressure (SBP) of 85±5 mm Hg during prehospital care. Success depends on transport to definitive care within the 'golden hour'. As future conflicts may demand longer prehospital/transport times, we sought to determine safety of prolonged permissive hypotension (PH). METHODS: Adult male swine were randomized into three experimental groups. Non-shock (NS)/normotensive underwent anesthesia only. NS/PH was bled to SBP of 85±5 mm Hg for 6 hours of prolonged field care (PFC) with SBP maintained via crystalloid, then recovered. Experimental group underwent controlled hemorrhage to mean arterial pressure 30 mm Hg until decompensation (Decomp/PH), followed by 6 hours of PFC. Hemorrhaged animals were then resuscitated with whole blood and observed for 24 hours. Physiologic variables, blood, tissue samples, and neurologic scores were collected. RESULTS: Survival of all groups was 100%. Fluid volumes to maintain targeted SBP in PFC were significantly higher in the hemorrhage group than sham groups. After 24 hours' recovery, no significant differences were observed in neurologic scores or cerebrospinal fluid markers of brain injury. No significant changes in organ function related to treatment were observed during PFC through recovery, as assessed by serum chemistry and histological analysis. CONCLUSIONS: After 6 hours, a prolonged PH strategy showed no detrimental effect on survival or neurologic outcome despite the increased ischemic burden of hemorrhage. Significant fluid volume was required to maintain SBP-a potential logistic burden for prehospital care. Further work to define maximum allowable time of PH is needed. STUDY TYPE: Translational animal model. LEVEL OF EVIDENCE: N/A.

Cerebral Blood Flow in Polytrauma: Transcranial Doppler Analysis in a Nonhuman Primate Shock Model.

BACKGROUND: In combat-related trauma, resuscitation goals are to attenuate tissue hypoxia and maintain circulation. During hemorrhagic shock, compensatory and autoregulatory mechanisms are activated to preserve cerebral blood flow. Transcranial Doppler (TCD) ultrasonography may be an ideal noninvasive modality to monitor cerebral hemodynamics. Using a nonhuman primate (NHP) model, we attempted to characterize cerebral hemodynamics during polytraumatic hemorrhagic shock using TCD ultrasonography. MATERIALS AND METHODS: The ophthalmic artery was insonated at multiple time points during varying stages of shock. Hemorrhage was controlled and pressure targeted to 20 mmHg to initiate and maintain the shock period. Mean flow velocity (MFV), peak systolic velocity (PSV), end diastolic velocity (EDV), pulsatility index (PI), and resistance index (RI) were recorded. Results represent mean ± standard deviation; statistical significance is P < 0.05; n = 12. RESULTS: Compared to baseline, MFV, PSV, EDV, and RI show significant changes after 60 min of hemorrhagic shock, (9.81 ± 3.60 cm/s; P < 0.01), (21.15 ± 8.59 cm/s; P < 0.01), (5.15 ± 0.21 cm/s; P < 0.01), (0.70 ± 0.11; P < 0.05), respectively. PI did not change during hemorrhagic shock. At end of prehospital care (T30), cerebral flow recovers for MFV, PSV, and RI while EDV remained decreased at T30 (6.15 ± 1.13 cm/s; P < 0.01) and 1 h of simulated transport (T90) (5.87 ± 0.62 cm/s; P < 0.01). Changes in PI at T30 and T90 were not significant. MFV diminished (16.45 ± 3.85 cm/s; P < 0.05) at T90. CONCLUSIONS: This study establishes baseline and hemorrhagic shock values for NHP cerebral blood flow velocities and cerebrovascular indices. TCD ultrasonography may represent an important area of research for targeted resuscitation investigations using a hemorrhagic shock model in NHPs.

Exploratory Laparotomy for Proximal Vascular Control in Combat-Related Injuries.

BACKGROUND: Combat casualties have endured an increase in traumatic lower extremity amputations secondary to improvised explosive devices. Often surgical control of the proximal vasculature is required. We evaluate the safety profile of exploratory laparotomy (EXLAP) for proximal control (PC) in combat-injured patients. METHODS: Records of 845 combat casualties from June 2009 to December 2011 were reviewed. Patients undergoing EXLAP were divided by indication into PC and non-PC groups. Demographics, Injury Severity Score, mechanism of injury, transfusion requirements, EXLAP findings, reoperation rates, and abdominal-related complications were recorded. RESULTS: 44 patients were identified as PC and 91 as non-PC. Age was similar (23.7 ± 4.1 vs. 24.0 ± 4.6, p = 0.7138), and all were male. Improvised explosive devices blast was the most common mechanism of injury. Injury Severity Score (25.8 ± 8.2 vs. 21.4 ± 9.1, p = 0.0075), lower extremity amputation (93.1% vs. 28.6%, p = 0.0001), and transfusion requirements were different. Days to fascial closure (1.8 ± 1.9 vs. 1.7 ± 2.8, p = 0.8308) and number of EXLAPs were similar (2.4 ± 1.3 vs. 2.1 ± 1.5, p = 0.2581). PC had higher complications (43.1% vs. 24.2%, p = 0.0292). CONCLUSION: PC demonstrated an increase in abdominal complications. The reason for this remains unclear. Alternative approaches of achieving proximal vascular control may avoid the morbidity associated with laparotomy, and predeployment training of such procedures should be considered for the general surgeon. Further studies are warranted to determine best practices for these patients.

Evaluating the impact of a minimally invasive pediatric surgeon on hospital practice: comparison of two children's hospitals.

PURPOSE: Widespread adoption of minimally invasive surgery (MIS) techniques in pediatric surgery has progressed slowly, and the shift in practice patterns has been variable among surgeons. We hypothesized that a pediatric surgeon committed to MIS could effectively change surgical practice by creating an emphasis on MIS. METHODS: Annual case volumes from 2000 to 2009 at two tertiary care pediatric hospitals, one with a dedicated minimally invasive pediatric surgeon, were evaluated for trends in MIS for ten different operations. Univariate analyses of the differences between hospitals in the use of the open versus laparoscopic approach were performed. The Breslow-Day test was used to examine differences in use of laparoscopic procedures across hospitals in early versus middle and middle versus late time periods. RESULTS: Between the two hospitals, for 9 of the 10 types of surgery, the number of laparoscopic and open procedures differed significantly (p values ranged from <0.0001 to 0.003). Over the 10-year period, the hospital with a dedicated MIS surgeon had a larger proportion of procedures done laparoscopically for all years. This difference reached statistical significance for appendectomy (p < 0.0001), congenital diaphragmatic hernia (p < 0.0002), chest wall reconstruction (p < 0.0001), cholecystectomy (p = <0.0001), gastrostomy (p < 0.0001), nissen fundoplication (p < 0.0001) oophorectomy (p < 0.0001), pyloromyotomy (p < 0.0001) and splenectomy (p = 0.0006). After grouping the years into early (2000-2003), middle (2004-2006) and late (2007-2009) categories, the hospital with a dedicated MIS surgeon had a significantly higher rate of increase in use of laparoscopic surgery between the early and middle years for four procedures: diaphragmatic hernia repair (p = 0.003), chest wall reconstruction (p = 0.0086), cholecystectomy (0.0083) and endorectal pull-through (p = 0.025). CONCLUSION: The presence of a dedicated minimally invasive pediatric surgeon led to a significant change in surgical practice with an overall trend of increasing MIS several years in advance of a hospital that did not have a dedicated MIS surgeon. This has implications for resident training in academic medical centers and potential patient care outcomes.

Ratio-driven resuscitation predicts early fascial closure in the combat wounded.

BACKGROUND: Operation Iraqi Freedom and Operation Enduring Freedom have seen the highest rates of combat casualties since Vietnam. These casualties often require massive transfusion (MT) and immediate surgical attention to control hemorrhage. Clinical practice guidelines dictate ratio-driven resuscitation (RDR) for patients requiring MT. With the transition from crystalloid to blood product resuscitation, we have seen fewer open abdomens in combat casualties. We sought to determine the effect RDR has on achieving early definitive abdominal fascial closure in combat casualties undergoing exploratory laparotomy. METHODS: Records of 1,977 combat casualties admitted to a single US military hospital from April 2003 to December 2011 were reviewed. Patients receiving an MT and laparotomy in theater constituted the study cohort. The cohort was divided into RDR, defined as a ratio of 0.8-U to 1.2-U packed red blood cells to 1-U fresh frozen plasma, and No-RDR groups. Age, injury patterns, mechanism of injury, injury severity, blood products, number of laparotomies, and days to fascial closure were collected. Assessed outcomes were number of days (early ≤ 2 days) and number of laparotomies to achieve fascial closure. RESULTS: The mean age of the study cohort (n = 172) was 24.0 years, and mean Injury Severity Score (ISS) was 24.8. Improvised explosive device blast was the most common mechanism of injury (74.4%). The cohort was divided into RDR patients (n = 73) and no RDR (n = 99). There was no difference in mean age, mean ISS, or rate of nontherapeutic exploratory laparotomies between the groups. RDR patients had a significantly lower abdominal injury rate (34.2% vs. 72.7%, p < 0.01), had fewer laparotomies (2.7 vs. 4.3, p = 0.003), and achieved primary fascial closure faster (2.4 days vs. 7.2 days, p = 0.004). On multivariate analysis, RDR (2.74; 95% confidence interval, 1.44-5.2) was an independent predictor for early fascial closure. CONCLUSION: Adherence to RDR guidelines resulted in significantly decreased number of abdominal operations and was identified as an independent predictor for early fascial closure. Further investigation is warranted to validate these findings. LEVEL OF EVIDENCE: Therapeutic study, level III.

Cerebellar inactivation impairs memory of learned prism gaze-reach calibrations.

Three monkeys performed a visually guided reach-touch task with and without laterally displacing prisms. The prisms offset the normally aligned gaze/reach and subsequent touch. Naive monkeys showed adaptation, such that on repeated prism trials the gaze-reach angle widened and touches hit nearer the target. On the first subsequent no-prism trial the monkeys exhibited an aftereffect, such that the widened gaze-reach angle persisted and touches missed the target in the direction opposite that of initial prism-induced error. After 20-30 days of training, monkeys showed long-term learning and storage of the prism gaze-reach calibration: they switched between prism and no-prism and touched the target on the first trials without adaptation or aftereffect. Injections of lidocaine into posterolateral cerebellar cortex or muscimol or lidocaine into dentate nucleus temporarily inactivated these structures. Immediately after injections into cortex or dentate, reaches were displaced in the direction of prism-displaced gaze, but no-prism reaches were relatively unimpaired. There was little or no adaptation on the day of injection. On days after injection, there was no adaptation and both prism and no-prism reaches were horizontally, and often vertically, displaced. A single permanent lesion (kainic acid) in the lateral dentate nucleus of one monkey immediately impaired only the learned prism gaze-reach calibration and in subsequent days disrupted both learning and performance. This effect persisted for the 18 days of observation, with little or no adaptation.

Purkinje cell spike firing in the posterolateral cerebellum: correlation with visual stimulus, oculomotor response, and error feedback.

Complex (CS)- and simple-spike (SS) discharge from single Purkinje cells (Pc) in the posterolateral cerebellum of two monkeys was recorded during a visually guided reach-touch task. A visual target appeared (TA) off-gaze at a random location on a screen. On initiation of arm reach, the target disappeared, then reappeared (TR) after a fixed delay. TR was either at the same location (baseline condition) or a shifted location at a fixed distance and direction from TA location (shift condition). Across trials, we observed one or two peaks of CS activity, depending on the reach condition. The first CS (T1 CS) peak was tuned to the location of TA on the screen, following TA by approximately 150 ms. The second CS (T2 CS) peak occurred only in the shift condition, was tuned to the shift location of TR, and followed TR by approximately 150 ms. The locational preferences of T1 and T2 CS peaks were the same. T1 and T2 CSs preceded saccades to TA and TR at the preferred location and occurred during reaches with either arm. T1 CSs occurred during trials in which the target appeared, and there was a saccade to target, but no subsequent arm reach followed. SS firing varied with TA/TR in the same preferred location as for the accompanying CS. We conclude that posterolateral Pc CS and SS firing changes following an off-gaze visual target appearance in a preferred location when there is a subsequent saccade to that location.