Tomohiko Masuno

The abdominal compartment syndrome as a second insult during systemic neutrophil priming provokes multiple organ injury.

In our recent clinical study of damage control laparotomy, the abdominal compartment syndrome (ACS) emerged as an independent risk factor for postinjury multiple organ failure (MOF). We and others have shown previously that the ACS promotes the systemic production of proinflammatory cytokines. Our study objective was to develop a clinically relevant two-event animal model of postinjury MOF using the ACS as a second insult during systemic neutrophil priming to provoke organ dysfunction. Male adult rats underwent hemorrhagic shock (30 mmHg × 45 min) and were resuscitated with crystalloids and shed blood. The timing of postshock systemic neutrophil (PMN) priming was determined by the surface expression of CD11b via flow cytometry. Finding maximal PMN priming at 8 h, but no priming at 2 h (early) and 18 h (late), the ACS (25 mmHg × 60 min) was introduced at these time points. At 24 h postshock, lung injury was assessed by lung elastase concentration and Evans blue dye extravasation in bronchoalveolar lavage. Liver and renal injuries were determined by serum alanine aminotransferase, serum creatinine, and blood urea nitrogen. The ACS during the time of maximal systemic PMN priming (8 h) provoked lung and liver injury, but did not if introduced at 2 or 18 h postshock when there was no evidence of systemic PMN priming. The 24-h mortality of this two-event model was 33%. These findings corroborate the potential for the ACS to promote multiple organ injury when occurring at the time of systemic PMN priming. This clinically relevant two-event animal model of PMN organ injury may be useful in elucidating therapy strategies to prevent postinjury MOF.

Hemoglobin-Based Oxygen Carriers in Trauma Care: Scientific Rationale for the US Multicenter Prehosptial Trial

BackgroundThe greatest need for blood substitutes worldwide is in patients with unanticipated acute blood loss, and trauma is the most likely scenario. The blood substitutes reaching advanced clinical trials today are red blood cell (RBC) substitutes derived from hemoglobin. The hemoglobin-based oxygen carriers (HBOCs) tested currently in advanced clinical trials are polymerized hemoglobin solutions.MethodsIn the USA, the standard approach to restoring oxygen delivery for hemorrhagic shock has been crystalloid administration to expand intravascular volume, followed by stored RBCs for critical anemia. Allogeneic RBCs, however, may have adverse immunoinflammatory effects that increase the risk of postinjury multiple organ failure (MOF). Phase II in hospital clinical trials, as well as in vitro and in vivo work, suggest that resuscitation with an HBOC—in lieu of stored RBCs—attenuates the systemic inflammatory response invoked in the pathogenesis of MOF. Specifically, an HBOC has been shown to obviate stored RBC-provoked polymorphonuclear neutrophil (PMN) priming, endothelial activation, and systemic release of interleukins (IL) 6, 8, and 10. In a 2-event rodent study of shock-induced PMN-mediated acute respiratory distress syndrome (ARDS), the simulated prehospital administration of an HBOC markedly attenuated lung injury.ResultsBased on this background and work by others, we have initiated a US multicenter prehospital trial in which severely injured patients with major blood loss [systolic blood pressure (SBP) ≤90 mmHg] are randomized to initial field resuscitation with crystalloid versus HBOC. During the hospital phase, the control group is further resuscitated with stored RBCs whereas the study group receives HBOC (up to 6 units) in the first 12 hours. The primary study endpoint is decreased 30-day mortality, and secondary endpoints include reductions in administration of allogeneic RBCs and uncrossmatched RBCs; avoiding circulating hemoglobin levels <5 g/dl; and decreased ARDS and MOF.ConclusionsTo date, >500 injured patients have been enrolled in this multicenter trial, and the final interim analyses support the original target of 720.

Time course of recovery from cerebral vulnerability after severe traumatic brain injury : A microdialysis study

BACKGROUND The aim of this study was to evaluate the time course of recovery from cerebral vulnerability, using microdialysis (MD) technique and cerebral vascular autoregulation measurement, to clarify the appropriate timing of subsequent major surgical procedures, and to minimize the possibility of secondary brain injury in patients with severe traumatic brain injury (STBI). METHODS In 3,470 MD samples of 25 patients with STBI, cerebral extracellular biomarkers (glucose, lactate, pyruvate, glycerol, and glutamate) were measured. In addition, to estimate cerebral vascular autoregulaton, the pressure reactivity index (PRx) was calculated with intracranial pressure (ICP) and mean arterial pressure. The data with ICP, cerebral perfusion pressure (CPP), and PRx were collected hourly for 7 days after injury and they were compared with MD biomarkers daily. RESULTS During the study period, the average ICP and CPP remained stable and were within the threshold of STBI treatment guidelines. After injury, the extracellular glucose concentration decreased, and the levels of glycerol, glutamate, and lactate/pyruvate ratio (LPR), which indicate cerebral ischemia and neural cell damage, increased. On the fourth day after injury, the extracellular glucose concentration improved, and the value of LPR decreased. The average PRx decreased daily and became negative on the fifth day after injury. CONCLUSION Our results indicated that cerebral vascular autoregulation would recover on the fourth day after STBI, and cerebral perfusion might be increased by recovery of autoregulation. Thus, subsequent nonemergent surgery should be performed at least 4 days after STBI to prevent secondary brain injury. In addition, we should keep in mind that the cerebral vulnerability might persist for 4 days after suffering STBI.

Quantitative pupillometry and neuron-specific enolase independently predict return of spontaneous circulation following cardiogenic out-of-hospital cardiac arrest: a prospective pilot study

This study aimed to identify neurological and pathophysiological factors that predicted return of spontaneous circulation (ROSC) among patients with out-of-hospital cardiac arrest (OHCA). This prospective 1-year observational study evaluated patients with cardiogenic OHCA who were admitted to a tertiary medical center, Nippon Medical School Hospital. Physiological and neurological examinations were performed at admission for quantitative infrared pupillometry (measured with NPi-200, NeurOptics, CA, USA), arterial blood gas, and blood chemistry. Simultaneous blood samples were also collected to determine levels of neuron-specific enolase (NSE), S-100b, phosphorylated neurofilament heavy subunit, and interleukin-6. In-hospital standard advanced cardiac life support was performed for 30 minutes.The ROSC (n = 26) and non-ROSC (n = 26) groups were compared, which a revealed significantly higher pupillary light reflex ratio, which was defined as the percent change between maximum pupil diameter before light stimuli and minimum pupil diameter after light stimuli, in the ROSC group (median: 1.3% [interquartile range (IQR): 0.0–2.0%] vs. non-ROSC: (median: 0%), (Cut-off: 0.63%). Furthermore, NSE provided the great sensitivity and specificity for predicting ROSC, with an area under the receiver operating characteristic curve of 0.86, which was created by plotting sensitivity and 1-specificity. Multivariable logistic regression analyses revealed that the independent predictors of ROSC were maximum pupillary diameter (odds ratio: 0.25, 95% confidence interval: 0.07–0.94, P = 0.04) and NSE at admission (odds ratio: 0.96, 95% confidence interval: 0.93–0.99, P = 0.04). Pupillary diameter was also significantly correlated with NSE concentrations (r = 0.31, P = 0.027). Conclusively, the strongest predictors of ROSC among patients with OHCA were accurate pupillary diameter and a neuronal biomarker, NSE. Quantitative pupillometry may help guide the decision to terminate resuscitation in emergency departments using a neuropathological rationale. Further large-scale studies are needed.

536: SERIAL MEASUREMENTS OF AUDITORY BRAINSTEM RESPONSE CAN PREDICT PATIENT OUTCOMES WITH MORE PRECISION

effect of rAIH on neuroinflammation in non-spinal CNS regions is not known, nor is its effect on microglia, CNS immune cells that mediate inflammatory responses to CIH. We hypothesized that rAIH would down-regulate microglial inflammatory gene expression in a CNS region-dependent manner. Methods: Using real time PCR, we measured mRNA levels of inflammatory factors following rAIH treatment in 8 healthy adult Sprague-Dawley rats. A comparison group of 8 control rats were subjected to identical exposure conditions but received room air in place of episodic 10.5% O2. We compared the cellular sources of gene expression in immunomagnetically-isolated microglia and CNS tissue homogenates from the frontal cortex, brainstem, and upper and lower cervical spinal cord. Results: We found that rAIH did not elicit increases in the relative expression of the inflammatory genes COX-2, IL-1beta, IL-6, or TNF-alpha in either microglia or homogenate samples in any CNS region evaluated, compared with controls (all p>0.05 vs. normoxia). Conclusions: These data indicate that while rAIH is not anti-inflammatory in this rat strain, it does not appear to promote neuroinflammation in either microglia or tissue homogenates in any of the CNS regions studied here. These results have important implications for the safety of rAIH as a potential therapy to enhance neuroplasticity and motor function in patients with spinal injury or other neurologic disorders.

Hemoglobin-Based Oxygen Carriers in Trauma Care: The US Multicenter Prehosptial Trial

The current generation of blood substitutes tested in clinical trials are red blood cell (RBC) substitutes, i.e., they are designed primarily to transport oxygen. The products that are now being used in advanced phase clinical trials are derived from hemoglobin and thus are often referred to as hemoglobin-based oxygen carriers (HBOCs). The potential benefits of HBOCs are well known (Table 10.1). The objectives of this brief overview are to outline emerging applications of HBOCs in trauma care and review the scientific background for ongoing patient trials in the USA.