Deleterious effect of sustained neuroinflammation in pediatric traumatic brain injury.

INTRODUCTION: Despite improved management of traumatic brain injury (TBI), it still leads to lifelong sequelae and disability, particularly in children. Chronic neuroinflammation (the so-called tertiary phase), in particular, microglia/macrophage and astrocyte reactivity, is among the main mechanisms suspected of playing a role in the generation of lesions associated with TBI. The role of acute neuroinflammation is now well understood, but its persistent effect and impact on the brain, particularly during development, are not. Here, we investigated the long-term effects of pediatric TBI on the brain in a mouse model. METHODS: Pediatric TBI was induced in mice on postnatal day (P) 7 by weight-drop trauma. The time course of neuroinflammation and myelination was examined in the TBI mice. They were also assessed by magnetic resonance, functional ultrasound, and behavioral tests at P45. RESULTS: TBI induced robust neuroinflammation, characterized by acute microglia/macrophage and astrocyte reactivity. The long-term consequences of pediatric TBI studied on P45 involved localized scarring astrogliosis, persistent microgliosis associated with a specific transcriptomic signature, and a long-lasting myelination defect consisting of the loss of myelinated axons, a decreased level of myelin binding protein, and severe thinning of the corpus callosum. These results were confirmed by reduced fractional anisotropy, measured by diffusion tensor imaging, and altered inter- and intra-hemispheric connectivity, measured by functional ultrasound imaging. In addition, adolescent mice with pediatric TBI showed persistent social interaction deficits and signs of anxiety and depressive behaviors. CONCLUSIONS: We show that pediatric TBI induces tertiary neuroinflammatory processes associated with white matter lesions and altered behavior. These results support our model as a model for preclinical studies for tertiary lesions following TBI.

Brainstem dysfunction in critically ill patients.

The brainstem conveys sensory and motor inputs between the spinal cord and the brain, and contains nuclei of the cranial nerves. It controls the sleep-wake cycle and vital functions via the ascending reticular activating system and the autonomic nuclei, respectively. Brainstem dysfunction may lead to sensory and motor deficits, cranial nerve palsies, impairment of consciousness, dysautonomia, and respiratory failure. The brainstem is prone to various primary and secondary insults, resulting in acute or chronic dysfunction. Of particular importance for characterizing brainstem dysfunction and identifying the underlying etiology are a detailed clinical examination, MRI, neurophysiologic tests such as brainstem auditory evoked potentials, and an analysis of the cerebrospinal fluid. Detection of brainstem dysfunction is challenging but of utmost importance in comatose and deeply sedated patients both to guide therapy and to support outcome prediction. In the present review, we summarize the neuroanatomy, clinical syndromes, and diagnostic techniques of critical illness-associated brainstem dysfunction for the critical care setting.

Persistently Altered Metabolic Phenotype following Perinatal Excitotoxic Brain Injury.

Excitotoxicity plays a key role during insults to the developing brain such as neonatal encephalopathy, stroke, and encephalopathy of prematurity. Such insults affect many thousands of infants each year. Excitotoxicity causes frank lesions due to cell death and gliosis and disturbs normal developmental process, leading to deficits in learning, memory, and social integration that persist into adulthood. Understanding the underlying processes of the acute effects of excitotoxicity and its persistence during brain maturation provides an opportunity to identify mechanistic or diagnostic biomarkers, thus enabling and designing possible therapies. We applied mass spectrometry to provide metabolic profiles of brain tissue and plasma over time following an excitotoxic lesion (intracerebral ibotenate) to the neonatal (postnatal day 5) mouse brain. We found no differences between the plasma from the control (PBS-injected) and excitotoxic (ibotenate-injected) groups over time (on postnatal days 8, 9, 10, and 30). In the brain, we found that variations in amino acids (arginine, glutamine, phenylananine, and proline) and glycerophospholipids were sustaining acute and delayed (tertiary) responses to injury. In particular, the effect of the excitotoxic lesion on the normal profile of development was linked to alterations in a fingerprint of glycerophospolipids and amino acids. Specifically, we identified increases in the amino acids glutamine, proline, serine, threonine, tryptophan, valine, and the sphingolipid SM C26:1, and decreases in the glycerophospholipids, i.e., the arachidonic acid-containing phosphatidylcholine (PC aa) C30:2 and the PC aa C32:3. This study demonstrates that metabolic profiling is a useful approach to identify acute and tertiary effects in an excitotoxic lesion model, and generating a short list of targets with future potential in the hunt for identification, stratification, and possibly therapy.

Role of microglia in a mouse model of paediatric traumatic brain injury.

The cognitive and behavioural deficits caused by traumatic brain injury (TBI) to the immature brain are more severe and persistent than TBI in the mature brain. Understanding this developmental sensitivity is critical as children under four years of age sustain TBI more frequently than any other age group. Microglia (MG), resident immune cells of the brain that mediate neuroinflammation, are activated following TBI in the immature brain. However, the type and temporal profile of this activation and the consequences of altering it are still largely unknown. In a mouse model of closed head weight drop paediatric brain trauma, we characterized i) the temporal course of total cortical neuroinflammation and the phenotype of ex vivo isolated CD11B-positive microglia/macrophage (MG/MΦ) using a battery of 32 markers, and ii) neuropathological outcome 1 and 5days post-injury. We also assessed the effects of targeting MG/MΦ activation directly, using minocycline a prototypical microglial activation antagonist, on these processes and outcome. TBI induced a moderate increase in both pro- and anti-inflammatory cytokines/chemokines in the ipsilateral hemisphere. Isolated cortical MG/MΦ expressed increased levels of markers of endogenous reparatory/regenerative and immunomodulatory phenotypes compared with shams. Blocking MG/MΦ activation with minocycline at the time of injury and 1 and 2days post-injury had only transient protective effects, reducing ventricular dilatation and cell death 1day post-injury but having no effect on injury severity at 5days. This study demonstrates that, unlike in adults, the role of MG/MΦ in injury mechanisms following TBI in the immature brain may not be negative. An improved understanding of MG/MΦ function in paediatric TBI could support translational efforts to design therapeutic interventions.

Pro-epileptogenic effects of viral-like inflammation in both mature and immature brains.

BACKGROUND: Infectious encephalitides are most often associated with acute seizures during the infection period and are risk factors for the development of epilepsy at later times. Mechanisms of viral encephalitis-induced epileptogenesis are poorly understood. Here, we evaluated the contribution of viral encephalitis-associated inflammation to ictogenesis and epileptogenesis using a rapid kindling protocol in rats. In addition, we examined whether minocycline can improve outcomes of viral-like brain inflammation. METHODS: To produce viral-like inflammation, polyinosinic-polycytidylic acid (PIC), a toll-like receptor 3 (TLR3) agonist, was applied to microglial/macrophage cell cultures and to the hippocampus of postnatal day 13 (P13) and postnatal day 74 (P74) rats. Cell cultures permit the examination of the inflammation induced by PIC, while the in vivo setting better suits the analysis of cytokine production and the effects of inflammation on epileptogenesis. Minocycline (50 mg/kg) was injected intraperitoneally for 3 consecutive days prior to the kindling procedure to evaluate its effects on inflammation and epileptogenesis. RESULTS: PIC injection facilitated kindling epileptogenesis, which was evident as an increase in the number of full limbic seizures at both ages. Furthermore, in P14 rats, we observed a faster seizure onset and prolonged retention of the kindling state. PIC administration also led to an increase in interleukin 1ß (IL-1ß) levels in the hippocampus in P14 and P75 rats. Treatment with minocycline reversed neither the pro-epileptogenic effects of PIC nor the increase of IL-1ß in the hippocampus in both P14 and P75 rats. CONCLUSIONS: Hippocampal injection of PIC facilitates rapid kindling epileptogenesis at both P14 and P75, suggesting that viral-induced inflammation increases epileptogenesis irrespective of brain maturation. Minocycline, however, was unable to reverse the increase of epileptogenesis, which might be linked to its absence of effect on hippocampal IL-1ß levels at both ages.

Contribution of mast cells to injury mechanisms in a mouse model of pediatric traumatic brain injury.

The cognitive and behavioral deficits caused by traumatic brain injury (TBI) to the immature brain are more severe and persistent than injuries to the adult brain. Understanding this developmental sensitivity is critical because children under 4 years of age of sustain TBI more frequently than any other age group. One of the first events after TBI is the infiltration and degranulation of mast cells (MCs) in the brain, releasing a range of immunomodulatory substances; inhibition of these cells is neuroprotective in other types of neonatal brain injury. This study investigates for the first time the role of MCs in mediating injury in a P7 mouse model of pediatric contusion-induced TBI. We show that various neural cell types express histamine receptors and that histamine exacerbates excitotoxic cell death in primary cultured neurons. Cromoglycate, an inhibitor of MC degranulation, altered the inflammatory phenotype of microglia activated by TBI, reversing several changes but accentuating others, when administered before TBI. However, without regard to the time of cromoglycate administration, inhibiting MC degranulation did not affect cell loss, as evaluated by ventricular dilatation or cleaved caspase-3 labeling, or the density of activated microglia, neurons, or myelin. In double-heterozygous cKit mutant mice lacking MCs, this overall lack of effect was confirmed. These results suggest that the role of MCs in this model of pediatric TBI is restricted to subtle effects and that they are unlikely to be viable neurotherapeutic targets. © 2016 Wiley Periodicals, Inc.

Prognosis of Prolonged Intensive Care Unit Stay After Aortic Valve Replacement for Severe Aortic Stenosis in Octogenarians.

OBJECTIVES: Octogenarians considered for cardiac surgery encounter more complications than other patients. Postoperative complications raise the question of continuation of high-cost care for patients with limited life expectancy. Duration of hospitalization in intensive care after cardiac surgery may differ between octogenarians and other patients. The objectives were evaluating the mortality rate of octogenarians experiencing prolonged hospitalization in intensive care and defining the best cut-off for prolonged intensive care unit length of stay. DESIGN: A single-center observational study. SETTING: A postoperative surgical intensive care unit in a tertiary teaching hospital in Paris, France. PARTICIPANTS: All consecutive patients older than 80 years considered for aortic valve replacement for aortic stenosis were included. MEASUREMENTS AND MAIN RESULTS: Mortality rate was determined among patients experiencing prolonged stay in intensive care with organ failure and without organ failure. An ROC curve determined the optimal cut-off defining prolonged hospitalization in intensive care according to the occurrence of postoperative complications. Multivariate analysis determined risk factors for early death or prolonged intensive care stay. The optimal cut-off defining prolonged intensive care unit length of stay was 4 days. Low ventricular ejection fraction (odds ratio [OR] = 0.95; 95% confidence interval [CI] 0.96-0.83; p = 0.0016), coronary disease (OR = 2.34; 95% CI 1.19-4.85; p = 0.014), and need for catecholamine (OR = 2.79; 95% CI 1.33-5.88; p = 0.0068) were associated with eventful postoperative course. There was not a hospitalization duration beyond which the prognosis significantly worsened. CONCLUSIONS: Prolonged length of stay in ICU without organ failure is not associated with increased mortality. No specific duration of hospitalization in intensive care was associated with increased mortality. Continuation of care should be discussed on an individual basis.

The Anti-Inflammatory Effects of the Small Molecule Pifithrin-µ on BV2 Microglia.

Neonatal encephalopathy (NE) is a leading cause of childhood death and disability in term infants. Treatment options for perinatal brain injury are limited and developing therapies that target multiple pathways within the pathophysiology of NE are of great interest. Pifithrin-µ (PFT-µ) is a drug with striking neuroprotective abilities in a preclinical model of hypoxia-ischemia (HI)-induced NE wherein cell death is a substantial cause of injury. Work from neurons and tumor cells reports that PFT-µ is able to inhibit p53 binding to the mitochondria, heat shock protein (HSP)-70 substrate binding and activation of the NF-kB pathway. The purpose of this study is to understand whether the neuroprotective effects of PFT-µ also include direct effects on microglia. We utilized the microglial cell line, BV2, and we studied the dose-dependent effect of PFT-µ on M1-like and M2-like phenotype using qRT-PCR and Western blotting, including the requirement for the presence of p53 or HSP-70 in these effects. We also assessed phagocytosis and the effects of PFT-µ on genes within metabolic pathways related to phenotype. We noted that PFT-µ robustly reduced the M1-like (lipopolysaccharide, LPS-induced) BV2 response, spared the LPS-induced phagocytic ability of BV2 and had no effect on the genes related to metabolism and that effects on phenotype were partially dependent on the presence of HSP-70 but not p53. This study demonstrates that the neuroprotective effects of PFT-µ in HI-induced NE may include an anti-inflammatory effect on microglia and adds to the evidence that this drug might be of clinical interest for the treatment of NE.

Brain damage of the preterm infant: new insights into the role of inflammation.

Epidemiological studies have shown a strong association between perinatal infection/inflammation and brain damage in preterm infants and/or neurological handicap in survivors. Experimental studies have shown a causal effect of infection/inflammation on perinatal brain damage. Infection including inflammatory factors can disrupt programmes of brain development and, in particular, induce death and/or blockade of oligodendrocyte maturation, leading to myelin defects. Alternatively, in the so-called multiple-hit hypothesis, infection/inflammation can act as predisposing factors, making the brain more susceptible to a second stress (sensitization process), such as hypoxic-ischaemic or excitotoxic insults. Epidemiological data also suggest that perinatal exposure to inflammatory factors could predispose to long-term diseases including psychiatric disorders.

Activation of microglial N-methyl-D-aspartate receptors triggers inflammation and neuronal cell death in the developing and mature brain.

OBJECTIVE: Activated microglia play a central role in the inflammatory and excitotoxic component of various acute and chronic neurological disorders. However, the mechanisms leading to their activation in the latter context are poorly understood, particularly the involvement of N-methyl-D-aspartate receptors (NMDARs), which are critical for excitotoxicity in neurons. We hypothesized that microglia express functional NMDARs and that their activation would trigger neuronal cell death in the brain by modulating inflammation. METHODS AND RESULTS: We demonstrate that microglia express NMDARs in the murine and human central nervous system and that these receptors are functional in vitro. We show that NMDAR stimulation triggers microglia activation in vitro and secretion of factors that induce cell death of cortical neurons. These damaged neurons are further shown to activate microglial NMDARs and trigger a release of neurotoxic factors from microglia in vitro, indicating that microglia can signal back to neurons and possibly induce, aggravate, and/or maintain neurologic disease. Neuronal cell death was significantly reduced through pharmacological inhibition or genetically induced loss of function of the microglial NMDARs. We generated Nr1 LoxP(+/+) LysM Cre(+/-) mice lacking the NMDAR subunit NR1 in cells of the myeloid lineage. In this model, we further demonstrate that a loss of function of the essential NMDAR subunit NR1 protects from excitotoxic neuronal cell death in vivo and from traumatic brain injury. INTERPRETATION: Our findings link inflammation and excitotoxicity in a potential vicious circle and indicate that an activation of the microglial NMDARs plays a pivotal role in neuronal cell death in the perinatal and adult brain.

Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro.

Microglia mediate multiple facets of neuroinflammation, including cytotoxicity, repair, regeneration, and immunosuppression due to their ability to acquire diverse activation states, or phenotypes. Modulation of microglial phenotype is an appealing neurotherapeutic strategy but a comprehensive study of classical and more novel microglial phenotypic markers in vitro is lacking. The aim of this study was to outline the temporal expression of a battery of phenotype markers from polarised microglia to generate an in vitro tool for screening the immunomodulatory potential of novel compounds. We characterised expression of thirty-one macrophage/microglial phenotype markers in primary microglia over time (4, 12, 36, and 72 h), using RT-qPCR or multiplex protein assay. Firstly, we selected Interleukin-4 (IL-4) and lipopolysaccharide (LPS) as the strongest M1-M2 polarising stimuli, from six stimuli tested. At each time point, markers useful to identify that microglia were M1 included iNOS, Cox-2 and IL-6 and a loss of M2a markers. Markers useful for quantifying M2b-immunomodulatory microglia included, increased IL-1RA and SOCS3 and for M2a-repair and regeneration, included increased arginase-1, and a loss of the M1 and M2b markers were discriminatory. Additional markers were regulated at fewer time points, but are still likely important to monitor when assessing the immunomodulatory potential of novel therapies. Further, to facilitate identification of how novel immunomodulatory treatments alter the functional affects of microglia, we characterised how the soluble products from polarised microglia affected the type and rate of neuronal death; M1/2b induced increasing and M2a-induced decreasing neuronal loss. We also assessed any effects of prior activation state, to provide a way to identify how a novel compound may alter phenotype depending on the stage of injury/insult progression. We identified generally that a prior M1/2b reduced the ability of microglia to switch to M2a. Altogether, we have characterised a profile of phenotype markers and a mechanism of assessing functional outcome that we can use as a reference guide for first-line screening of novel immunomodulatory therapies in vitro in the search for viable neuroprotectants.

Neuroprotective effects of dexmedetomidine against glutamate agonist-induced neuronal cell death are related to increased astrocyte brain-derived neurotrophic factor expression.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) plays a prominent role in neuroprotection against perinatal brain injury. Dexmedetomidine, a selective agonist of α2-adrenergic receptors, also provides neuroprotection against glutamate-induced damage. Because adrenergic receptor agonists can modulate BDNF expression, our goal was to examine whether dexmedetomidine's neuroprotective effects are mediated by BDNF modulation in mouse perinatal brain injury. METHODS: The protective effects against glutamate-induced injury of BDNF and dexmedetomidine alone or in combination with either a neutralizing BDNF antibody or an inhibitor of the extracellular signal-regulated kinase pathway (PD098059) were compared in perinatal ibotenate-induced cortical lesions (n = 10-20 pups/groups) and in mouse neuronal cultures (300 µM of ibotenate for 6 h). The effect of dexmedetomidine on BDNF expression was examined in vivo and in vitro with cortical neuronal and astrocyte isolated cultures. RESULTS: Both BDNF and dexmedetomidine produced a significant neuroprotective effect in vivo and in vitro. Dexmedetomidine enhanced Bdnf4 and Bdnf5 transcription and BDNF protein cortical expression in vivo. Dexmedetomidine also enhanced Bdnf4 and Bdnf5 transcription and increased BDNF media concentration in isolated astrocyte cultures but not in neuronal cultures. Dexmedetomidine's protective effect was inhibited with BDNF antibody (mean lesion size ± SD: 577 ± 148 µm vs. 1028 ± 213 µm, n = 14-20, P < 0.001) and PD098059 in vivo but not in isolated neuron cultures. Finally, PD098059 inhibited the increased release of BDNF induced by dexmedetomidine in astrocyte cultures. CONCLUSION: These results suggest that dexmedetomidine increased astrocyte expression of BDNF through an extracellular signal-regulated kinase-dependent pathway, inducing subsequent neuroprotective effects.

Admission risk factors for cerebral vasospasm in ruptured brain arteriovenous malformations: an observational study.

INTRODUCTION: Cerebral vasospasm is a well-documented complication of aneurismal subarachnoid hemorrhage but has not been extensively studied in brain arteriovenous malformations (BAVMs). Here, our purpose was to identify risk factors for cerebral vasospasm after BAVM rupture in patients requiring intensive care unit (ICU) admission. METHODS: Patients admitted to our ICU from January 2003 to May 2010 for BAVM rupture were included in this observational study. Clinical, laboratory and radiological features from admission to ICU discharge were recorded. The primary endpoint was cerebral vasospasm by transcranial Doppler (TCD-VS) or cerebral infarction (CI) associated with vasospasm. Secondary endpoints included the Glasgow Outcome Scale (GOS) at ICU discharge. RESULTS: Of 2,734 patients admitted to our ICU during the study period, 72 (2.6%) with ruptured BAVM were included. TCD-VS occurred in 12 (17%) and CI in 6 (8%) patients. All patients with CI had a previous diagnosis of TCD-VS. A Glasgow Coma Scale score <8 was a risk factor for both TCD-VS (relative risk (RR), 4.7; 95% confidence interval (95% CI), 1.6 to 26) and CI (RR, 7.8; 95% CI, 0.1 to 63). Independent risk factors for TCD-VS by multivariate analysis were lower Glasgow Coma Scale score (odds ratio (OR) per unit decrease, 1.38; 95% CI, 1.13 to 1.80), female gender (OR, 4.86; 95% CI, 1.09 to 25.85), and younger age (OR per decade decrease, 1.39; 95% CI, 1.05 to 1.82). The risk of a poor outcome (GOS <4) at ICU discharge was non-significantly increased in the patients with TCD-VS (RR, 4.9; 95% CI, 0.7 to 35; P = 0.09). All six patients with CI had poor outcomes. CONCLUSIONS: This is the first cohort study describing the incidence and risk factors for cerebral vasospasm after BAVM rupture. Larger studies are needed to investigate the significance of TCD-vasospasm and CI in these patients.

Automated weaning from mechanical ventilation: Results of a Bayesian network meta-analysis.

PURPOSE: Mechanical ventilation (MV) weaning is a crucial step. Automated weaning modes reduce MV duration but the question of the best automated mode remains unanswered. Our objective was to compare the major automated modes for MV weaning in critically ill and post-operative adult patients. MATERIAL AND METHODS: We conducted a network Bayesian meta-analysis to compare different automated modes. We searched MEDLINE, EMBASE and Cochrane central registry for randomized control trials comparing automated weaning modes either to another automated mode or to standard-of-care. The primary outcome was the duration of MV weaning extracted from the original trials. RESULTS: 663 articles were screened and 26 trials (2097patients) were included in the final analysis. All automated modes included in the study (ASV°, Intellivent ASV, Smartcare, Automode°, PAV° and MRV°) outperformed standard-of-care but no automated mode reduced the duration of mechanical ventilation weaning as compared to others in the network meta-analysis. CONCLUSION: Compared to standard weaning practice, all automated modes significantly reduced the duration of MV weaning in critically ill and post-operative adult patients. When cross-compared using a network meta-analysis, no specific mode was different in reducing the duration of MV weaning. The study was registered in PROSPERO (CRD42015024742).

Poor performances of EuroSCORE and CARE score for prediction of perioperative mortality in octogenarians undergoing aortic valve replacement for aortic stenosis.

BACKGROUND AND OBJECTIVE: Although results of cardiac surgery are improving, octogenarians have a higher procedure-related mortality and more complications with increased length of stay in ICU. Consequently, careful evaluation of perioperative risk seems necessary. The aims of our study were to assess and compare the performances of EuroSCORE and CARE score in the prediction of perioperative mortality among octogenarians undergoing aortic valve replacement for aortic stenosis and to compare these predictive performances with those obtained in younger patients. METHODS: This retrospective study included all consecutive patients undergoing cardiac surgery in our institution between November 2005 and December 2007. For each patient, risk assessment for mortality was performed using logistic EuroSCORE, additive EuroSCORE and CARE score. The main outcome measure was early postoperative mortality. Predictive performances of these scores were assessed by calibration and discrimination using goodness-of-fit test and area under the receiver operating characteristic curve, respectively. RESULTS: During this 2-year period, we studied 2117 patients, among whom 134/211 octogenarians and 335/1906 nonoctogenarians underwent an aortic valve replacement for aortic stenosis. When considering patients with aortic stenosis, discrimination was poor in octogenarians and the difference from nonoctogenarians was significant for each score (0.58, 0.59 and 0.56 vs. 0.82, 0.81 and 0.77 for additive EuroSCORE, logistic EuroSCORE and CARE score in octogenarians and nonoctogenarians, respectively, P < 0.05). Moreover, in the whole cohort, logistic EuroSCORE significantly overestimated mortality among octogenarians. CONCLUSION: Predictive performances of these scores are poor in octogenarians undergoing cardiac surgery, especially aortic valve replacement. Risk assessment and therapeutic decisions in octogenarians should not be made with these scoring systems alone.

Misleading abdominal pain following extracorporeal renal lithotripsy.

INTRODUCTION: Extracorporeal shockwave lithotripsy (ESWL) is a useful technique for the treatment of kidney and urinary tract stones but appears also to cause some extrarenal complications. CASE PRESENTATION: We report the case of a 33-year-old Caucasian man with a history of Crohn's disease who presented septic shock due to a jejunum perforation 6 h following an ESWL for a right ureteral stone. The perforation, which occurred at the exact site of a previous surgical anastomosis, was revealed on a CT scan which found an unusual aspect probably due to cavitation and bubbles formation induced by ESWL. CONCLUSION: This case emphasizes the particular aspect of CT scan and the extrarenal potential danger of the ESWL procedure. Some precautions and dedicated patient information must be taken when used in patients with chronic inflammation of the digestive tract or history of intestinal surgery.

Clinical review: initial management of blunt pelvic trauma patients with haemodynamic instability.

Pelvic trauma can lead to severe, uncontrollable haemorrhage and death related to prolonged shock and multiple organ failure. Massive retroperitoneal haematoma should be assumed to be present in cases of post-traumatic haemodynamic instability associated with pelvic fracture in the absence of extrapelvic haemorrhagic lesions. This review describes the pathophysiology of retroperitoneal haematoma in trauma patient with blunt pelvic fracture, considering the roles of venous and arterial bleeding. Efficacy and safety of haemostatic procedures are also discussed, and particular attention is given to the efficacy of pelvic angiographic embolization and external pelvic fixation. A decision making algorithm is proposed for the treatment of trauma patients with pelvic fracture that takes haemodynamic status and associated lesions into account.