Sarah Watts

Prolonged permissive hypotensive resuscitation is associated with poor outcome in primary blast injury with controlled hemorrhage.

Objective:To determine the effects of primary blast injury (PBI) on survival and the physiological response to resuscitation after hemorrhagic shock. Background:Air-blast injury is a significant clinical problem that can reduce blood oxygenation and modify the response to hemorrhage. PBI has specific physiological effects that have not been fully accounted for in resuscitation strategies. Permissive hypotension is a widely adopted strategy in trauma resuscitation. However, the choice of resuscitation strategy requires a full understanding of the mechanisms of injury and their physiological consequences. Methods:Terminally anesthetized pigs were divided into 4 groups and subjected to either air-blast injury (B) or no blast (S). All received a controlled hemorrhage of 30% blood volume and resuscitation with 0.9% saline to a normotensive (Normot, systolic blood pressure 110 mm Hg) or hypotensive (Hypot, 80 mm Hg) end point for up to 8 hours. (n = 6 in each B and n = 8 in each S subgroup). Results:Survival time was significantly shorter with Hypot (P < 0.0001 Peto log rank). The effect was in the animals subjected to B (P = 0.0005) (mean survival time [95% CI]; BNormot 422 [313–531] vs. BHypot137 [94–181] min), but not those given S (P = 0.06) (SNormot 480 [all survived] vs. SHypot 352 [210–494] min). PBI exacerbated a profound metabolic acidosis during Hypot, possibly due to an overwhelming compromise in tissue oxygen delivery. Conclusions:Prolonged hypotensive resuscitation is not compatible with survival after primary blast. Casualties most likely to be in this category are those injured by blast in confined spaces or by enhanced blast weapons. The risk of rebleeding associated with normotensive resuscitation needs to be balanced with the metabolic derangement associated with hypotensive resuscitation.

A proactive approach to the coagulopathy of trauma: the rationale and guidelines for treatment.

Prevalence of coagulopathy in trauma According to the British Committee for Standards in Haematology and the American College of Pathologists, prolongation of the activated partial thromboplastin time (APTT) and prothrombin time (PT) to 1.5 times the mean normal value indicates a coagulopathy requiring blood product replacement [1-3]. A number of studies have indicated that coagulopathy is common after severe trauma and that it results from a number of causes including metabolic acidosis, hypothermia, dilution of coagulation factors by resuscitation fluids and consumption of coagulation factors [4-10]. Coagulopathy is especially associated with some forms of injury, e.g. brain injury, because of the release of tissue thromboplastins from damaged brain matter [11; 12]. A UK civilian study by Brohi et al [13], using the definitions given above, clearly demonstrated that major trauma patients (Injury Severity Score, ISS >15) can present at hospital with a coagulopathy: 24% of 1088 trauma patients (median ISS 20) analyzed on arrival at the Emergency Department (ED) were coagulopathic. The majority (75%) of patients had suffered blunt trauma and the median time from injury to hospital was 73 minutes; this is compared to 7.6% blunt force (motor vehicle crash, fall, assault, crush) in 876 patients on the UK military Joint Theatre Trauma Registry (01 April 2006 to 30 September 2007, OP HERRICK and OP TELIC only), and a median injury to ED handover time of 97 minutes for UK military priority 1 casualties [14]. The incidence of coagulopathy increased with severity of injury (assessed by ISS), independent of the volume of pre-hospital resuscitation fluid (reliably recorded by a physician). The authors comment that the patients had received minimal pre-hospital fluid resuscitation (median values of 500 ml crystalloid or 1000 ml colloid) and that the development of coagulopathy in these patients was unrelated to the volume or type of intravenous fluid given. A second survey [15] based on 8724 severely injured patients (96% blunt injuries) from the German Trauma Registry Database confirms the presence of coagulopathy in 34% of all severely injured patients arriving in the Emergency Department. This study used a similar definition of coagulopathy to that employed by Brohi et al [13] and identified a similar time to hospital. The presence of coagulopathy was positively associated with the volume of pre-hospital fluid, injury severity and delay between injury and arrival at hospital [15]. Even in patients with minimal pre-hospital resuscitation, coagulopathy was present in 10% of cases [15]. Despite the limited statistical analysis in this study it supports the conclusion that coagulopathy is present in a significant proportion of severely-injured patients by the time they arrive at hospital. Early coagulopathy was also reported by MacLeod et al [16] in a retrospective analysis of 7638 trauma patients admitted to a Level 1 Trauma Centre between Jan 1995 and Dec 2000, although as a group these patients were less severely injured (median ISS 9) than those described by Brohi et al [13]. Additionally, MacLeod et al [16] were unable to account for medication that might have contributed to the coagulopathy, for example warfarin treatment or pre-hospital fluid administration. A number of other smaller studies [17; 18] and anecdotal comments [19]] have also documented coagulopathy in trauma patients on arrival at hospital. Furthermore, early coagulopathy is associated with increased morbidity and mortality [13; 15; 16; 18]. Although it is always a concern that studies with negative conclusions are less likely to be published than those with a positive conclusion, the collective evidence strongly suggests that a proportion of severely injured patients are already coagulopathic by the time they arrive in the Emergency Department and the remainder are at high risk of rapidly developing a coagulopathy. Clearly the true incidence of coagulopathy will depend on the definition adopted. There is evidence that bleeding time and thromboelastographic measurements are better indicators of dilutional and hypothermia induced coagulopathy [20]. Using this methodology the true incidence of coagulopathy associated with major trauma may well be significantly higher than reported.

Utility of interim ROTEM® values of clot strength, A5 and A10, in predicting final assessment of coagulation status in severely injured battle patients

BACKGROUND Proactive management of trauma-related coagulopathy requires early identification and rapid assessment in order to allow targeted resuscitation. This study determined whether early (interim) ROTEM(®) (TEM International GmbH, Munich, Germany) values could predict hypocoagulopathy in seriously injured military patients. METHODS Normal ranges for ROTEM(®) values were obtained from 50 volunteers. 108 samples were collected during the early phase of clinical management from 48 severe trauma patients. The blood was subject to EXTEM analysis and compared to the 95% tolerance limits from the volunteers. Coagulopathy (was deemed to be present if EXTEM MCF was below 40 mm, which is in the range indicating clinical concern defined by the ROTEM(®) Expert Working Group. RESULTS The normal range data was broadly similar to ROTEM(®) published data. Admission samples were available from 31 battlefield casualties, and 39% of these were coagulopathic 51% of the samples from all 48 patients were coagulopathic (EXTEM MCF<40 mm) and interim EXTEM values of these at 5 and 10 min (A5 and A10) predicted coagulopathy with sensitivities/specificities of 0.96/0.58 (A5) and 1.00/0.70 (A10). In addition, statistical comparison of clotting domains between normal volunteers and trauma patients suggests a difference in clot strengths due to a difference in platelet function rather than platelet number (mean 142 × 10(9)l(-1)). CONCLUSIONS The A10 value of ROTEM(®) provides an early sensitive and specific assessment of coagulopathy after military trauma and may be of utility in guiding bespoke resuscitation. We found some speculative evidence that in major trauma platelet function is particularly affected.

Targeted resuscitation improves coagulation and outcome.

BACKGROUND: Acute trauma coagulopathy in seriously injured casualties may be initiated by tissue hypoperfusion. A targeted (or novel hybrid [NH]) resuscitation strategy was developed to overcome poor tissue oxygen delivery associated with prolonged hypotension. METHODS: Under the Animals (Scientific Procedures) Act 1986, terminally anesthetized large white pigs were divided into four groups (n = 6). Groups 1 and 2 received blast injury and 3 and 4 no blast (sham). All were given a controlled hemorrhage (35% blood volume) and an uncompressed grade IV liver injury. Five minutes later, all were resuscitated with 0.9% saline to a systolic arterial pressure (SAP) of 80 mm Hg. After 60 minutes, the NH groups (1 and 3) were resuscitated to a SAP (110 mm Hg), whereas hypotensive groups (2 and 4) continued with SAP 80 mm Hg for up to 8 hours from onset of resuscitation. RESULTS: Mean survival time was shorter in group 2 (258 minutes) compared with groups 1, 3, and 4 (452 minutes, 448 minutes, and 369 minutes). By the end of the study, hypotension was associated with a significantly greater prothrombin time (1.73 ± 0.10 and 1.87 ± 0.15 times presurgery, groups 2 and 4) compared with NH (1.44 ± 0.09 and 1.36 ± 0.06, groups 1 and 3, p = 0.001). Blast versus sham had no significant effect on prothrombin time (p = 0.56). Peak levels of interleukin 6 were significantly lower in NH groups. Arterial base excess was significantly lower with hypotension (−18.4 mmol/L ± 2.7 mmol/L and −12.1 mmol/L ± 3.2 mmol/L) versus NH (−3.7 mmol/L ± 2.8 mmol/L and −1.8 mmol/L ± 1.8 mmol/L, p = 0.0001). Hematocrit was not significantly different between groups (p = 0.16). CONCLUSION: Targeted resuscitation (NH) attenuates the development of acute trauma coagulopathy and systemic inflammation with improved tissue perfusion and reduced metabolic acidosis in a model of complex injury. This emphasizes the challenge of choosing a resuscitation strategy for trauma patients where the needs of tissue perfusion must be balanced against the risk of rebleeding during resuscitation.

Blast injury research models

Blast injuries are an increasing problem in both military and civilian practice. Primary blast injury to the lungs (blast lung) is found in a clinically significant proportion of casualties from explosions even in an open environment, and in a high proportion of severely injured casualties following explosions in confined spaces. Blast casualties also commonly suffer secondary and tertiary blast injuries resulting in significant blood loss. The presence of hypoxaemia owing to blast lung complicates the process of fluid resuscitation. Consequently, prolonged hypotensive resuscitation was found to be incompatible with survival after combined blast lung and haemorrhage. This article describes studies addressing new forward resuscitation strategies involving a hybrid blood pressure profile (initially hypotensive followed later by normotensive resuscitation) and the use of supplemental oxygen to increase survival and reduce physiological deterioration during prolonged resuscitation. Surprisingly, hypertonic saline dextran was found to be inferior to normal saline after combined blast injury and haemorrhage. New strategies have therefore been developed to address the needs of blast-injured casualties and are likely to be particularly useful under circumstances of enforced delayed evacuation to surgical care.

Evaluation of Prehospital Blood Products to Attenuate Acute Coagulopathy of Trauma in a Model of Severe Injury and Shock in Anesthetized Pigs

ABSTRACT Acute trauma coagulopathy (ATC) is seen in 30% to 40% of severely injured casualties. Early use of blood products attenuates ATC, but the timing for optimal effect is unknown. Emergent clinical practice has started prehospital deployment of blood products (combined packed red blood cells and fresh frozen plasma [PRBCs:FFP], and alternatively PRBCs alone), but this is associated with significant logistical burden and some clinical risk. It is therefore imperative to establish whether prehospital use of blood products is likely to confer benefit. This study compared the potential impact of prehospital resuscitation with (PRBCs:FFP 1:1 ratio) versus PRBCs alone versus 0.9% saline (standard of care) in a model of severe injury. Twenty-four terminally anesthetised Large White pigs received controlled soft tissue injury and controlled hemorrhage (35% blood volume) followed by a 30-min shock phase. The animals were allocated randomly to one of three treatment groups during a 60-min prehospital evacuation phase: hypotensive resuscitation (target systolic arterial pressure 80 mmHg) using either 0.9% saline (group 1, n = 9), PRBCs:FFP (group 2, n = 9), or PRBCs alone (group 3, n = 6). Following this phase, an in-hospital phase involving resuscitation to a normotensive target (110 mmHg systolic arterial blood pressure) using PRBCs:FFP was performed in all groups. There was no mortality in any group. A coagulopathy developed in group 1 (significant increase in clot initiation and dynamics shown by TEG [thromboelastography] R and K times) that persisted for 60 to 90 min into the in-hospital phase. The coagulopathy was significantly attenuated in groups 2 and 3 (P = 0.025 R time and P = 0.035 K time), which were not significantly different from each other. Finally, the volumes of resuscitation fluid required was significantly greater in group 1 compared with groups 2 and 3 (P = 0.0067) (2.8 ± 0.3 vs. 1.9 ± 0.2 and 1.8 ± 0.3 L, respectively). This difference was principally due to a greater volume of saline used in group 1 (P = 0.001). Prehospital PRBCs:FFP or PRBCs alone may therefore attenuate ATC. Furthermore, the amount of crystalloid may be reduced with potential benefit of reducing the extravasation effect and later tissue edema.

Characterization of the response to primary blast injury

Lung injuries, predominantly arising from blast exposure, are a clinical problem in a significant minority of current military casualties. This special feature consists of a series of articles on lung injury. This first article examines the mechanism of the response to blast lung (primary blast injury to the lung). Subsequent articles examine the incidence of blast lung, clinical consequences and current concepts of treatment, computer (in silico) modelling of lung injury and finally chemical injuries to the lungs. Blast lung is caused by a shock wave generated by an explosion causing widespread damage in the lungs, leading to intrapulmonary haemorrhage. This, and the ensuing inflammatory response in the lung, leads to a compromise in pulmonary gas exchange and hypoxia that can worsen over several hours. There is also a characteristic cardio-respiratory effect mediated via an autonomic reflex causing apnoea (or rapid shallow breathing), bradycardia and hypotension (the latter possibly also due to the release of nitric oxide). An understanding of this response, and the way it modifies other reflexes, can help the development of new treatment strategies for this condition and for the way it influences the patients response to concomitant injuries.

A pre-clinical evaluation of silver, iodine and Manuka honey based dressings in a model of traumatic extremity wounds contaminated with Staphylococcus aureus.

Prevention of extremity war wound infection remains a clinical challenge. Staphylococcus aureus is the most common pathogen in delayed infection. We hypothesised that choice of wound dressings may affect bacterial burden over 7 days reflecting the current practice of delayed primary closure of wounds within this timeframe. A randomised controlled trial of 3 commercially available dressings (Inadine(®) (Johnson & Johnson, NJ, USA), Acticoat(®) (Smith & Nephew, Hull, UK), Activon Tulle (Advancis Medical, Nottingham, UK)) was conducted in a rabbit model of contaminated forelimb muscle injury. A positive control group treated with antibiotics was included. Groups were compared to a saline soaked gauze control. The primary outcome was a statistically significant reduction (p < 0.05) in tissue S. aureus at 7 days post-injury. Secondary outcome measurements included bacteraemias, observational data, whole blood determination, ELISA for plasma biomarkers, PCR array analysis of wound healing gene expression and muscle/lymph node histopathology. Antibiotic, Inadine and Acticoat groups had statistically significant lower bacterial counts (mean 7.13 [95% CI 0.00-96.31]×10(2); 1.66 [0.94-2.58]×10(5); 8.86 [0.00-53.35]×10(4)cfu/g, respectively) and Activon Tulle group had significantly higher counts (2.82 [0.98-5.61]×10(6)cfu/g) than saline soaked gauze control (7.58 [1.65-17.83]×10(5)cfu/g). There were no bacteraemias or significant differences in observational data or whole blood determination. There were no significant differences in muscle/loss or pathology and lymph node cross-sectional area or morphology. There were some significant differences between treatment groups in the plasma cytokines IL-4, TNFα and MCP-1 in comparison to the control. PCR array data demonstrated more general changes in gene expression in the muscle tissue from the Activon Tulle group than the Inadine or Acticoat dressings with a limited number of genes showing significantly altered expression compared to control. This study has demonstrated that both Acticoat(®) and Inadine(®) dressings can reduce the bacteria burden in a heavily contaminated soft tissue wound and so they may offer utility in the clinical setting particularly where surgical treatment is delayed.

Limb Wounding and Antisepsis: Iodine and Chlorhexidine in the Early Management of Extremity Injury

Extremity injury and contamination as consequence are features of high-energy wounding. A leading cause of disability and the commonest cause of late complications, prevention of wound infection determines the ultimate outcome in these populations. Multiple variables influence the development of infection, one of which is the dressing used on the wound. Antiseptic-soaked gauze dressings feature in the early management of limb trauma despite a lack of evidence to support this. Iodine and chlorhexidine are ubiquitous in other aspects of health care however, and a plethora of studies detail their role in skin antisepsis, the recommendations from which are often anecdotally applied to acute wounding. To contextualize the role for antiseptic dressing use in acute, significant limb injury this review explores the evidence for the use of chlorhexidine and iodine in skin antisepsis. The paucity of experimental data available for antiseptic use in early wound management and the need for further research to address this evidence void is highlighted.

The Development of an Experimental Model of Contaminated Muscle Injury in Rabbits

Extent of tissue trauma and contamination determine outcome in extremity injury. In contrast to fracture, osteomyelitis, and closed muscle injury studies, there are limited small animal models of extremity muscle trauma and contamination. To address this we developed a model of contaminated muscle injury in rabbits. Twenty-eight anesthetized New Zealand White rabbits underwent open controlled injury of the flexor carpi ulnaris (FCU). Twenty-two animals had subsequent contamination of the injured muscle with Staphylococcus aureus. All animals were sacrificed at 48 hours and the level of muscle injury and contamination determined by quantitative histological and microbiological analysis. A 1-kg mass dropped 300 mm onto the mobilized FCU resulted in localized necrosis of the muscle belly. Delivery of a mean challenge of 3.71 × 106 cfu/100 µL S aureus by droplet spread onto the injured muscle produced a muscle contamination of 8.79 × 106 cfu/g at 48 hours. Ipsilateral axillary lymph nodes demonstrated clinically significant activation. All animals had normal body temperature and hematological parameters throughout and blood and urinalysis culture at autopsy were negative for organisms. This model allows reproducible muscle injury and contamination with the organism ubiquitous to extremity wound infection at a level sufficient to allow quantitative assessment of subsequent wound care interventions without incurring systemic involvement.