Comments Off on Dabigatran Reversal Agent – Idarucizumab
Thanks to Rob MacSweeney‘s fantastic Critical Care Reviews I learned of Idarucizumab, a monoclonal antibody fragment that binds the (pesky) anticoagulant dabigatran. Two industry-supported studies this week show rapid, complete reversal of anticoagulation in healthy volunteers(1) and patients who were either bleeding or undergoing procedures(2). The dose given to patients was 5g intravenously.
An accompanying editorial(3) highlights that the clinical study did not have a control group, and these patients had a high mortality. Further controlled studies examining patient-orientated outcomes will be helpful.
Of interest, another editorialist(4) lists other potential antidotes for Non-vitamin-K antagonist oral anticoagulants (NOACs) that have been or are being tested: an antidote against all oral direct factor Xa inhibitors called andexanet alpha (a recombinant activated factor X that binds direct factor Xa inhibitors), and a modified thrombin has been shown to be effective in vitro and in animals for reversal of dabigatran and potentially also other direct thrombin inhibitors.
1. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial
The Lancet Volume 386, No. 9994, p680–690, 15 August 2015
BACKGROUND: Idarucizumab is a monoclonal antibody fragment that binds dabigatran with high affinity in a 1:1 molar ratio. We investigated the safety, tolerability, and efficacy of increasing doses of idarucizumab for the reversal of anticoagulant effects of dabigatran in a two-part phase 1 study (rising-dose assessment and dose-finding, proof-of-concept investigation). Here we present the results of the proof-of-concept part of the study.
METHODS: In this randomised, placebo-controlled, double-blind, proof-of-concept phase 1 study, we enrolled healthy volunteers (aged 18-45 years) with a body-mass index of 18·5-29·9 kg/m2 into one of four dose groups at SGS Life Sciences Clinical Research Services, Belgium. Participants were randomly assigned within groups in a 3:1 ratio to idarucizumab or placebo using a pseudorandom number generator and a supplied seed number. Participants and care providers were masked to treatment assignment. All participants received oral dabigatran etexilate 220 mg twice daily for 3 days and a final dose on day 4. Idarucizumab (1 g, 2 g, or 4 g 5-min infusion, or 5 g plus 2·5 g in two 5-min infusions given 1 h apart) was administered about 2 h after the final dabigatran etexilate dose. The primary endpoint was incidence of drug-related adverse events, analysed in all randomly assigned participants who received at least one dose of dabigatran etexilate. Reversal of diluted thrombin time (dTT), ecarin clotting time (ECT), activated partial thromboplastin time (aPTT), and thrombin time (TT) were secondary endpoints assessed by measuring the area under the effect curve from 2 h to 12 h (AUEC2-12) after dabigatran etexilate ingestion on days 3 and 4. This trial is registered with ClinicalTrials.gov, number NCT01688830.
FINDINGS: Between Feb 23, and Nov 29, 2013, 47 men completed this part of the study. 12 were enrolled into each of the 1 g, 2 g, or 5 g plus 2·5 g idarucizumab groups (nine to idarucizumab and three to placebo in each group), and 11 were enrolled into the 4 g idarucizumab group (eight to idarucizumab and three to placebo). Drug-related adverse events were all of mild intensity and reported in seven participants: one in the 1 g idarucizumab group (infusion site erythema and hot flushes), one in the 5 g plus 2·5 g idarucizumab group (epistaxis); one receiving placebo (infusion site haematoma), and four during dabigatran etexilate pretreatment (three haematuria and one epistaxis). Idarucizumab immediately and completely reversed dabigatran-induced anticoagulation in a dose-dependent manner; the mean ratio of day 4 AUEC2-12 to day 3 AUEC2-12 for dTT was 1·01 with placebo, 0·26 with 1 g idarucizumab (74% reduction), 0·06 with 2 g idarucizumab (94% reduction), 0·02 with 4 g idarucizumab (98% reduction), and 0·01 with 5 g plus 2·5 g idarucizumab (99% reduction). No serious or severe adverse events were reported, no adverse event led to discontinuation of treatment, and no clinically relevant difference in incidence of adverse events was noted between treatment groups.
INTERPRETATION: These phase 1 results show that idarucizumab was associated with immediate, complete, and sustained reversal of dabigatran-induced anticoagulation in healthy men, and was well tolerated with no unexpected or clinically relevant safety concerns, supporting further testing. Further clinical studies are in progress.
2. Idarucizumab for Dabigatran Reversal
N Engl J Med. 2015 Aug 6;373(6):511-20
BACKGROUND: Specific reversal agents for non-vitamin K antagonist oral anticoagulants are lacking. Idarucizumab, an antibody fragment, was developed to reverse the anticoagulant effects of dabigatran.
METHODS: We undertook this prospective cohort study to determine the safety of 5 g of intravenous idarucizumab and its capacity to reverse the anticoagulant effects of dabigatran in patients who had serious bleeding (group A) or required an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the determination at a central laboratory of the dilute thrombin time or ecarin clotting time. A key secondary end point was the restoration of hemostasis.
RESULTS: This interim analysis included 90 patients who received idarucizumab (51 patients in group A and 39 in group B). Among 68 patients with an elevated dilute thrombin time and 81 with an elevated ecarin clotting time at baseline, the median maximum percentage reversal was 100% (95% confidence interval, 100 to 100). Idarucizumab normalized the test results in 88 to 98% of the patients, an effect that was evident within minutes. Concentrations of unbound dabigatran remained below 20 ng per milliliter at 24 hours in 79% of the patients. Among 35 patients in group A who could be assessed, hemostasis, as determined by local investigators, was restored at a median of 11.4 hours. Among 36 patients in group B who underwent a procedure, normal intraoperative hemostasis was reported in 33, and mildly or moderately abnormal hemostasis was reported in 2 patients and 1 patient, respectively. One thrombotic event occurred within 72 hours after idarucizumab administration in a patient in whom anticoagulants had not been reinitiated.
CONCLUSIONS: Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947.).
3. Targeted Anti-Anticoagulants
N Engl J Med. 2015 Aug 6;373(6):569-71
4. Antidotes for anticoagulants: a long way to go
The Lancet Volume 386, No. 9994, p634–636, 15 August 2015
There was a jam-packed line up for the Pre-hospital and Air Ambulance Day which was Co-hosted by the Norwegian Air Ambulance Foundation.
My highlights were:
Dr Rasmus Hesselfeldt works in Denmark where they have a pretty good EMS system with ambulances, RRV’s and PHC doctors. Road conditions are good with the longest travel distance of 114 miles. So would the introduction of a HEMS service improve outcomes? He did an observational study looking at year of data post-trial and compared this with 5 months pre-trial. Trauma patients with ISS > 15 and medical emergencies greater than 30 min by road to the Trauma Centre (TC). Primary endpoint was time to TC, secondary outcomes were number of secondary transfers and 30 day mortality.
Results: Increase in on scene time 20 min vs 28 min, time to hospital increased but time to TC was less – 218 min vs 90 min, reduced mortality, increased direct transfer to TC and fewer secondary transfers.
Full article here: A helicopter emergency medical service may allow faster access to highly specialised care. Dan Med J. 2013 Jul;60(7):A4647
Prof Dan Davis ran through pre-hospital intubation. It seems that this man has spent his life trying to perfect airway management. Peter Rosen was his mentor and imprinted on him that RSI is the cornerstone of airway management.
So surely pre-hospital intubation saves lives. The evidence however begs to differ, or does it? As with all evidence we need to consider the validity of the results and luckily Prof Davis has spent a lot of time thinking through the reasons why there no evidence.
During his research he opened a huge can of worms:
1. Hyperventilation was common – any EtCO2 <30mmHg lead to a doubling in mortality.
2. First pass intubation is great, but not if you let your patient become hypoxic or hypotension or worse still both!
3. Hospital practice had similar issues.
So really the RSI processes he was looking at weren’t great.
The good news is that things have improved and he can now boast higher first pass rates and lower complication rates for his EMS system. His puts this success down to training.
The AIRPORT study was discussed at last years LTC. This year we have the results. 21 HEMS services in 6 countries were involved in the data collection including GSA HEMS. The headline findings are that intubation success rates are high (98%) with a complication rate of 10-12%. The more difficult airways were seen in the non-trauma group. 28.2% patients died (mainly cardiac arrest).
Matt Thomas reported on REVIVE – a pre-hospital feasibility study looking at airway management in OHCA (I-Gel vs LMA Supreme vs standard care). It was never powered to show a difference in these groups, the main aim was to see if research in this very challenging area was possible. And the answer is YES. The paramedics involved recruited more patients than expected and stuck to the protocol (prob better that docs would have!). A randomised controlled trial to look at the I-Gel vs ETT is planned.
Finally, Pre-hospital Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) seems eminently possible – Dr Nils Petter Oveland showed us the training manikin they developed for training. Through training on this manikin they achieved an average skin to balloon time of 3.3mins. Animal data supports this procedure as a bridge to definitive care in non compressible haemorrhage.
London HEMS will be starting (P)REBOA in the New Year.
So now it’s stand up science, I’m off for my glass of wine…………….
Check out what they’re saying about the London Trauma Conference on Twitter
Comments Off on Restricting transfusion in upper GI bleeding
Improved outcomes and reduced complications were associated with a restrictive transfusion strategy in patients with upper gastrointestinal bleeding. Note that patients with “massive exsanguinating bleeding” were excluded from the study so this shouldn’t be extrapolated to such presentations.
The benefit seemed to be most marked in patients with variceal haemorrhage, but not those with the most severe Child-Pugh class. In portal hypertensive-related bleeding, transfusion may increase portal pressure and exacerbate bleeding.
The patients were ‘scoped within 6 hours, and less than 10% received FFP or platelets. Both groups averaged over 5 litres of crystalloid in the first 72 hours.
Transfusion Strategies for Acute Upper Gastrointestinal Bleeding
N Engl J Med. 2013 Jan 3;368(1):11-21
BACKGROUND: The hemoglobin threshold for transfusion of red cells in patients with acute gastrointestinal bleeding is controversial. We compared the efficacy and safety of a restrictive transfusion strategy with those of a liberal transfusion strategy.
METHODS: We enrolled 921 patients with severe acute upper gastrointestinal bleeding and randomly assigned 461 of them to a restrictive strategy (transfusion when the hemoglobin level fell below 7 g per deciliter) and 460 to a liberal strategy (transfusion when the hemoglobin fell below 9 g per deciliter). Randomization was stratified according to the presence or absence of liver cirrhosis.
RESULTS: A total of 225 patients assigned to the restrictive strategy (51%), as compared with 61 assigned to the liberal strategy (14%), did not receive transfusions (P<0.001) [corrected].The probability of survival at 6 weeks was higher in the restrictive-strategy group than in the liberal-strategy group (95% vs. 91%; hazard ratio for death with restrictive strategy, 0.55; 95% confidence interval [CI], 0.33 to 0.92; P=0.02). Further bleeding occurred in 10% of the patients in the restrictive-strategy group as compared with 16% of the patients in the liberal-strategy group (P=0.01), and adverse events occurred in 40% as compared with 48% (P=0.02). The probability of survival was slightly higher with the restrictive strategy than with the liberal strategy in the subgroup of patients who had bleeding associated with a peptic ulcer (hazard ratio, 0.70; 95% CI, 0.26 to 1.25) and was significantly higher in the subgroup of patients with cirrhosis and Child-Pugh class A or B disease (hazard ratio, 0.30; 95% CI, 0.11 to 0.85), but not in those with cirrhosis and Child-Pugh class C disease (hazard ratio, 1.04; 95% CI, 0.45 to 2.37). Within the first 5 days, the portal-pressure gradient increased significantly in patients assigned to the liberal strategy (P=0.03) but not in those assigned to the restrictive strategy.
CONCLUSIONS: As compared with a liberal transfusion strategy, a restrictive strategy significantly improved outcomes in patients with acute upper gastrointestinal bleeding. (Funded by Fundació Investigació Sant Pau; ClinicalTrials.gov number, NCT00414713.).
Comments Off on Blood products in trauma & survivor bias
The observation that patients with haemorrhagic trauma in military and civilian settings do better if they receive coagulation factors and platelets is yet to be replicated in a randomised trial. It has been suggested that the effect may in part be a consequence of survivor bias – ie. that if a patient lives long enough to received some thawed fresh frozen plasma, then they were already more likely to be a survivor and therefore more survivors will be represented in the ‘FFP’ groups vs a ‘no-FFP’ comparison group.
An attempt to eliminate survivor bias was made in the PROMMTT study, which documented the timing of transfusions during active resuscitation and patient outcomes in adult trauma patients who received a transfusion of at least 1 unit of RBCs within 6 hours of admission.
Increased ratios of plasma:RBCs and platelets:RBCs were independently associated with decreased 6-hour mortality, when haemorrhagic death predominated. In the first 6 hours, patients with ratios less than 1:2 were 3 to 4 times more likely to die than patients with ratios of 1:1 or higher.
A prospective trial is underway to identify the optimal ratio of blood products, in the PROPPR study, in which 1:1:1 ratio of plasma:platelets:RBC will be compared with 1:1:2.
The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) Study
Arch Surg. 2012 Oct 15:1-10
Objective: To relate in-hospital mortality to early transfusion of plasma and/or platelets and to time-varying plasma:red blood cell (RBC) and platelet:RBC ratios.
Design: Prospective cohort study documenting the timing of transfusions during active resuscitation and patient outcomes. Data were analyzed using time-dependent proportional hazards models.
Setting: Ten US level I trauma centers.
Patients: Adult trauma patients surviving for 30 minutes after admission who received a transfusion of at least 1 unit of RBCs within 6 hours of admission (n = 1245, the original study group) and at least 3 total units (of RBCs, plasma, or platelets) within 24 hours (n = 905, the analysis group).
Main Outcome Measure: In-hospital mortality.
Results: Plasma:RBC and platelet:RBC ratios were not constant during the first 24 hours (P < .001 for both). In a multivariable time-dependent Cox model, increased ratios of plasma:RBCs (adjusted hazard ratio = 0.31; 95% CI, 0.16-0.58) and platelets:RBCs (adjusted hazard ratio = 0.55; 95% CI, 0.31-0.98) were independently associated with decreased 6-hour mortality, when hemorrhagic death predominated. In the first 6 hours, patients with ratios less than 1:2 were 3 to 4 times more likely to die than patients with ratios of 1:1 or higher. After 24 hours, plasma and platelet ratios were unassociated with mortality, when competing risks from nonhemorrhagic causes prevailed.
Conclusions: Higher plasma and platelet ratios early in resuscitation were associated with decreased mortality in patients who received transfusions of at least 3 units of blood products during the first 24 hours after admission. Among survivors at 24 hours, the subsequent risk of death by day 30 was not associated with plasma or platelet ratios.
Comments Off on Swallow a camera in GI bleed
Two recent studies evaluate the use of a novel ingestable camera to diagnose upper gastrointestinal bleeding in emergency department patients.
The potential advantages of video capsule endoscopy over traditional endoscopy could include immediate availability, avoidance of sedation, patient tolerance, and the ability to rule out active bleeding in the emergency department.
The device used was the PillCam ESO2 – shown here in this animation:
Further research is needed. These small interesting studies demonstrate the potential for this imaging technology to be used in stable patients presenting to emergency departments. Since it can only diagnose rather than treat, it would not appear to have any role in unstable patients.
Video capsule endoscopy in the emergency department: a prospective study of acute upper gastrointestinal hemorrhage.
Ann Emerg Med. 2013 Apr;61(4):438-443
STUDY OBJECTIVE: Video capsule endoscopy has been used to diagnose gastrointestinal hemorrhage and other small bowel diseases but has not been tested in an emergency department (ED) setting. The objectives in this pilot study are to demonstrate the ability of emergency physicians to detect blood in the upper gastrointestinal tract with capsule endoscopy after a short training period, measure ED patient acceptance of capsule endoscopy, and estimate the test characteristics of capsule endoscopy to detect acute upper gastrointestinal hemorrhage.
METHODS: During a 6-month period at a single academic hospital, eligible patients underwent video capsule endoscopy (Pillcam Eso2; Given Imaging) in the ED. Video images were reviewed by 4 blinded physicians (2 emergency physicians with brief training in capsule endoscopy interpretation and 2 gastroenterologists with capsule endoscopy experience).
RESULTS: A total of 25 subjects with acute upper gastrointestinal hemorrhage were enrolled. There was excellent agreement between gastroenterologists and emergency physicians for the presence of fresh or coffee-ground blood (0.96 overall agreement; κ=0.90). Capsule endoscopy was well tolerated by 96% of patients and showed an 88% sensitivity (95% confidence interval 65% to 100%) and 64% specificity (95% confidence interval 35% to 92%) for the detection of fresh blood. Capsule endoscopy missed 1 bleeding lesion located in the postpyloric region, which was not imaged because of expired battery life.
CONCLUSION: Video capsule endoscopy is a sensitive way to identify upper gastrointestinal hemorrhage in the ED. It is well tolerated and there is excellent agreement in interpretation between gastroenterologists and emergency physicians.
Capsule endoscopy in acute upper gastrointestinal hemorrhage: a prospective cohort study
Endoscopy. 2013 Jan;45(1):12-9
BACKGROUND AND STUDY AIMS: Capsule endoscopy may play a role in the evaluation of patients presenting with acute upper gastrointestinal hemorrhage in the emergency department.
METHODS: We evaluated adults with acute upper gastrointestinal hemorrhage presenting to the emergency departments of two academic centers. Patients ingested a wireless video capsule, which was followed immediately by a nasogastric tube aspiration and later by esophagogastroduodenoscopy (EGD). We compared capsule endoscopy with nasogastric tube aspiration for determination of the presence of blood, and with EGD for discrimination of the source of bleeding, identification of peptic/inflammatory lesions, safety, and patient satisfaction.
RESULTS:The study enrolled 49 patients (32 men, 17 women; mean age 58.3 ± 19 years), but three patients did not complete the capsule endoscopy and five were intolerant of the nasogastric tube. Blood was detected in the upper gastrointestinal tract significantly more often by capsule endoscopy (15 /18 [83.3 %]) than by nasogastric tube aspiration (6 /18 [33.3 %]; P = 0.035). There was no significant difference in the identification of peptic/inflammatory lesions between capsule endoscopy (27 /40 [67.5 %]) and EGD (35 /40 [87.5 %]; P = 0.10, OR 0.39 95 %CI 0.11 - 1.15). Capsule endoscopy reached the duodenum in 45 /46 patients (98 %). One patient (2.2 %) had self-limited shortness of breath and one (2.2 %) had coughing on capsule ingestion.
CONCLUSION:In an emergency department setting, capsule endoscopy appears feasible and safe in people presenting with acute upper gastrointestinal hemorrhage. Capsule endoscopy identifies gross blood in the upper gastrointestinal tract, including the duodenum, significantly more often than nasogastric tube aspiration and identifies inflammatory lesions, as well as EGD. Capsule endoscopy may facilitate patient triage and earlier endoscopy, but should not be considered a substitute for EGD.
Comments Off on Alternative ‘universal’ plasma donor
The group usually considered the universal donor for fresh frozen plasma because it contains no anti-A or anti-B antibodies is Type AB. Due to its limited availability the trauma service of the Mayo Clinic in Minnesota has been issuing thawed group A plasma to its flight crews who retrieve major trauma casualties from rural centres. This is given with packed group O red cells to patients who meet their prehospital massive transfusion protocol criteria. Some patients will inevitably receive ABO-incompatible plasma (namely patients with Group B or AB blood) which could theoretically give rise to haemolytic transfusion reactions, in which donor antibodies bind host red cells, activate complement, and give rise to anaemia, disseminated intravascular coagulation, acute kidney injury, and death. However:
- the transfusion of platelets containing ABO-incompatible plasma is common, with up to 2 units of incompatible plasma per apheresis platelet unit, whereas haemolytic reactions to platelets are rare (1 in 9,000 incompatible platelet transfusions);
- all reports of haemolytic reactions are caused by products that contain Group O plasma and there has never been a documented case of haemolysis as a result of products containing Group A plasma
A retrospective review showed no increased rates of adverse events with Type A compared with AB or ABO-compatible plasma. Since only a small absolute number of patients received an ABO-incompatible plasma transfusion, it could be argued that the study is underpowered (a point acknowledged by the authors). However this is very important and useful information for resource-limited settings.
Emergency use of prethawed Group A plasma in trauma patients
J Trauma Acute Care Surg. 2013 Jan;74(1):69-74
BACKGROUND: Massive transfusion protocols lead to increased use of the rare universal plasma donor, Type AB, potentially limiting supply. Owing to safety data, with a goal of avoiding shortages, our blood bank exploited Group A rather than AB for all emergency release plasma transfusions. We hypothesized that ABO-incompatible plasma transfusions had mortality similar to ABO-compatible transfusions.
METHODS: Review of all trauma patients receiving emergency release plasma (Group A) from 2008 to 2011 was performed. ABO compatibility was determined post hoc. Deaths before blood typing were eliminated. p < 0.05 was considered statistically significant.
RESULTS: Of the 254 patients, 35 (14%) received ABO-incompatible and 219 (86%) received ABO-compatible transfusions. There was no difference in age (56 years vs. 59 years), sex (63% vs. 63% male), Injury Severity Score (ISS) (25 vs. 22), or time spent in the trauma bay (24 vs. 26.5 minutes). Median blood product units transfused were similar: emergency release plasma (2 vs. 2), total plasma at 24 hours (6 vs. 4), total red blood cells at 24 hours (5 vs. 4), plasma-red blood cells at 24 hours (1.3:1 vs. 1.1:1), and plasma deficits at 24 hours (2 vs. 1). Overall complications were similar (43% vs. 35%) as were rates of possible transfusion-related acute lung injury (2.9% vs. 1.8%), acute lung injury (3.7% vs. 2.5%), adult respiratory distress syndrome (2.9% vs. 1.8%), deep venous thrombosis (2.9% vs. 4.1%), pulmonary embolism (5.8% vs. 7.3%), and death (20% vs. 22%). Ventilator (6 vs. 3), intensive care unit (4 vs. 3), and hospital days (9 vs. 7) were similar. There were no hemolytic reactions. Mortality was significantly greater for the patients who received incompatible plasma if concurrent with a massive transfusion (8% vs. 40%, p = 0.044). Group AB plasma use was decreased by 96.6%.
CONCLUSION: Use of Group A for emergency release plasma resulted in ABO-incompatible transfusions; however, this had little effect on clinical outcomes. Blood banks reticent to adopt massive transfusion protocols owing to supply concerns may safely use plasma Group A, expanding the pool of emergency release plasma donors.
LEVEL OF EVIDENCE: Therapeutic study, level IV; prognostic study, level III.
Comments Off on What happened to HIFU?
High intensity focused ultrasound (HIFU) was hailed as the ‘surgery of the future’ a few years ago(1). As it’s now the future, where is it?
HIFU uses ultrasound to increase the heat within tissues at a specific area, causing local necrosis and cautery without injuring surrounding tissues. It is used to treat some cancers, but has shown promise in haemorrhage control. In animal studies it reduced or stopped bleeding in liver(2), spleen(3), and vascular injuries(4).
It has been proposed to offer a promising method for hemorrhage control in both civilivan and miltary trauma(5). Automated systems have been developed and tested that identify bleeding using Doppler ultrasound techniques that then allow targeting of the HIFU beam to the bleeding tissue(6). The United States Army has identified the need for a such systems and has designed a remotely operated robotic haemostatic system to save lives of soldiers. This was presented in 2006(7).
I would love to know where we are with this technology, and why nothing seems to have appeared about it in the literature for the last few years. If you have any information, please fill us in via the comments box.
1. High intensity focused ultrasound: surgery of the future?
Br J Radiol. 2003 Sep;76(909):590-9 Full text
2. Liver hemostasis using high-intensity focused ultrasound
Ultrasound Med Biol. 1997;23(9):1413-20
3. Control of splenic bleeding by using high intensity ultrasound
J Trauma. 1999 Sep;47(3):521-5
4. Hemostasis of punctured blood vessels using high-intensity focused ultrasound
Ultrasound Med Biol. 1998 Jul;24(6):903-10
5. Hemorrhage control using high intensity focused ultrasound
Int J Hyperthermia. 2007 Mar;23(2):203-11
6. Focused ultrasound: concept for automated transcutaneous control of hemorrhage in austere settings.
Aviat Space Environ Med. 2009 Apr;80(4):391-4
7. Remotely Operated Robotic High Intensity Focused Ultrasound (HIFU) Manipulator System for Critical Systems for Trauma and Transport (CSTAT)
Presented at the IEEE Ultrasonics Symposium, October 3-6, 2006, Vancouver, Canada – Full Text Here
The highlight for me was Mr Jonny Morrison speaking on Resuscitative Emergency Balloon Occlusion of the Aorta (REBOA). He is a British military surgeon currently out in Texas studying balloon occlusion of the aorta on pigs. Looking at trauma deaths, the next unexpected survivors will come from the uncontrollable haemorrhage group (truncal and junctional zones). This is by no means a new technique – described in the 1950’s during the Korean War – but like the early Star Wars chapters, needed to wait for technology to advance to make it feasible. It has the effect of cross clamping the aorta which provides afterload support, increases cerebral and coronary perfusion and provides proximal inflow control – without the mess of a resuscitative thoracotomy and greater access.
The placement of the balloon is determined by the location of the injury (see photo) and falls into two zones. Zone 1 is the thoracic aorta and is used for truncal haemorrhage control, avoid Zone 2 where the celiac axis etc originates and Zone 3 is infrarenal, used for junctional bleeding and pelvic haemorrhage.
His studies have determined that for Zone 3 amenable bleeds balloon occlusion up to 60min is the optimal time. Any longer and the debt of the metabolic load is paid by increased inotropic support requirements. He also compared REBOA to the current standard treatment for junctional injuries, Celox™ gauze. If coagulation is normal then both treatments perform similarly, the benefit is seen in coagulopathic patients where REBOA outperforms the gauze.
Has REBOA been used on humans? Yes a case series of 13 – the technique improved the BP allowing time to get to definitive surgery (blogged here 2.5 years ago!).
The Zone 1 studies are looking at continuous vs intermittent balloon occlusion. The jury is still out as to which is better. With the intermittent occlusion (20min on, 1min off) there are inevitably some losses when the balloon is deflated, conversely the metabolic debt generated by continuous occlusion is too great in some also leading to deaths.
What was very clear is that for this technique to have an impact it must be delivered proactively and pre-hospital. The challenges that need to be overcome are access to the femoral artery and blind accurate placement.
Prof Karim Brohi brought the conference to a close with a summary of what we have learned about coagulation in trauma this year. Here are three things;
- FFP is good but as 43% deaths due to trauma in the UK are secondary to bleeding and occur in the first 3hr we are failing our patients by administering the treatment on average at 2.5hrs.
- Fibrinogen levels are low in coagulopathic trauma patients; we should give cryoprecipitate early and aim for Fib ≥2.0
- And finally whilst TEG is recommended to guide treatment and can provide results within 5 min, there are some aspects of coagulation it does not detect i.e. fibrinolysis was only detected in 8% of coagulopathic trauma patients – when measured in the plasma it was then detectable in 80%.
These are the highlights of the 2012 London Trauma Conference. I hope this whistle stop tour through these days has been informative and though provoking. I can assure you telephone hacking was not used to bring you this information and to my knowledge is correct.
This is Lou Chan, roving reporter for Resus ME! signing off.
‘London raises her head, shakes off the debris of the night from her hair, and takes stock of the damage done. The sign of a great fighter in the ring is can he get up from a fall after being knocked down… London does this every morning.’
Day 2 of the LTC was really good. There were some cracking speakers who clearly had the ‘gift’ when it comes to entertaining the audience. No death by PowerPoint here (although it seems Keynote is now the presentation software of choice!). The theme of the day was prehospital care and major incidents.
The golden nuggets to take away include: (too many to list all of course)
- ‘Pull’ is the key to rapid extrication from cars if time critical from the Norweigan perspective. Dr Lars Wik of the Norweigen air ambulance presented their method of rapid extrication. Essentially they drag the car back on the road or away from what ever it has crashed into to control the environment and make space (360 style). They put a paramedic in the car whilst this is happening. They then make a cut in the A post near the roof, secure the rear of the car to a fire truck or fixed object with a chain and put another chain around the lower A post and steering wheel that is then winched tight. This has the effect of ‘reversing’ the crash and a few videos showed really fast access to the patient. The car seems to peel open. As they train specifically for it, there doesn’t seem to be any safety problems so far and its much quicker than their old method. I guess it doesnt matter really how you organise a rapid extrication method as long as it is trained for and everyone is on the same page.
- Dr Bob Winter presented his thoughts on hangings – to date no survivor of a non-judicial hanging has had a C-spine injury, so why do we collar them? Also there seems no point in cooling them. All imaging and concern for these patients should be based on the significant soft tissue injury that can be caused around the neck.
- Drownings – if the patient is totally submerged probably reasonable to search for 30mins in water that is >6 degrees or 90mins if <6 degrees. After that it becomes a body recovery (unless there is an air pocket or some exceptional circumstance). Patients that have drowned should have early ventilatory support if they show any signs of resp distress.
- Drs Julian Thompson and Mark Byers reassured us on a variety of safety issues at major incidents. It seems the risk to rescuers from secondary bombs at scene is low. Very few terrorist attacks world wide, ever, have had secondary devices so rescuers should be reassured (a bit). Greatest risk to the rescuer, like always, are the silly simple things that are a risk every day, like tripping over your own feet! With reference to chemical incidents, simple PPE seems to be sufficient for the vast majority of incidents, even fairly significant chemical ones, all this mucking about in full air tight suits is probably pointless and means patients cant be treated (at all). This led to the debate of how much risk should we, as rescue staff, accept? Clearly there are no absolute answers but minimising all risk to the rescuer is often at conflict with your ability to rescue. Where the balance should lie is a matter for organisations and individuals I guess.
- Sir Prof Keith Porter also gave us an update on the future of Prehospital emergency medicine as a recognised medical specialty. As those in the know, know, the specialty has been recognised by the GMC and the first draft of trainees are currently in post. More deaneries will be following suit soon to begin training but it is likely to take some time to build up large numbers of trained specialists. Importantly for those of us who already have completed our training there will be an option to sub specialise in PHEM but it will involve undertaking the FIMC exam. Great, more exams – see you there.
Day 3 – Major trauma
The focus of day 3 was that of damage control. Damage control surgery and damage control resucitation. We had indepth discussions about how to manage pelvic trauma and some of the finer points of trauma resuscitation.
Specific points raised were:
- Pelvic binders are great and can replace an ex fix if the abdomen needs opening to fix a spleen for example.
- You can catheterise patients with pelvic fractures (one gentle try).
- Most pelvic bleeds are venous which is why surgeons who can pack a pelvis is better than a radiologist who can mainly only treat arterial bleeds.
- Coagulopathy in trauma is not DIC and is probably caused by peripheral hypoperfusion.
- All the standard clotting tests that we use (INR etc) are useless and take too long to do. ROTEM or TEG is much better but still not perfect.
Also, as I am sure will please many – pressure isn’t flow so dont use pressors in trauma!
The Bleeding Trauma Patient
by Dr Pete Sherren
By popular request, Here are the slides from a presentation given by HEMS critical care physician Dr Pete Sherren.
These notes accompany the slides:
Hypothermia, acidaemia and coagulopathy or the ‘lethal triad’, is a well described entity in the trauma population and is associated with significant mortality . Traditionally the aetiology of a trauma induced coagulopathy was thought to be multifactorial and involve hypothermia, acidaemia, dilutional coagulopathy, pre-existing bleeding diathesis and disseminated intravascular coagulation (Figure 1).
In 2003 Brohi et al showed that around 25% of severely injured trauma patients present to hospital with a significant coagulopathy which was unrelated to fluid administration . This early coagulopathy has become known as the Acute Traumatic coagulopathy (ATC) or Acute Coagulopathy of Trauma Shock (ACoTS). It is associated with an increase in transfusion requirements, injury severity scores, organ dysfunction and mortality rates [2-5].
ATC is an impairment of haemostasis involving a dynamic interaction between endogenous anticoagulants and fibrinolysis that is initiated immediately after an injury . ATC is driven by an endothelial injury and hypoperfusion, which results in in increased thrombomodulin expression and activation of protein C (Figure 3). The inhibitory effect of activated protein C on clotting factors V/VIII and plasminogen activator inhibitor-1 (PAI-1), would appear key in the development of ATC [5,6].
Damage control resuscitation (DCR) describes a package of care for the haemorrhaging trauma patient. It involves early damage control surgery, haemostatic resuscitation and permissive hypotension. DCR aims to control haemorrhage early while aggressively targeting the ATC and lethal triad. DCR has emerged as the accepted standard of care and some observational studies have suggested a survival benefit .
- Damage Control Surgery – The priority for any haemorrhaging trauma patient is good haemostasis. Unstable patients with major trauma do not tolerate prolonged definitive surgery and hence the emergence of damage control surgery. The aim of damage control surgery is to normalise physiology at the expense of anatomy.
- Haemostatic resuscitation – Describes the aggressive early use of packed red blood cells, clotting products and coagulation adjuncts in an attempt to mitigate the effects of the ATC and lethal triad in major trauma patients. The exact PRBC:FFP ratio remains unclear, but should ideally be less than 2:1 . In massive transfusions along with appropriate FFP, platelet and fibrinogen supplementation, consideration should be given to early adjunctive therapies such as tranexamic acid  while maintaining ionised calcium levels greater than 1.0 mmol/L .
- Permissive hypotension – Involves titrated volume resuscitation, which targets a subnormal end point that maintains organ viability until haemorrhage is controlled. By avoiding overzealous fluid resuscitation which targets normotension, the hope is to preserve the first and often best clot. Although permissive hypotension is frequently employed in traumatic haemorrhage, there is really only robust evidence that it is advantageous in penetrating trauma . In blunt trauma there is a relative paucity of good evidence to guide practice, while strong evidence exists for maintaining cerebral perfusion pressures when there are associated head injuries. The end points for resuscitation will depend on age, premorbid autoregulatory state and acute pathology.
DCR is an ever evolving concept and potential emerging management strategies include –
- Thromboelastometry (TEG/ROTEM) to guide haemostatic resuscitation instead of ratio based transfusions.
- Prothrombin complex concentrate (FII, VII, IX and X) in non-warfarin patients
- Fibrinogen complex concentrate (fibrinogen and FXIII) over cryoprecipitate.
- Alkalising agents such as Tris-hydroxymethyl aminomethane (THAM) in massive transfusion with severe acidaemia
- Novel hybrid resuscitation strategies.
- High flow/low pressure resuscitation – endothelial resuscitation and microvascular washout.
- Suspended Animation
- Platelet function analysis in trauma with platelet mapping and aggregometry vs traditional PF-100
- Early coagulation dysfunction is common in trauma patients with haemorrhagic shock.
- Tailored management of the ‘lethal triad’ and ATC is essential.
- DCR is an emerging standard of care; however, some of its components are pushing the boundaries of what is good evidence based medicine.
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3. Davenport R, Manson J, De’Arth H, Platton S, Coates A, Allard S, Hart D, Pearse RM, Pasi J, MacCullum P, Stanworth S, Brohi K. Functional definition and characterization of acute traumatic coagulopathy. Crit Care Med. 2011;39(12):2652-2658.
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