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
Comments Off on Pre-SMACC mini RAGE
Currently the RAGE Podcast site is recovering from a cold, so here are the show notes for the pre-SMACC mini RAGE episode released June 2015.
And here are the references:
It’s a knockout
Helicopter Emergency Medical Services
Survival benefit of a physician-staffed HEMS assistance for severely injured patients
The next RAGE Podcast will air late August / early September
Comments Off on London Cardiac Arrest Symposium 2014
The focus of the entire day is cardiac arrest and this is the second day of the London Cardiac Arrest Symposium.
Professor Niklas Nielsen kicked off with a presentation of his Targeted Temperature Management trial. It seems that even now there is uncertainty in the interpretation of this latest study. I take heart from the knowledge that Prof Nielsen has changed the practice of his institution to reflect the findings of his study – I have certainly changed my practice. But we need to remain aware that there is more work to be done to answer the multiple questions that remain and the need for further RCTs is recognised.
The management of Cardiac arrest after avalanche is not a clinical scenario that I imagine I’ll ever find myself in. The management is well documented in the ICAR MEDCOM guidelines 2012. Dr Peter Paal reminded us that you’re not dead until you’re rewarmed and dead unless: with asystole, CPR may be terminated (or withheld) if a patient is lethally injured or completely frozen, the airway is blocked and duration of burial >35 min, serum potassium >12 mmol L(-1), risk to the rescuers is unacceptably high or a valid do-not-resuscitate order exists.
The age old question about prognostication after cardiac arrest was tackled by Prof Mauro Oddo. He covered the evidence for clinical examination, SSPE, EEG, and neurone specific enolase. Bottom line, all of these modalities are useful but none are specific enough to be used as a stand alone test so multiple modalities are required.
SAMU is leading the way with prehospital ECMO. They have mastered the art of cannulation (in the Louvre no less!) but there haven’t enough cases to demonstrate a mortality benefit. The commencement of ECMO prehospital reduces low flow time and theoretically should improve outcomes. This is begging for a RCT.
The experience of the Italians with in hospital ECMO shoes a better survival rate for in-hospital rather than out of hospital cardiac arrests, explained Dr Tomasso Mauri. They treat patients with a no flow time of <6min and low flow rate of <45min and had a 31% ICU survival rate. If you want to learn more about ED ECMO go to http://edecmo.org.
The Douglas Chamberlain lecture this year was Selective aortic arch perfusion presented by Prof James Manning. He spoke about the use of this technique in cardiac arrest and also in trauma (where it is known to you as Zone 1 REBOA).
In cardiac arrest the aim is to improve coronary perfusion, to preserve perfusion to the heart and the brain, offer a route of rapid temperature control and offer a direct route of administration of adrenaline. Coronary perfusion is seen to be supra normal after SAAP. And the suggested place for SAAP is prior to ECMO.
It’s more familiar ground talking about SAAP in trauma. This Zone 1 occlusion preserves cerebral and cardiac perfusion while blood loss is limited and rapid fluid resuscitation can occur.
You can hear Prof Manning on SAAP over at EMCrit (of course!).
It’s been another great conference. Put the dates for next year’s London Trauma & Cardiac Arrest Conferences in your diary: 8th-10th December 2015!
Happy Holidays & Keep Well
Day three is Air Ambulance and pre-hospital day and the great and the good are here en mass.
The heavy weights are coming out to make their points…..
Unarguably the best lecture of the day was delivered by our very own Cliff Reid on prehospital training. Using Sydney HEMS induction training he highlighted the challenges posed to prehospital services training doctors and paramedics rotating through the service.
Turning a good inhospital doctor into a great prehospital one in the space of an induction program requires focus. Knowledge is therefore not the focus of training, performance is. Often doctors already possess the clinical skills and knowledge and it is the application of these pre existing skills in challenging environments when cognitively overloaded that is the key.
The Sydney HEMS program provides the mindware and communication skills the practitioner needs to do this and drills these skills in simulated environments. He uses perturbation, so like the Bruce protocol exercise test the simulations just get harder until you are at the very limits of your bandwidth. Debriefing of course is important but the recommended protracted debrief is often impractical and unnecessary so simulations designed with cognitive traps are used to highlight learning points and are drilled until the message is received. In this way tress exposure enhances cognitive resilience. And importantly they use cross training, so the doctors and the paramedics undergo the same program so each member of the team understands the challenges faced by the other.
Does this sound like fun? For the shrinking violets out there it could be seen as threatening. But for the adrenaline junkies…….hell yeah!
It’s truly a training ethos that I buy into and I’d love to be able to achieve that standard of training in my own service.
Microwaves seem to be the future if diagnostic testing. This modality is fast, is associated with a radiation dose lower than that of a mobile phone, non invasive, portable and has been shown to provide good information. It can be used on heads for intracranial haemorrhage and stroke or chests for pneumothorax detection. It’s all in the early stages but seems like it will be a viable option in the future.
For further reading check out:
Diagnosis of subdural and intraparenchymal intracranial hemorrhage using a microwave-based detector
Clinical trial on subdural detection
How would you transfer a psychotic patient requiring specialist intervention that can only be received after aeromedical transfer? Stefan Mazur of MedSTAR, the retrieval service in South Australia shared their experience with ketamine to facilitate the safe transfer of these patients with no reports of adverse effects on the mental state of the patient, as first described by Minh Le Cong and colleagues. Is there no end to the usefulness of this drug? No wonder we’re experiencing a supply issue in the UK!
And finally, the ultimate reflective practice should include the post mortem of our critically sick patients. The approach the forensic pathologist takes is similar to a clinician (with the time pressure removed). They read the scene and use this information to predict injuries (sound familiar?). Post mortem CT scanning with recon provides yet another layer of information. We are missing a trick if we don’t seek this feedback to correlate with our clinical findings. Even better, rare practical skills are often routinely performed as part of the post mortem – we should be making use of this opportunity to train.
I’ve travelled almost the entire length of England to get to the London Trauma Conference this year. What could be more important than attending one of the best conferences of the year? Examining for the DipRTM at the Royal College of Surgeons in Edinburgh
So was it worth the 4am start? Absolutely!
My highlights would be Tom Evens explaining why trauma can be regarded like an elite sport. His background is as a sports coach in addition to his medical accomplishments and walking us through the journey he went through with the athlete he was coaching demonstrates the changes that need to occur when cultivating a performance culture and the results speak for themselves.
I can see similarities in the techniques used by athletes and those we are using in medicine now. Developing a highly performing team isn’t easy as anyone involved in the training of these teams will know.
Dr Jerry Nolan answered some questions about cervical spine movement in airway management. The most movement is seen in the upper cervical spine and there is no surprise that there is an increased incidence of cervical spine injury in unconscious patients (10%). The bottom line is that no movement clinicians will make of the cervical spine is greater than that at the time of injury. And whether it be basic airway manoeuvres, laryngoscopy or cricoid pressure the degree of movement is in the same ball park and unlikely to cause further injury. He states that he would use MILS like cricoid pressure and have a low threshold for releasing it if there are difficulties with the intubation. Of course many of us don’t use cricoid pressure in RSI anymore………..
After watching Tom and Jerry we heard that ATLS has had its day. Dr Matthew Wiles implores us to reserve ATLS for the inexperienced and move away from this outdated system and move to training in teams using local policies. The Cochrane reviewers found an increase in knowledge but no change in outcomes.
And finally Dr Deasy has convinced me that I will be replaced by a robot roaming around providing remote enhanced care. On the up side I might be the clinician providing that support.
More from me on this fantastic conference soon. In the meantime follow it on Twitter!
Almost two-thirds of patients with extradural haematoma and bilateral fixed dilated pupils survived after surgery, with over half having a good outcome
Neurosurgeon, HEMS doctor, and all round good egg Mark Wilson was on the RAGE podcast recently and mentioned favourable outcomes from neurosurgery in patients with extradural (=epidural) haematomas who present with bilateral fixed dilated pupils (BFDP). Here’s his paper that gives the figures – a systematic review and meta-analysis.
A total of 82 patients with BFDP who underwent surgical evacuation of either subdural or extradural haematoma were identified from five studies – 57 with subdural (SDH) and 25 with extradural haematomas (EDH).
In patients with EDH and BFDP mortality was 29.7% (95% CI 14.7% to 47.2%) and 54.3% had a favourable outcome (95% CI 36.3% to 71.8%).
Only 6.6% of patients with SDH and BFDP had a good functional outcome.
Clearly there is potential for selection bias and publication bias, but these data certainly suggest an aggressive surgical approach is appropriate in some patients with BFDP.
The authors comment on the pessimism that accompanies these cases, which potentially denies patients opportunities for recovery:
“We believe that 54% of patients with extradural haematoma with BFDPs having a good outcome is an underappreciated prognosis, and the perceived poor prognosis of BFDPs (from all causes) has influenced decision making deeming surgery inappropriately futile in some cases.”
Scotter J, Hendrickson S, Marcus HJ, Wilson MH.
Prognosis of patients with bilateral fixed dilated pupils secondary to traumatic extradural or subdural haematoma who undergo surgery: a systematic review and meta-analysis.
Emerg Med J 2014 e-pub ahead of print Nov 11;:1–7
Primary objective To review the prognosis of patients with bilateral fixed and dilated pupils secondary to traumatic extradural (epidural) or subdural haematoma who undergo surgery.
Methods A systematic review and meta-analysis was performed using random effects models. The Cochrane Central Register of Controlled Trials and PubMed databases were searched to identify relevant publications. Eligible studies were publications that featured patients with bilateral fixed and dilated pupils who underwent surgical evacuation of traumatic extra-axial haematoma, and reported on the rate of favourable outcome (Glasgow Outcome Score 4 or 5).
Results Five cohort studies met the inclusion criteria, collectively reporting the outcome of 82 patients. In patients with extradural haematoma, the mortality rate was 29.7% (95% CI 14.7% to 47.2%) with a favourable outcome seen in 54.3% (95% CI 36.3% to 71.8%). In patients with acute subdural haematoma, the mortality rate was 66.4% (95% CI 50.5% to 81.9%) with a favourable outcome seen in 6.6% (95% CI 1.8% to 14.1%).
Conclusions and implications of key findings Despite the poor overall prognosis of patients with closed head injury and bilateral fixed and dilated pupils, our findings suggest that a good recovery is possible if an aggressive surgical approach is taken in selected cases, particularly those with extradural haematoma.
Comments Off on Early femur fixation recommended
The Eastern Association for the Surgery of Trauma recommends early (<24 hours) open reduction and internal fracture fixation in trauma patients with open or closed femur fractures.
They acknowledge the strength of the evidence is low, but suggests a trend toward lower risk of infection, mortality, and venous thromboembolic disease.
They conclude: “the desirable effects of early femur fracture stabilization probably outweigh the undesirable effects in most patients“
Check out the rest of the EAST Trauma Guidelines
Optimal timing of femur fracture stabilization in polytrauma patients: A practice management guideline from the Eastern Association for the Surgery of Trauma
Femur fractures are common among trauma patients and are typically seen in patients with multiple injuries resulting from high-energy mechanisms. Internal fixation with intramedullary nailing is the ideal method of treatment; however, there is no consensus regarding the optimal timing for internal fixation. We critically evaluated the literature regarding the benefit of early (<24 hours) versus late (>24 hours) open reduction and internal fixation of open or closed femur fractures on mortality, infection, and venous thromboembolism (VTE) in trauma patients.
A subcommittee of the Practice Management Guideline Committee of the Eastern Association for the Surgery of Trauma conducted a systematic review and meta-analysis for the earlier question. RevMan software was used to generate forest plots. Grading of Recommendations, Assessment, Development, and Evaluations methodology was used to rate the quality of the evidence, using GRADEpro software to create evidence tables.
No significant reduction in mortality was associated with early stabilization, with a risk ratio (RR) of 0.74 (95% confidence interval [CI], 0.50–1.08). The quality of evidence was rated as “low.” No significant reduction in infection (RR, 0.4; 95% CI, 0.10–1.6) or VTE (RR, 0.63; 95% CI, 0.37–1.07) was associated with early stabilization. The quality of evidence was rated “low.”
In trauma patients with open or closed femur fractures, we suggest early (<24 hours) open reduction and internal fracture fixation. This recommendation is conditional because the strength of the evidence is low. Early stabilization of femur fractures shows a trend (statistically insignificant) toward lower risk of infection, mortality, and VTE. Therefore, the panel concludes the desirable effects of early femur fracture stabilization probably outweigh the undesirable effects in most patients.
Comments Off on Blunt traumatic arrest in kids
Traumatic cardiac arrest outcomes are not great, but they’re not so bad that resuscitation is futile – a subject I’ve ranted about before.
The largest study on blunt traumatic arrest in children to date has been published, showing that 340 / 7766 kids without signs of life in the field survived to hospital discharge. Neurological status at discharge was not documented. However, this represents 4.4%, or in other words for every 22 blunt traumatically arrested children who underwent prehospital resuscitation, one survived to discharge. The authors describe this survival as ‘dismal’. It’s not great, but my take on it is that survival is possible and in most cases resuscitation should be attempted.
The authors state:
“Based on these data, EMS providers should not be discouraged from resuscitating blunt pediatric trauma patients found in the field with no signs of life“
While the major focus should be on injury prevention, it is worthwhile considering whether more advanced resuscitation in the field could be provided to further increase the number of neurologically intact survivors.
Survival of pediatric blunt trauma patients presenting with no signs of life in the field
J Trauma Acute Care Surg. 2014 Sep;77(3):422-6
BACKGROUND: Prehospital traumatic cardiopulmonary arrest is associated with dismal prognosis, and patients rarely survive to hospital discharge. Recently established guidelines do not apply to the pediatric population because of paucity of data. The study objective was to determine the survival of pediatric patients presenting in the field with no signs of life after blunt trauma.
METHODS: We conducted a retrospective analysis of the National Trauma Data Bank research data set (2002-2010). All patients 18 years and younger with blunt traumatic injuries were identified (DRG International Classification of Diseases-9th Rev. codes 800-869). No signs of life (SOL) was defined on physical examination findings and included the following: pulse, 0; respiratory rate, 0; systolic blood pressure, 0; and no evidence of neurologic activity. These same criteria were reassessed on arrival at the emergency department (ED). Furthermore, we examined patients presenting to the ED who underwent resuscitative thoracotomy (Current Procedural Terminology code 34.02). Our primary outcome was survival to discharge from the hospital.
RESULTS: There were a total of 3,115,597 pediatric patients who were found in the field after experiencing blunt trauma. Of those, 7,766 (0.25%) had no SOL. Seventy percent of the patients with no SOL in the field were male. Survival to hospital discharge of all patients presenting with no SOL was 4.4% (n = 340). Twenty-five percent of the patients in the field with no SOL were successfully resuscitated in the field and regained SOL by the time they arrived to the ED (n = 1,913). Of those patients who regained SOL, 13.8% (n = 265) survived to hospital discharge. For patients in the field with no SOL, survival to discharge was significantly higher in patients who did not receive a resuscitative thoracotomy than in those who did.
CONCLUSION: Survival of pediatric blunt trauma patients in the field without SOL is dismal. Resuscitative thoracotomy poses a heightened risk of blood-borne pathogen exposure to involved health care workers and is associated with a significantly lower survival rate.
Comments Off on When to Stop Resuscitation
My talk at the SmaccGOLD conference in March 2014
Here are the slides:
A paediatric trauma centre study showed that in their system, seven people at the bedside was the optimum number to get tasks done in a paediatric resuscitation. As numbers increased beyond this, there were ‘diminishing marginal returns’, ie. the output (tasks completed) generated from an additional unit of input (extra people) decreases as the quantity of the input rises.
The authors comment that after a saturation point is reached, “additional team members contribute negative returns, resulting in fewer tasks completed by teams with the most members. This pattern has been demonstrated in other medical groups, with larger surgical teams having prolonged operative times and larger paramedic crews delaying the performance of cardiopulmonary resuscitation.“
There are several possible explanations:
- crowding limits access to the patient or equipment;
- “social loafing”- staff may feel less accountable for the overall group performance and less pressure to accomplish individual tasks;
- seven is the number recommended in that institution’s trauma activation protocol, with optimal role allocation described for a team of that size;
- teams with redundant personnel may experience role confusion and fragmentation, resulting in both repetition and omission of tasks.
In my view, excessive team size results in there being more individuals to supervise & monitor, and hence a greater cognitive load for the team leader (cue the resus safety officer). More crowding and obstruction threatens situational awareness. There is more difficulty in providing clear uninterrupted closed loop communication. And general resuscitation room entropy increases, requiring more energy to contain or reverse it.
However, for paediatric resuscitations requiring optimal concurrent activity to progress the resuscitation, I do struggle with less than five. Unless of course I’m in my HEMS role, when the paramedic and I just crack on.
More on Making Things Happen in resus.
Factors Affecting Team Size and Task Performance in Pediatric Trauma Resuscitation.
Pediatr Emerg Care. 2014 Mar 19. [Epub ahead of print]
OBJECTIVES: Varying team size based on anticipated injury acuity is a common method for limiting personnel during trauma resuscitation. While missing personnel may delay treatment, large teams may worsen care through role confusion and interference. This study investigates factors associated with varying team size and task completion during trauma resuscitation.
METHODS: Video-recorded resuscitations of pediatric trauma patients (n = 201) were reviewed for team size (bedside and total) and completion of 24 resuscitation tasks. Additional patient characteristics were abstracted from our trauma registry. Linear regression was used to assess which characteristics were associated with varying team size and task completion. Task completion was then analyzed in relation to team size using best-fit curves.
RESULTS: The average bedside team ranged from 2.7 to 10.0 members (mean, 6.5 [SD, 1.7]), with 4.3 to 17.7 (mean, 11.0 [SD, 2.8]) people total. More people were present during high-acuity activations (+4.9, P < 0.001) and for patients with a penetrating injury (+2.3, P = 0.002). Fewer people were present during activations without prearrival notification (-4.77, P < 0.001) and at night (-1.25, P = 0.002). Task completion in the first 2 minutes ranged from 4 to 19 (mean, 11.7 [SD, 3.8]). The maximum number of tasks was performed at our hospital by teams with 7 people at the bedside (13 total).
CONCLUSIONS: Resuscitation task completion varies by team size, with a nonlinear association between number of team members and completed tasks. Management of team size during high-acuity activations, those without prior notification, and those in which the patient has a penetrating injury may help optimize performance.