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Three Part Question

In [anticoagulated patients] can [prothrombin complex concentrate in the prehospital phase] be [used safely and in a timely fashion for those with clinically significant bleeding]?

Clinical Scenario

You are the emergency department (ED) duty doctor for resus, and get a pre-alert from the ambulance service about a patient with a witnessed fall at home, who is anticoagulated with warfarin. Injuries suggest intra-abdominal bleeding and observations indicate haemorrhagic shock. Whilst preparing to receive the patient you consider whether use of PCC, which is established practice in your ED, could be brought forward safely to the patient in the pre-hospital phase of their care, and how much time could this bring PCC forward by?

Search Strategy

CINAHL, EMBASE, Medline and Pubmed were searched, with no limitation on date or language, via the NICE Healthcare Databases Advanced Search portal (search strategy: 447896). ClinicalTrials.gov and PROSPERO were searched with a simpler search string.
218 search results for "(((factor ADJ2 complex) OR PCC OR prothrombin* OR beriplex OR octaplex OR Kcentra OR warfarin* OR coumadin*).ti,ab AND (trauma* OR injur* OR haemo* OR hemo* OR bleed*).ti,ab) AND (pre-hospital* OR EMS OR PHE* OR ambulance* OR aeromed* OR paramedic* OR (enhanced AND care) OR ECT OR HEMS OR (Air AND Ambulance) OR (emergency AND (doctor OR physician))).ti" as of 13th June 2018

CINAHL: 14
EMBASE: 190
Medline: 14
Pubmed: 0

ClinicalTrials.gov: 209 studies matching ‘PCC’ or synonyms. None relating to pre-hospital use.
PROSPERO: 2 reviews ongoing regarding use of PCC in reversing anticoagulation, none relevant to pre-hospital use.
TRIP: No relevant results not already identified in HDAS strategy

Search Outcome

Total: 218 results, with 35 duplicated. After removal of these, 183 articles screened based on title or abstract with regard to the three part question using the Rayyan free open access platform(1), with 178 excluded.
- 172 at title
- 6 at abstract (3 not prehospital, 1 not blood product based, 2 were use of blood products, but no PCC use)

5 articles were directly relevant to the clinical question posed, with:

2 case report/series, specifically use of PCC by a predominantly pre-hospital triage and primary transfer service (London’s Air Ambulance) and another by a primary transfer and secondary retrieval service (Emergency Medical Retrieval Service, Scotland)
1 retrospective case review, specifically use of PCC by a secondary transfer (air) service
2 conference abstracts, one specifically a Standard Operating Procedure (SOP) for PCC use prehospitally and another a review/commentary of developing a pre-hospital transfusion service across multiple states.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Vines C et al 2017 UK	72 patients, 34 in intervention arm Inclusion: INR >1.5, receipt of 4 factor PCC and significant bleed (known intracranial haemorrhage; known ongoing, intra-abdominal, retroperitoneal, or pelvic blood loss; prolonged altered mental status prior to CT) and presumptive evidence of ongoing blood loss based on persistent hypotension or tachycardia resistant to fluid. Exclusion: <18 years old Site/Country: Single academic centre, USA. Review period: April 2014 to June 2016 inclusive	Retrospective Cohort Study (2+)	Proportion of patients with an INR ? 1.5 upon tertiary care hospital arrival	82% with INR <1.5 (0% in control), p<0.01	An author received grant money for commercial research on idarucizumab for dabigatran reversal (Disclosure rather than weakness) Of 114 exclusions, 26 had no pre/post INR recorded (outside of study remit as retrospective)
			Difference in time to INR ? 1.5	181 vs 322 minutes, p<0.01
			Difference in thromboembolic complications, length of stay, ICU length of stay, and inpatient mortality.	Non-significant differences in length of ICU or hospital stay, administration of blood products, thromboembolic complication. In-hospital mortality 21% vs 5%, p<0.05.
Robertson et al 2014 UK	7 patients meeting criteria for PCC. Inclusion: known to be on warfarin or with congenital factor IX deficiency AND presence of major haemorrhage (limb or life-threatening bleeding) or head injury Exclusion: age <16 years and pregnancy. 1170 missions during review period (August 2008 – January 2012 inclusive)	Retrospective Case Series (3)	Number of patients eligible for PCC therapy consideration	7 patients meeting criteria for PCC administration	Intra-mission intervals not specified Duration of hospital stay not specified Patient functional outcome not specified e.g. CPC score
			Use of PCC where (indicated or not)	3 patients treated of 7 meeting criteria, 2 not meeting criteria were given PCC
			Hospital and 30 day outcome	Of the 3 where PCC warranted: 1 died in hospital (withdrawal of treatment), 2 survivors (both hospital and at 30 days). Of the 2 where PCC given outside of criteria, both had no CT prior to transfer and withdrawal of treatment, one with first presentation of primary frontal tumour and another with massive intracerebral and subdural bleed.
Lendrum R et al 2013 UK	1 patient, 84 year old, on warfarin with POC INR 2.9. Obvious head injury after road traffic collision as a pedestrian.	Case Report (3)	Reduction of INR from >2	INR 1.2 on arrival (hospital) from 2.9 (HEMS)	Time/duration of injection/infusion not specified Time interval from first and subsequent INR not specified Patient functional outcome not specified e.g. CPC score
			Clinical improvement (inferred)	Subarachnoid blood and temporal cerebral contusions, small pelvic haematoma. Patient discharged from hospital 1 month later

Comment(s)

Use of PCC is established clinical practice in the emergency reversal of anticoagulation in hospital practice. Many enhanced care teams e.g. Air Ambulance/HEMS services carry blood products pre-hospitally(2), mainly in the form of packed red cells and plasma (fresh frozen or lyophilised), and will have established links with local transfusion laboratories for the supply and strict clinical governance surrounding these products. This could provide an opportunity to, in the appropriate clinical context through the use of SOPs(3), bring forward PCC to patients with suspicion of or confirmed, clinically significant bleeding. Services performing retrieval work may have an added interest given the timelines usually involved and that rural hospitals may not have PCC(4). Vines et al describe the use of PCC delivered by a non-physician crew (flight nurse and paramedic)(5) with the transferring facility physician prescribing the PCC, and in a region with middle distances for flight (77-117 miles) which provides context for the improvement in timelines (181 vs 322 minutes). Robertson et al highlight that of their 1170 cases, 15 with acquired coagulopathy and major haemorrhage could have been candidates for PCC, of whom some received FFP. Whilst still not part of current UK MHP practice, the option of a blood product not requiring cold chain and the specific clinical governance associated with PRBCs, FFP and platelets is an attractive one and has been the subject of previous and ongoing interest.

Clinical Bottom Line

Use of PCC has been demonstrated to be logistically possible and is likely to have an equivalent (if not superior) clinical effect to use in hospital by reducing time to administration, in appropriate groups of patients. (Grade D recommendation). Abbreviations: Computed Tomography (CT), Intensive Care Unit (ICU), International Normalised Ratio (INR), Helicopter Emergency Medical Service (HEMS), Cerebral performance category (CPC), Standard Operating Procedures (SOPs) References 1. Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan-a web and mobile app for systematic reviews. Syst Rev [Internet]. 2016;5(1):1–10. Available from: http://dx.doi.org/10.1186/s13643-016-0384-4 2. Naumann DN, Hancox JM, Raitt J, Smith IM, Crombie N, Doughty H, et al. What fluids are given during air ambulance treatment of patients with trauma in the UK, and what might this mean for the future? Results from the RESCUER observational cohort study. BMJ Open [Internet]. 2018 Jan 1;8(1). Available from: http://bmjopen.bmj.com/content/8/1/e019627.abstract 3. Weaver A, Chesters A, Davies G, Lockey D. Pre-hospital care standard operating procedure-use of human prothrombin complex (octaplex). Br J Haematol. 2012;157:84. 4. Robertson LC, McKinlay JAC, Munro PT, Hearns S. Use of prothrombin complex concentrates: 4-Year experience of a national aeromedical retrieval service servicing remote and rural areas. Emerg Med J. 2014;31(2):109–14. 5. University of Mississippi Medical Center. Department of Helicopter Transport [Internet]. [cited 2018 Jun 13]. Available from: https://www.umc.edu/UMMC/Outreach-Programs/MS-Center-for-Emergency-Services/Critical-Care-Transport/AirCare-Home/Department-of-Helicopter-Transport-Home.html

References

1. Vines, Claire Tesseneer, Stephanie J Cox, Robert D Darsey, Damon A Carbrey, Kristin Puskarich, Michael A Air Ambulance Delivery and Administration of Four-factor Prothrombin Complex Concentrate Is Feasible and Decreases Time to Anticoagulation Reversal Academic Emergency Medicine 2018; 33-40
2. Robertson, Laura Catriona McKinlay, Jayne A.C. Munro, Philip T. Hearns, Stephen Use of prothrombin complex concentrates: 4-Year experience of a national aeromedical retrieval service servicing remote and rural areas Emergency Medicine Journal 2014, 109-114
3. Lendrum, Robbie A. Kotze, Jean Pierre Lockey, David J. Weaver, Anne E. Case studies in prehospital care from London HEMS: Pre-hospital administration of prothrombin complex concentrate to the head-injured patient Emergency Medicine Journal 2013; 247-248