Introduction Prothrombin complex concentrates (PCCs) are recommended as first-line treatment for acquired or congenital factor II, VII, IX and X deficiencies in situations of major haemorrhage. The Emergency Medical Retrieval Service (EMRS) provides critical care and aeromedical retrieval to patients in remote and rural Scotland. It has an important role in the care of these patients.
Method We sought to determine the incidence of haemorrhage requiring PCC administration in our cohort of patients, and to assess compliance with current national guidelines regarding their storage and use. We searched our database for all patients that received PCCs, or met current guidelines for their administration, and followed them through to hospital discharge. We also conducted a telephone survey of all hospitals served by the EMRS to determine compliance with national standards.
Results During the 42-month study period, 1170 retrieval missions were conducted. Twenty-six retrieved patients had a congenital or acquired clotting factor deficiency and seven met criteria for PCC administration. Of these, only three received PCCs prior to transfer to definitive care. Telephone survey revealed that all the rural general hospitals were served by the EMRS stock PCCs, but only one out of 15 GP-led community hospitals had access to PCCs.
Conclusions In the remote and rural setting where access to definitive care may be limited or delayed, timely administration of PCCs in appropriate patients may improve outcomes. As many rural hospitals do not have access to PCCs, the ability of the EMRS to provide this treatment may improve patient care.
- critical care transport
- emergency care systems, remote and rural medicine
- prehospital care
- remote and rural medicine
- Trauma, head
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- critical care transport
- emergency care systems, remote and rural medicine
- prehospital care
- remote and rural medicine
- Trauma, head
Prothrombin complex concentrates (PCCs) were developed in the late 1950s for the treatment of patients with haemophilia B (congenital factor IX deficiency). PCCs are highly purified clotting factor concentrates prepared from pooled human plasma by fractionation techniques. They contain factor IX along with variable amounts of factors II, VII and X, and are produced in 3-factor (ie, factors II, IX and X) or 4-factor preparations, with a final clotting factor concentration 25 times that of plasma.1 In the UK, PCCs are licensed for the treatment and perioperative prophylaxis of haemorrhage in patients with congenital deficiency of factors II, VII, IX and X, if specific coagulation factors are not available, or acquired deficiency of factors II, VII, IX and X. The most common acquired deficiency of these clotting factors is oral anticoagulation with the coumarin-derivative, warfarin.
PCCs were first used to reverse over-anticoagulation by Taberner et al in 1976,2 and were first included as possible agents to reverse warfarin in the 1998 British Haematology Society guidelines.3 They are now recommended as first-line treatment in the UK for the urgent reversal of warfarin therapy in situations of major haemorrhage,4 where major haemorrhage is defined as limb or life-threatening bleeding that requires complete warfarin reversal within 6–8 h. It is recommended that PCCs be used in preference to fresh frozen plasma (FFP) in this setting, and that all hospitals managing patients on warfarin should stock licensed 4-factor PCC. PCCs also feature in US,5 European6 and Australasian7 anticoagulation guidelines.
Clinically, significant bleeding is a common problem in anticoagulated patients and related mortality is high, with an annual incidence of fatal haemorrhage of 0.3–1%.8 Intracranial haemorrhage is a particular concern. The risk is increased 10-fold in warfarinised patients over 50 years of age, compared with non-anticoagulated counterparts,9 and outcomes are worse in both the spontaneous and traumatic setting.10 ,11 All patients on warfarin who present with a head injury, regardless of severity, should have their International Normalized Ratio (INR) measured, and a low threshold for computed tomography (CT) imaging employed.12 Where there is a strong suspicion of intracranial haemorrhage after a head injury in a warfarinised patient, it is recommended that anticoagulation be reversed immediately, even before INR and CT results are available.4
Rapid warfarin reversal requires the replacement of deficient coagulation factors. PCCs possess several advantages over FFP in this setting. PCCs can completely reverse warfarin-induced anticoagulation within 15 min,13 and correct INR more rapidly and effectively than FFP alone,14–16 resulting in clinically measurable improvements, such as reduction in blood product requirements17 and haematoma extension.14 ,18 PCCs are administered in smaller infusion volumes than FFP; this decreases the risk of fluid overload,19 shortens delivery time and prevents further dilution of innate clotting factors. In addition, they possess a better safety profile, with no requirement for blood group matching, minimal viral transmission risk and no risk of transfusion-related acute lung injury.20 They also have the advantage of storage at room temperature, unlike FFP which must be thawed before delivery. Although early concerns were raised regarding thromboembolic complications with PCC use, these no longer exist for the indicated patient groups, and there is evidence that high-dose PCCs (>40 IU kg−1) can be used safely in even high-risk patients.21 These features, and the evidence for improved outcomes with earlier anticoagulant reversal, make PCCs ideal for use in the prehospital setting in appropriate patients. With the ageing population and ever increasing number of patients on warfarin,22 they are likely to be used more frequently in this setting in the future.
The aim of our study was, therefore, to determine the incidence of haemorrhage requiring PCC administration in our cohort of patients and assess compliance with current national guidelines regarding their storage and use.
The Emergency Medical Retrieval Service (EMRS) is a government funded national service that provides aeromedical retrieval to patients in remote and rural areas of Scotland. It provides patients with life-threatening illness rapid access to critical care interventions and timely transfer to definitive care. The majority of activity is secondary retrieval; retrieval of patients already in a healthcare facility under the care of a healthcare professional. The remaining activity (approximately 20%) is primary retrieval; directly from the scene of an incident. The healthcare facilities served a range from rural general hospitals to isolated General Practitioner (GP) surgeries, and there is a wide variation in resources available at the retrieval sites, for instance, most retrieval centres that the EMRS serves do not have 24 h access to CT imaging. In the majority of secondary retrieval cases, the time from initial presentation to reaching definitive care exceeds 6 h. This is due to a combination of geographical, transport and clinical factors. The EMRS is, by necessity, self-sufficient, and brings critical care interventions, monitoring and treatment directly to the patient regardless of location. Patients are triaged to definitive care depending on clinical diagnosis and presenting location and, where appropriate, transfers are conducted by the EMRS, predominantly using fixed or rotor-wing aircraft.
The study was conducted in two parts. First, we sought to determine the incidence of haemorrhage requiring PCC administration in patients managed by the EMRS and compliance with guidelines recommending their use. Second, we aimed to determine adherence to guidelines on hospital stockade of PCCs in the centres served by the EMRS.
Data for all missions conducted by the EMRS is contemporaneously collected and stored on a database. Patients are followed up at 24–48 h and on hospital discharge to determine definite diagnosis, management and outcome. The EMRS database was hand-searched by two researchers (LR and JM) from database inception to the present time (a 42-month period from 1 August 2008 to 1 February 2012) for all patients that received PCCs or met current guidelines for the administration of PCCs. Criteria for inclusion were the presence of major haemorrhage or head injury in a patient known to be on warfarin or with a congenital deficiency of factor IX. Major haemorrhage was defined as limb or life-threatening bleeding. Exclusion criteria were age <16 years and pregnancy. The following details were recorded for each patient when available: age, gender, underlying reason for factor IX deficiency, indication for PCC administration, clotting screen result prior to PCC use, CT imaging prior to PCC use if clinically indicated, PCC use and dose, use of other blood products (blood, FFP, cryoprecipitate and platelets), documented immediate adverse effects of PCC administration and clinical outcome at initial (24–48 h) and 30-day follow-up.
National guidelines recommend that all hospitals managing patients on warfarin therapy should stock licensed 4-factor PCCs.4 In the second part of our study, we conducted a telephone survey (over the period of 1 week in February 2012) of all hospitals served by the EMRS to determine compliance with this standard (see online supplementary appendix A). Data collection included the following details: type of hospital (rural general hospital vs GP-led community hospital), ability to measure INR, availability of CT imaging, access to PCCs and FFP, and authorisation requirements for administration of these products.
During the 42-month period studied, the EMRS conducted 1170 retrieval missions. PCCs were not routinely carried by the EMRS during this time. They could be obtained by request, on an individual patient basis, however, this necessitated a delay in mission activation time due to location of blood transfusion services distant from the EMRS base. In each case, the decision to take PCCs to the patient was made by the retrieval consultant, based on a risk/benefit analysis taking into account the clinical situation, referring hospital resources and logistical variables.Twenty-four patients had a congenital or acquired deficiency of factor IX, and seven patients met criteria for PCC administration (figure 1). One was excluded from further analysis due to lack of available data. Details of the six patients in whom PCCs were indicated are given in table 1.
Five were on warfarin therapy, and one had a background of haemophilia B. In three out of six patients, the clinical indication for PCC use was presence or suspicion of life-threatening intracranial haemorrhage. In one patient, this was not clearly associated with any history of trauma but was confirmed on CT imaging at the retrieval site prior to PCC administration (Case 3). In the remaining two patients, the indication for PCC use was suspicion of an intracranial haemorrhage in the setting of a pre-existing head injury. Both patients underwent CT brain imaging following PCC administration and transfer to tertiary neurosurgical care. This confirmed an intracranial haemorrhage in one of the two patients (Case 1). The second patient was subsequently found to have collapsed secondary to cardiac causes. In the remaining three out of six patients, PCCs were indicated due to non-intracranial major haemorrhage.
Of the six patients who met indications, three received PCCs prior to transfer to definitive care. All received 4-factor PCCs (Beriplex or Octaplex) in a dose of 25 IU kg−1. In two cases, this was available at the retrieval site, and in one case was brought by the EMRS team. Three patients did not receive PCCs despite meeting recommended indications. This may have been due to non-availability of PCCs at the referring site; two received FFP instead. Five out of six (83%) patients survived to initial follow-up at 24–48 h, and four to follow-up at 30 days. One patient had treatment withdrawn and subsequently died. Immediate adverse effects of PCC administration (eg, new headache, hypersensitivity reactions/anaphylaxis) were not documented in any patient.
During the audit period, an additional two patients received PCCs, although they did not meet the national guidelines recommending administration in confirmed major haemorrhage, or suspicion of intracranial haemorrhage in the setting of trauma, in a patient on warfarin (table 2).
Both cases involved warfarinised patients presenting with a history of headache preceding catastrophic neurological collapse, with a Glasgow Coma Score ≤4 and raised INR at presentation. They were transferred to a tertiary neurosurgical centre for further investigation and management. PCCs were administered by the EMRS team prior to transfer based on the suspicion of major intracranial haemorrhage and delay in accessing diagnostic imaging. The diagnosis of intracranial haemorrhage was confirmed in one patient on arrival at tertiary care. In the other patient, CT imaging revealed a previously undiagnosed primary frontal tumour. Both patients eventually had active treatment withdrawn and subsequently died.
A final subset of 15 patients was identified, with major haemorrhage in the setting of acquired coagulopathy not related to warfarin therapy (table 3).
Coagulopathy in these patients was secondary to hepatic failure as a result of paracetamol overdose or chronic alcohol misuse. Records for these patients were scrutinised and excluded from the above analysis as they did not meet criteria for PCC administration. None of the patients were given PCCs prior to transfer to definitive care, however, attempts to reverse clotting factor deficiencies were made in eight patients through the use of intravenous vitamin K and/or blood products. At initial follow-up, two patients in this cohort had died, two were awaiting liver transplant, eight had survived and the outcome was unrecorded in three cases. This group of patients may benefit from PCC administration if indications are amended in the future.
In the second part of this study, data on compliance with current guidelines regarding warfarin monitoring and PCC availability was collected by telephone survey for all rural hospitals served by the EMRS: six rural general hospitals and 15 GP-led community hospitals. The questionnaire used is given in online supplementary appendix A. All rural general hospitals had the ability to monitor INR and access to both FFP and PCCs as required. Ten out of 15 community hospitals had the ability to monitor INR; in nine cases this was by point-of-care testing rather than formal laboratory study. Only one of these hospitals reported access to FFP, and one reported access to PCCs (figure 2).
Warfarin use has increased dramatically in the last decade, and this trend is expected to continue. Given the high incidence of significant bleeding on warfarin, the ability to effectively reverse anticoagulation is vital.22 Timely use of PCCs in this setting is advised,4 and may reduce the associated morbidity and mortality. Despite this, some countries have been slow to adopt PCCs, and even in the UK, where guidelines do exist, many hospitals do not stock these agents. It was therefore reassuring to find that all six rural general hospitals in Scotland served by the EMRS stock 4-factor PCCs in accordance with national guidelines. Ten out of the 15 GP-led community hospitals have the ability to monitor INR and adjust warfarin therapy, however, only one stocked PCCs at the time of our survey. Given the clear guidelines for PCC use, relative ease of storage and their value in reversing warfarin, particularly in a remote setting, we would recommend that this is reviewed by each centre.
A significant proportion of the Scottish population do not have easy access to tertiary medical services. In these cases, the EMRS has a vital role in bringing high-quality consultant-led specialist medical care to the patient. This includes critical care interventions, invasive monitoring and medical treatments, including blood products on an individual patient basis. In the setting of major haemorrhage in a patient on warfarin, the ability of the EMRS to routinely access PCCs may allow earlier administration of these agents and more rapid reversal of anticoagulation. The poor outcome of intracranial haemorrhage in warfarinised patients is thought to be due to haematoma extension as a consequence of incompletely reversed anticoagulation.23 Rapid termination of the deleterious effects of anticoagulation may, therefore, improve outcome and rapid INR reversal with PCCs has been shown to result in significant clinical benefits.14 ,17 ,18 Over a 4-year period, we identified seven patients who met criteria for PCC administration. In one case, where PCCs were administered prior to definitive transfer, this was achieved by provision of PCCs brought specifically by the EMRS. In a further three patients, PCCs would have been administered if available. PCCs were administered before transfer in a further two patients during the 4-year period due to clinical suspicion of significant intracranial haemorrhage. These cases highlight the challenges of delivering high-quality critical care in remote environments where access to diagnostic testing is limited.
In addition to reversal of warfarin-induced anticoagulation, there is growing interest in the use of PCCs for other indications. These include the treatment or prevention of haemorrhage in patients with acquired clotting factor deficiencies secondary to severe hepatic failure or critical illness and the management of major haemorrhage. In patients requiring massive transfusions, PCCs have been used to replace diluted coagulation factors.24 The practice is common in several European countries, however, it remains controversial.25 PCCs do not contain factors V, VIII or fibrinogen, all of which play a key role in haemostasis. In the UK, use of PCCs out with their currently licensed indications is not routinely recommended, although they may be considered on an individual patient basis. We identified a subgroup of 15 patients with acquired coagulopathy and major haemorrhage who could be considered for PCCs. None of these patients received PCCs although a significant number received coagulation factor replacement with FFP. This group may represent a potential source of PCC use in the future.
PCCs have an important role in the management of major haemorrhage in patients with acquired and congenital deficiencies of factors II, VII, IX and X, and timely administration in appropriate patients may improve outcomes. These patients may present in the remote and rural setting, where access to definitive care can be limited or delayed. This study has shown that there is a demand for PCC use that cannot always be met by the rural referring medical centre. Access to PCCs through the EMRS may improve compliance with national guidelines regarding PCC administration in these patients, and it is hoped that this may ultimately improve outcomes. This population audit has prompted review of practice within our service, and we now routinely stock PCCs and carry them to patients who may require them, including in the case of primary retrieval.
Contributors All authors included in this manuscript fulfil the criteria of authorship. In addition we can confirm that there is no one else who fulfils criteria but has not been included as an author or contributor.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
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