Nottingham Neonatal Service Clinical Guidelines

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1 ottingham eonatal Service Clinical Guidelines eonatal Haemostasis Full Title of Guideline: eonatal Haemostasis Dr C Young Consultant eonatologist, Dr D Jayasinghe Consultant eonatologist, Author (include and role): Dr H Arabi, Professor H Budge Professor of eonatology Division: Family Health Division & Speciality: Specialty: eonatal Version: 4 Ratified by: Scope (Target audience, state if Trust wide): Review date (when this version goes out of date): Explicit definition of patient group to which it applies (e.g. inclusion and exclusion criteria, diagnosis): Changes from previous version (not applicable if this is a new guideline, enter below if extensive): Summary of evidence base this eonatal Guidelines Group Staff caring for babies on the eonatal Unit 23 rd January 2024 Preterm and term infants being cared for on the eonatal Unit Inclusion of Major Haemorrhage Pathway Randomised Controlled Trial, Systematic Review guideline has been created from: This guideline has been registered with the trust. However, clinical guidelines are guidelines only. The interpretation and application of clinical guidelines will remain the responsibility of the individual clinician. If in doubt contact a senior colleague or expert. Caution is advised when using guidelines after the review date or outside of the Trust. 1 Introduction: Bleeding or thrombosis occurs more frequently in sick infants who are preterm. More rarely, an otherwise healthy infant with a congenital coagulation defect may present clinically in the newborn period. 1.1 ormal neonatal clotting values: These are dependent on both gestational and postnatal age. Levels of Vitamin K-dependant (and most other) clotting factors are at 50% or less compared to adult levels [1], and may be even lower in gestations below 29 weeks. The newborns haemostasis system matures during the early weeks and months of life with most parameters reaching adult values by 6 months of age. Although preterm infants show accelerated maturation of clotting and fibrinolytic systems [1,2], they may be unable to compensate when systemically unwell [2,3].

2 ottingham eonatal Service Clinical Guidelines There have been a number of studies since the original work of Andrew et al [1], establishing normal ranges for more preterm infants, including a study [4] investigating preterm infants between 23 and 26 weeks gestation. We have used more conservative normal ranges [6], based on 5 th -95 th centiles of 168 neonates, which correlate with the values given in the eonatal Formulary 7 th Edition (table 1), with the exception of the upper limit for APTT. <28 weeks [6] weeks [6] weeks [7] PT (sec) APTT (sec) Fibrinogen(g/dl) Table 1 B: The normal values given by laboratories at QMC and CH are adult values. D-dimers/FDPs (Fibrinogen degradation products): There are no established reference ranges in neonates, although they are often slightly raised - particularly if unwell or in the presence of consumptive coagulopathy. [8,9] 2 Investigation of coagulation in newborn infants 2.1 Indications for haemostasis testing of newborn infants: Haemorrhage i.e. purpura, mucosal bleeding, pulmonary haemorrhage, IVH, prolonged oozing from venepuncture or heelprick site. Severe metabolic disease, severe respiratory distress syndrome, liver disease (including hepatic impairment in HIE), or sepsis in the presence of active bleeding or evidence of DIC. There is no increased risk of coagulopathy in infants undergoing neuroprotective hypothermia. Unwell infants born to mothers who have received medications that interfere with vitamin K metabolism. These include anticonvulsants (phenytoin, barbiturates or carbamazepam), antitubercular drugs (rifampicin or isoniazid) and vitamin K antagonists (warfarin and phenprocoumarin). All neonates undergoing surgery or tissue biopsy. A family history of an inherited bleeding disorder. Discuss appropriate investigations with Haematologist first if antenatal alert plan not already made. Do not check clotting routinely in preterm infants, there is evidence that abnormal clotting values are not predictive of IVH, pulmonary haemorrhage or GI bleeding in the first week of life [6], and that routinely checking clotting values increases the use of FFP and clotting products with no evidence of benefit [10,11]. 2.2 Laboratory investigations Initial screening investigations usually comprise a full blood count and a base line coagulation screen which should include: APTT, PT, TCT and fibrinogen. (B: Fibrinogen will not be done routinely by the laboratory and should be specifically requested Coag and fibrin on otis). Send one EDTA sample and one full sodium citrate sample (blue top, 1.3mls), ideally a freeflowing venous sample and filled to the line to avoid inaccurate results. Blood sampling from a newborn infant should avoid contamination with intravenous fluid, particularly heparin as sample results can be heavily influenced if the sample was taken from a heparinised line, irrespective of discarded volume. If it is unavoidable that samples are

3 ottingham eonatal Service Clinical Guidelines taken from an arterial line, this should be clearly documented in the patient record, a heparinised syringe should not be used and the laboratory should be clearly informed at the time of the request so that coagulation results can be corrected in the laboratory for the presence of heparin. In collecting a sample for testing of coagulation by syringe, the blood sample should be expressed from syringe into collection tube and gently mixed. Overfilled or underfilled samples cannot be analysed or interpreted. Importantly, a sample sent for coagulation screen that is reported to be clotted implies an activated sample, but does not necessarily indicate normal clotting and should therefore be repeated if still clinically indicated. Interpreting laboratory results in neonatal coagulation disorders [8] Condition PT APTT Fibrinogen Platelets Acquired disorders Vitamin K deficiency DIC (any abnormality may be seen) Liver disease Inherited disorders Haemophilia A Haemophilia B VWD PT,Prothrombin time; APTT, activated partial thromboplastin time;, normal; DIC, disseminated intravascular coagulation; vwd, von Willebrand disease. / / / / Clinical Problems 3.1 Acquired problems of haemostasis Vitamin K deficiency bleeding See Guideline on Prophylaxis against Vitamin K deficiency bleeding. Concentration of the vitamin K dependent factors (FII, FVII, FIX, FX) are reduced in the newborn period and are functionally inactive in the absence of Vitamin K. Isolated prolongation of the PT is the earliest laboratory evidence of vitamin K deficiency, followed by prolongation of APTT. The diagnosis is confirmed by correction of these parameters by Vitamin K, or by assay of the specific factors. Management of Vitamin K deficiency bleeding (VKDB) Any infant suspected of VKDB should receive immediate slow IV Vitamin K (1 mg) (to avoid haematoma after IM injection), which will usually result in correction within a few hours. In infants who are actively bleeding, FFP ml/kg should be given in addition to vitamin K. Subsequent Vitamin K may be required if there is no improvement. Prothrombin Complex Concentrate (PCC) is available at QMC, and its use may be appropriate in the presence of life threatening haemorrhage or intracranial haemorrhage (after discussion with Haematologist), but this is rare in VKDB.

4 ottingham eonatal Service Clinical Guidelines Disseminated intravascular coagulation (DIC) DIC always occurs as a secondary event, and is associated with a number of perinatal and neonatal problems such as birth asphyxia, acidosis, RDS, sepsis, necrotizing enterocolitis (EC) and meconium aspiration syndrome. Intravascular activation of coagulation results in consumption and depletion of coagulation factors, which may be accompanied by capillary microthrombi. Bleeding or rarely thrombosis may occur, along with end organ damage due to ischaemia. Laboratory findings are prolonged APTT, PT and TCT. Fibrinogen and platelets are low, with red cell fragmentation on blood film though not always. Raised D-Dimers are a sensitive marker of early DIC but are not routinely monitored. Management of disseminated intravascular coagulation The priority should be to identify and correct the underlying cause and to treat hypoxia, acidosis, and hypotension. In compensated low grade DIC, in the absence of active bleeding, management of the cause and observation is appropriate [12]. However, blood product replacement is indicated for the treatment of clinical bleeding in the presence of DIC [2,8,13]: 1. If fibrinogen <1g/l, give Cryoprecipitate (5-10 ml/kg) which contains a higher concentration of FVIII and Fibrinogen per unit volume than FFP (see Appendix 1). The indication for requesting cryoprecipitate must be discussed with the oncall haematology registrar. 2. If platelet count < 50x 10 9 /l, give platelets (10-15 ml/kg) (See Guideline E7 - eonatal Thrombocytopenia). 3. FFP (10-15 ml/kg over 30 minutes) (unless cryoprecipitate and platelets have both been given, since if the cryoprecipitate plus platelets are indicated (as above) there is usually no need to give FFP in addition). 4. Red cell transfusion may be required. (see Guideline E1 Red Cell Transfusion in the newborn) Further management should be guided by the clinical picture and the repeated clotting screen. Careful consideration should be given to the overall volume of fluid being administered to the baby, particularly in pulmonary haemorrhage Intraventricular haemorrhage (IVH) /Intracranial (ICH) haemorrhage [2] Periventricular/intraventricular haemorrhage is the most common form of ICH in preterm infants of low birth weight, with an incidence around 20% of infants with birth weight less than 1500g, and up to 45% in infants less than 750g [14]. The aetiology is multifactorial with alteration in cerebral blood flow, fragility of immature germinal matrix vessels and endothelial ischaemia being more significant than impaired haemostasis, with the possible exception of thrombocytopenia [14]. There is no proven benefit achieved by prophylactic use of FFP or platelets in high risk newborns, and these products should not be routinely administered [15]. However, in newborn infants with pre-existing IVH, it may be appropriate to correct a coagulation abnormality and maintain platelet count above 100x 10 9 /l in order to prevent extension of the bleed. This should be discussed with the eonatal Consultant Pulmonary haemorrhage: See separate Guideline B13

5 ottingham eonatal Service Clinical Guidelines 3.2 Inherited coagulation deficiencies These are much less common than acquired problems in the neonatal period. However, there may not always be a family history to suggest the diagnosis. Perinatal management of inherited coagulation deficiencies When a significant positive family history is known to be present, a multidisciplinary management plan (Fetal -Maternal Medicine, eonatology and Haematology) for delivery and subsequent management of mother and infant should be in place. As there may not be a family history to suggest the diagnosis, even in the absence of positive family history, inherited coagulation deficiencies should be suspected if there is abnormal bleeding (for example, continued oozing from venepuncture sites/heel pricks, an excessive haematoma after IM injection) in an otherwise healthy baby. Umbilical or intracranial haemorrhages are less frequent. Samples for specific clotting factor assays are required for the diagnosis and should be taken after discussion with the Haematologist. B: If there is a family history of Von Willebrand Disease, there is no indication to test the newborn infant, BUT these babies should be followed up by a Haematologist. Where there is clinically significant ongoing haemorrhage give FFP (after taking the samples) while awaiting the results. The ongoing management of these disorders should be undertaken in conjunction with a Consultant Haematologist. 3.3 Major Haemorrhage ve Haemorrhage Procedure (link (CL/CGP/046))if: - estimated blood loss is equivalent to more than 50% of blood volume within 3 hours (i.e. >40mls/kg for a term baby) - there is evidence of haemorrhagic shock - systolic blood pressure falls by 25% as a result of haemorrhage Activation is via switch on This will establish a dedicated team within the lab and Haematologists to advise, process samples and make available specific packs of appropriate blood products. Please see appendix 3 for the paediatric flow charts within this pathway, or to access the full package. In the rare occurrence of uncontrolled bleeding, either from traumatic injury to a major blood vessel or subgaleal haemorrhage, there is some limited evidence emerging for the use of Recombinant Factor VIIa. This is primarily from adult practice, but there are some documented case studies of successfully controlling bleeding in preterm neonates using 100 micrograms/kg/dose of ovoseven [16]. However, contrary to the Massive Haemorrhage Procedure there is no current evidence for the use of Tranexamic Acid in eonates. 3.4 Jehovah s witness Jehovah s witnesses will not accept a transfusion of packed red cells, platelets or components. In the emergency management of a child when there is no time to make an application to the courts and the child is likely to die or suffer serious harm without transfusion, blood or components should be given whatever the wishes of the parents. Full

6 ottingham eonatal Service Clinical Guidelines documentation of the decision by two senior clinicians (consultants) is essential and the trust Legal department/duty manager must be informed. (UH Guideline to the management of patients refusing transfusion of blood and blood components) Audit points Clotting screens carried out in appropriate circumstances. The appropriate use of clotting products on the neonatal unit. All clotted clotting samples repeated if still clinically indicated. Appendix 1 Fresh frozen plasma and cryoprecipitate 7 Volume of preparation provided FFP, USA source Virus inactivated ml of plasma containing CPDA Cryoprecipitate, USA source ml WBC <5X10 6 /unit <5X10 6 /unit *Electrolytes: Sodium mmol Potassium mmol Citrate mmol Lactate mmol Hydroxyl mmol Fibrinogen Factor VIII Other clotting factors Other plasma proteins Added chemicals Points to ote: Prescribing * Typical values are given Content per unit: mg/ml >0.7 IU/ml in >75% packs >0.7 IU/ml Content per pool of 10 units: Fibrinogen mg/pack Factor VIII IU/pack von Willebrand Factor IU/pack As in slightly diluted plasma. citrate phosphate dextrose adenine -75 ml. obulins.

7 ottingham eonatal Service Clinical Guidelines Appendix 2: Flow chart for Massive Haemorrhage (Trauma) in Paediatrics Activate Massive Haemorrhage Protocol 2222 via switch board Send Samples (X Match, Fbc, Coagulation, Fibrinogen) Collect & Transfuse Red Cells (20ml/kg) Instigate resuscitation & haemorrhage prevention measures Tranexamic Acid 15mg/kg IV bolus(max 1g) then 2mg/kg/hr infusion over 8 Correct Acidosis & Hypothermia Contact Haematologist (may be initiated by Blood Bank) Collect & Transfuse Pack 2 accordingly Enquire about available blood results but DO OT WAIT for results before transfusing Send repeat samples Check ABG, K +, Ca ++ Patient Still Bleeding? Send for Haemorrhage Pack 3 Liaise with Haematologist Collect Pack 3 & Transfuse accordingly Check available blood results Send repeat samples Patient Still Bleeding? Discuss with Consultant Haematologist Further components require authorisation from Consultant Haematologist Transfusion Targets Hb 80g/l Platelets > 50 x 10 9 /l PT/PTT < 1.5 x normal Fibrinogen > 1 g/l

8 ottingham eonatal Service Clinical Guidelines Appendix 3: Flow chart for Massive Haemorrhage in Paediatrics (non-trauma) Activate Massive Haemorrhage Protocol 2222 via switch board Discuss blood component requirements with lab Send Samples (X Match, Fbc, Coagulation, Fibrinogen) Collect & Transfuse Red Cells (20ml/kg) Instigate resuscitation & haemorrhage prevention measures 15mg/kg IV bolus(max 1g) then 2mg/kg/hr infusion over 8hr Correct Acidosis & Hypothermia Contact Haematologist (may be initiated by Blood Bank) Patient still bleeding? Send repeat samples Enquire about available blood results. Use ROTEM results as a guide if available Collect 2 nd lot of components Transfuse as guided by results and Haematology advice Patient still bleeding? Send repeat samples Liaise with Consultant Haematologist Collect and transfuse further components as guided by results and Haematology advice Transfusion Targets Hb 80 g/l Platelets > 50 x 10 9 /l PT/PTT < 1.5 x normal Fibrinogen > 1.0 g/l

9 ottingham eonatal Service Clinical Guidelines References Andrew M, Paes B, Milner R, et al. Development of the human coagulation system in the healthy premature infant. Blood 1988;72: Williams MD, Chalmers EA, Gibson BES. The investigation and management of neonatal haemostasis and thrombosis. Br J Haematol 2002;119: Salonvaara M, Riikonen P, Kekomäki R, et al. Effects of gestational age and prenatal and perinatal events on the coagulation status in premature infants. Arch Dis Child Fetal eonatal Ed 2003;88:F eary E, Okafor I, Al-Awaysheh F, et al. Laboratory Coagulation Parameters in Extremely Premature Infants Born Earlier than 27 Gestational Weeks upon Admission to a eonatal Intensive Care Unit. eonatology 2013;104:222 7 Christensen RD, ussenzveig RH, Yaish HM, et al. Causes of hemolysis in neonates with extreme hyperbilirubinemia. J Perinatol 2014;34: doi: /jp Christensen RD, Baer VL, Lambert DK, et al. Reference intervals for common coagulation tests of preterm infants (CME). Transfusion 2014;54:627 32:quiz 626. Rennie JM, Roberton RC (orman RC. Textbook of neonatology. 3rd ed. Edinburgh: : Churchill Livingstone 1999 Chalmers EA. eonatal coagulation problems. Arch Dis Child Fetal eonatal Ed 2004;89:F doi: /adc Hudson IR, Gibson BE, Brownlie J, et al. Increased concentrations of D-dimers in newborn infants. Arch Dis Child 1990;65:383 Catford K, Muthukumar P, Reddy C, et al. Routine neonatal coagulation testing increases use of fresh-frozen plasma. Transfusion 2014;54: Stanworth SJ, Grant-Casey J, Lowe D, et al. The use of fresh-frozen plasma in England: high levels of inappropriate use in adults and children. Transfusion 2011;51: O Shaughnessy DF, Atterbury C, Bolton Maggs P, et al. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol 2004;126: Murray A, Roberts IA. eonatal transfusion practice. Arch Dis Child Fetal eonatal Ed 2004;89:F101-7 Ballabh P. Intraventricular hemorrhage in premature infants: mechanism of disease. Pediatr Res 2010;67:1 8 Randomised trial of prophylactic early fresh-frozen plasma or gelatin or glucose in preterm babies: outcome at 2 years. orthern eonatal ursing Initiative Trial Group. Lancet 1996;348: Mathew P. The use of rfviia in non-haemophilia bleeding conditions in paediatrics. A systematic review. Thromb Haemost 2004;92:738 46