Australasian Anaesthesia 2011 - Australian and New Zealand ...

128 Australasian Anaesthesia 2011The Management of Adult Jehovah’s Witnesses in Anaesthesia and Critical Care 1292. Anaesthesia techniquesWith respect to anaesthetic technique, again senior or consultant personnel should be involved. The patient, roomand fluids should be warmed to prevent hypothermia and subsequent coagulopathy.Venous congestion and venous ooze may be minimised by careful positioning and avoidance of highintra-thoracic pressures and hypercapnia.Where feasible, tourniquets and infiltration of vasoconstrictor agents should be used.Regional techniques, where possible, will minimse blood loss.Serial measurement and correction of coagulation profile and ionized calcium should be considered in longcases.Invasive monitoring should be considered to optimise tissue oxygen delivery, which is dependent upon haemoglobinconcentration, cardiac output and haemoglobin saturation. These factors may be manipulated using fluids, inotropesand increasing the FiO2.O 2 delivery (DO 2 ) = cardiac output x (1.39 x Hb x SaO 2 ) + 0.02 x PaO 23. Anaesthesia drugsA number of drugs may be used peri-operatively to minimise bleeding.a. Systemic antifibrinolytic agents, including tranexamic acid and eicoso-aminocaproic acid, inhibit plasminogenactivity and promote coagulation. Tranexamic acid is given as a 1g infusion followed by 1g Q8H. The infusion rateshould not exceed 100mg/min.b. Desmopressin or DDAVP induces the release of Factor VIII, prostacyclin, tissue plasminogen activator andvon Willibrand Factor from vascular endothelium. It has been demonstrated to reduce peri-operative blood lossassociated with uraemic and aspirin-induced platelet dysfunction. 15 The dose given is 0.3mcg/kg as an infusionover 30 minutes.c. Prothrombin Complex Concentrate or Prothrombinex contains recombinant factors II, VII, IX and X. It may beacceptable to some Jehovah’s Witness patients. The recommended dose is 25-50IU/kg. It is relatively deficient infactor VII so works best when given along with a small amount of FFP and/ or rFVIIa.d. Recombinant activated Factor 7 or Nova7 (rFVIIa) is reported to be effective in clinical situations associatedwith severe haemorrhage including cardiac surgery, trauma and obstetrics, but controlled clinical trials are scarce.Most case reports claim its use is associated with a reduction in blood loss and/ or transfusion requirements.Randomised controlled trials using rFVIIa in intra-cerebral haemorrhage demonstrate reduced growth of thehematoma but no improvement in survival or functional outcome. 16 Likewise trials in blunt trauma demonstratebenefit on blood loss and transfusion requirements but not mortality. 17 Its use is complicated by the occurrence ofarterial and venous thromboses, especially in the elderly population and those with risk factors for peripheralvascular disease. As it is an off-license indication, there is no recommended dose, but between 50 and 90mcg/kgis generally given.e. Individual clotting factors may be acceptable to some Jehovah’s Witnesses.f. Haemoglobin based oxygen carriers (HBOCs) could be employed in the future where available. They havebeen in development for over 70 years; however interest has been renewed since the 1980’s, prompted by boththe emergence of HIV and the death of trauma victims from exsanguination in the pre-hospital setting; including ataccident scenes, in ambulances and on the battlefield. Despite this there are currently no haemoglobin basedoxygen carriers approved for human use in Australia, the US or European Union; reflecting both a controversialhistory and the challenge of creating an ideal blood substitute.HBOC DEVELOPMENTHaemoglobin based oxygen carriers contain purified haemoglobin derived from either bovine red cells, expiredhuman red cells or from recombinant technology. Free human haemoglobin has a tetrameric structure of 2 alphaand 2 beta polypeptide chains. It rapidly dissociated into alpha/beta dimers which are cleared by glomerular filtrationwith an intravascular half life of only 30 minutes. Dissociated haemoglobin causes renal failure and scavenges nitricoxide causing hypertension. In addition, due to low concentrations of 2,3 DPG, free haemoglobin is ineffective atoxygenation due to its high affinity for oxygen, with a P50 of 10 to 14mmHg. In order to become therapeuticallyuseful, free haemoglobin requires modification by polymerisation and/ or cross-linkage to prevent dissociation intoalpha/beta dimers, right shift the oxyhaemoglobin dissociation curve and to increase its half life in the circulation.The modified haemoglobin is then incorporated into an electrolyte solution.HBOC ADVANTAGESHaemoglobin solutions have the advantage of being non-immunogenic. They do not contain any intact red bloodcells, which express ABO antigens, therefore cross-matching the product or typing the patient is not necessary.The products undergo an extensive purification process to remove potential contaminants including proteins,red blood cell stroma, bacteria, endotoxins, viruses and prions and are therefore guaranteed to be disease free.Haemoglobin based oxygen carriers may be stored far longer than the 42 days permitted for packed cells,between 12 months to 3 years, depending on the product. Hemopure is the easiest product to store and transportas it does not require refrigeration and may be stored for up to three years at room temperature.Haemoglobin solutions are developed to right shift the oxyhaemoglobin dissociation curve compared to nativehaemoglobin. Hemopure contains bovine haemoglobin; it has a P50 of 40mmHg compared to 27mmHg for humanred blood cells. It therefore releases oxygen more readily to the tissues and, on a gram-for-gram basis, restoresoxygenation three times more effectively than a transfusion of stored human red blood cells. PolyHeme containshuman haemoglobin, it has a P50 of 20-22mmHg which is comparable to packed cells.HBOC DISADVANTAGESThere are a number of disadvantages of haemoglobin based oxygen carriers compared to blood. Despite modification,they have a short intravascular half life of 16 to 24 hours, compared to 60 to 90 days for red blood cells, makingrepeat administration necessary. Cost is also higher than transfused red blood cells when compared on a unit-tounitbasis.Use of haemoglobin based oxygen carriers also interferes with many common laboratory tests, especially thosewhich are measured spectrophotometrically. Albumin, alkaline phosphatase, bilirubin and creatinine may all beinaccurate. Optical methods of measuring coagulation will be misleading. Plasma will have a pink discolorationand routine laboratory tests will not be able to differentiate between haemolysis and the presence of a haemoglobinsolution. Plasma free haemoglobin levels are measured to determine the amount of haemoglobin based oxygencarrier present in the specimen but the decision to give additional doses must be determined clinically.The incidence of adverse effects is not insignificant (approximately ≥ 5%), with complaints of jaundice, nausea,mild to moderate increases in blood pressure, vomiting, oliguria, dysphagia and flatulence.There are also reports of serious adverse events including myocardial infarction and death, however these risksmay be acceptable when allogeneic blood is either not available or effective or not acceptable to the patient.Furthermore, haemoglobin solutions have a maximum recommended dose, reflecting the maximum dose studiedin clinical trials to-date, which may provide temporary oxygen-carrying support, or an “oxygen bridge” but may notbe sufficient to completely avoid red cell transfusions in patients experiencing massive or continued blood loss.HBOC PRODUCT HISTORYThere have been a number of haemoglobin oxygen carriers in production over the last 30 years but PolyHeme isprobably the most controversial and Hemopure possibly the most promising.PolyHeme is a haemoglobin based oxygen carrier derived from human hemoglobin and developed by NorthfieldLaboratories, Inc. Northfield was predominately a research and development company; PolyHeme was their onlyproduct. PolyHeme was the first blood substitute to reach a Phase III clinical trial in the US.The trial was designed to assess the survival benefit of administering PolyHeme to severely injured traumapatients in hemorrhagic shock, beginning in the pre-hospital setting and continuing for 12-hours post-injury inhospital. It had two primary endpoints of superiority and non-inferiority to standard treatment. It was undertakenbetween January 2004 and July 2006 at 29 Level I trauma centers across 19 states in the US under a Food andDrug Administration (FDA) special category (21CFR 50.24) that allowed its use without consent. The waived informedconsent rule was established by the FDA in 1996 and stipulated that to be used “available treatments …. (must be)unproven or unsatisfactory”. The only way to opt out from the study was by wearing a special bracelet prior toneeding emergency care. The study was highly criticised due to the absence of consent. Indeed continuation ofthe study into the in-hospital period was considered unethical as blood was then both readily available and a provenand satisfactory therapy for haemorrhagic shock.The results were published in the Journal of the American College of Surgeons in January 2009. 18 They concludedthere was no significant difference in outcome between the conventionally-resuscitated group and the PolyHemetreatedgroup. However PolyHeme was associated with an increased risk of myocardial infarction (3% versus 1%).In May 2009 PolyHeme failed to receive FDA regulatory approval, with the FDA stating the risks of PolyHemeoutweighed the benefits. In June 2009 Northfield Laboratories Inc ceased operation and filed for bankruptcy.Hemopure, or HBOC-201, is developed from highly purified bovine haemoglobin. It is a third generation productdeveloped by Biopure. It has been available for human use in South Africa since 2001 and in Russia since 2011.There is also a “compassionate use” program in the US which makes Hemopure available when a life-threateningsituation exists and compatible red blood cell transfusion is either 1) not available 2) not effective or 3) not acceptableto the patient. Approval by the FDA is made on a case-by-case basis.Following a motor vehicle accident in October 2010, Australian Jehovah’s Witness Tamara Coakley received alife sustaining transfusion of 10 units of Hemopure, flown in from the US and made available via this “compassionateuse” scheme. Permission to use the product was granted by The Alfred Hospital Ethics Committee and theTherapeutic Goods Administration’s special access scheme. The manufacturer OPK Biotech paid for the costsinvolved.Hemopure has undergone a Phase III clinical trial evaluating its ability to reduce or eliminate perioperativetransfusion in orthopaedic patients. 19 Hemopure reduced the need for packed cell transfusion in 59% of patientsbut was associated with a significantly higher incidence of both adverse events (rate of adverse event/ patient 44%higher, p