Marrow aspirate material provides information on 2 Cytology of nucleated cells. 2 Qualitati ve and semi-qualitative analysis of haematopoiesis. 2 Assessment of iron stores. 2 Smears f or cytochemistry of atypical cells. Suspensions of marrow cells in medium are suitable for 2 Chromosome (cytogenetic) analysis. 2 Immunophenotype studies using monoclonal antibodies directed against cell surface antigens. 2 Aliquots of marrow can be cryopreserved for future molecular analysis. Marrow trephine biopsy yields information on 2 Marrow cellularity. 2 Identification/classif ication of abnormal cellular infiltrates. 2 Immunohistochemistry on infiltrates. Note: Cytology of trephine imprints can be helpful, especially when aspi- rate yields a \200\230dry tap \200\231. Trephine biopsy information complements that obtained at aspirati on. Contraindications None, other than physical limitations e.g. pain or restricted mobility. A void sites of previous radiotherapy (inevitably grossly hypocellular and not representative ). 570 Procedure 1. Bone marrow aspiration may be performed under local anesthesia alone, but shor t acting intravenous benzodiazepines (e.g. midazolam) may be administered \200\224with appr opriate monitoring (pulse oximetry), oxygen administration and available resuscitation equi pment \200\224when trephine biopsy is performed. General anesthesia rarely used (except in children). 2. Best position is with patient in L or R lateral position. 3. Skin and periosteum over th e posterior iliac spine are infiltrated with local anesthetic. 4. A small cutaneous incision is made, the aspirating needle is introduced through this and should penetrate the marrow cortex 3 \200\22310mm before removal of the trocar. 5. No more than 0.5 \200\2231mL marrow should be aspirated initially, and smears made promptly. 15-protocols.qxd 10.12.2003 04.32 PM Page 571 Protocols and procedures 6. Further material can be aspirated and placed in EDTA or other anti- coagulant media for other studies. 7. An Islam or Jamshidi needle is preferred for trephine biopsy. 8. The needle is advanced through the same puncture site to penetrate the cortex. 9. The trocar is removed and using firm hand pressure the needle is rotated clockwise and should be advanced as far as possible. 10. The needle is removed by gentle anti-clockwise rotation. In this manner an experienced operator should regularly obtain biopsy samples of 25 \200\22335mm in length. 11. Simple pressure dressings are sufficient aftercare and minor discom- fort at the locati on may be dealed with by simple analgesia such as paracetamol. 571 15-protocols.qxd 10.12.2003 04.32 PM Page 572 Administration of chemotherapy Cytotoxic chemotherapeutic drugs may cause serious harm if not pre- scribed, dispensed and administered with great care. Drugs should be pre- scribed, dispensed and administered by a n experienced multidisciplinary team with shared clear information on: 2 The fitness of the patient to receive chemotherapy (e.g. recent FBC for myelosuppressive agents, renal function studies for cisplatinum). 2 Appropriate protocol and chemotherapeutic regimen for the patient. 2 Prescribed drugs and individualized dosage for the patient \200\231s surface area (see p682), taking note of cumulative maximum doses (e.g. anthra- cyclines). 2 Appropriate supportive treatment required e.g. allopurinol, antiemetic prophylaxis, anti-infective prophylaxis, and hydration. Chemotherapy for IV administration should be reformulated carefully in accordance with the manufacturer \200\231s instructions by an experienced phar- macist using a class B laminar airflow hood. Care should be taken to ensure that the drug is administered within the expir y time after it has been reformulated in the form chosen. Many cytotoxic drugs are best administered as a slow IVI in dextrose or 0.9% saline over 30 minutes to 2h. Vesicants e.g. vincristine, daunorubicin, adriamycin and mitozantrone shoul d be administered as a slow IV \200\230push \200\231. However this should only be administ ered through the side access port of a freely flowing infusion of 0.9% saline or dextrose a nd should never be injected directly into a peripheral vein. If the patient does not have an indwelling intravenous catheter (Hickman line), a Teflon or silicone intravenous cannula of adequate bore ( \211 21G) should be inserted into a vein o f sufficient diameter to permit a freely flowing 0.9% saline infusion to be commenced. Site chosen should be one where cannula can be easily inserted and observed, can be fastened se curely and will not be subject to movement during drug administration. The veins of the for earm are the most suitable for this purpose followed by those on the dorsum of the hand. An tecubital fossae and other sites close to joints are best avoided. The risk of extravasatio n (see p578) is increased by the use of a cannula which has not been inserted recently and by the use of steel (butterfly) cannulae. 572 A slow \200\230push \200\231 injection should be administered carefully into the side acce ss port on the IV line with continuous observation of the drip chamber ensure that the infu sion is continuing to run during injection of the cytotoxic drug. The patient should be ask ed whether any untoward sensations are being experienced at the site of the infusion and th e site should be carefully observed to ensure that no extravasation is occurring. Patency o f the IV site should be verified regularly throughout the proce- dure. The saline or dextro se infusion should be continued for 30 minutes after the chemotherapy administration has be en completed before the cannula is removed. 15-protocols.qxd 10.12.2003 04.32 PM Page 573 Protocols and procedures The administration of potentially extravasable chemotherapy, site of can- nulation, conditi on of the site and any symptoms associated with adminis- tration should be clearly document ed in the patient \200\231s notes. 573 15-protocols.qxd 10.12.2003 04.32 PM Page 574 Antiemetics for chemotherapy Classification of drugs Dopamine antagonist \200\224block D2 receptors in the chemoreceptor trigger zone (CTZ). Exa mples are metoclopramide and domperidone \200\224both have additional effect on enhancing g astric emptying. Side effects include extrapyramidal reactions and occasionally oculogyric crisis. Phenothiazines \200\224examples are prochlorperazine and cyclizine \200\224particular benef it in opioid-induced nausea. Side effects include anticholinergic effects and drowsiness. Benzodiazepine \200\224lorazepam commonest used. Advantages are long t1/2 and additional an xiolytic effect. Side effects include drowsiness. 5HT3 antagonists \200\224block 5HT3 receptors in the CTZ. Examples include ondansetron, gra nisetron and tropesitron. Side effects include headaches, bowel disturbance and rashes. Cannabinoids \200\224nabilone depersonalisation experiences. is the major drug. Side effects include Steroids \200\224examples are dexamethasone and predniso(lo)ne. Side effects include funga l infection predisposition, hypertension, irritability and sleeplessness, gastric erosions and, with chronic use, diabetes and osteoporosis. Emesis with chemotherapy Categorized as: anticipatory, early or late. Anticipatory \200\224occurs in advance of chemotherapy. Psychogenic in origin, it occurs in patients with previous bad experiences of nausea and vomiting and almost unknown prior to first dose. May be largely prevented by ensuring a positive experience with first dose by u se of prophylactic antiemetics. Early \200\224occurs within minutes of IV chemotherapy administration or within hours of or al chemotherapy. The easiest to respond to antiemetics generally. 574 Late \200\224occurs after the end of a chemotherapy course \200\224up to 7d. The most diffi cult form to treat \200\224requires continuation of antiemetics throughout post chemo perio d and even the newer agents such as the 5HT3 receptor antagonists are relatively ineffectiv e. Antiemetics may be used singly or in combination. Choices determined largely by patient preferences and degree of emetic potential of the chemo regimen to be used. These may be di vided into high, medium and low. Highly emetogenic regimens Examples include cisplatinum, high dose cyclophosphamide and TBI . Suitable cocktail might be domperidone, 5HT3 antagonist and dexametha- sone lorazepam. 15-protocols.qxd 10.12.2003 04.32 PM Page 575 Protocols and procedures Medium emetogenic regimens Examples include anthracyclines, cytosine arabinoside. Suitable cocktail might be domperidone, cyclizine 5HT3 antagonist lorazepam. Low emetogenic regimens Examples include chlorambucil, vinca alkaloids, 6MP, fludarabine an d most steroid-containing protocols. Suitable choice would be metoclopramide or domperidone as single agent. 575 15-protocols.qxd 10.12.2003 04.32 PM Page 576 Intrathecal chemotherapy Usage 2 Given for both prophylaxis and treatment of CNS disease. 2 May be used in addition to other CNS disease strategies such as high dose IV methotrexate or cranial irradiation. 2 CNS involvement is detected by presence of blasts on CSF cytospin. 2 The ONLY cytotoxic d rugs used intrathecally are: \200\223 Methotrexate. \200\223 Cytosine arabinoside (ara-C). \200\223 Hydrocortisone. 2 All have strict upper dosage limits \200\224follow the protocol. (cid:2)(cid:2) Never us e any other cytotoxic drugs for injection \200\224fatal consequences may ensue. intrathecal Common protocols 1. CNS prophylaxis for ALL and high grade NHL: \200\223 methotrexate 10mg/m2 (max 12.5mg) 6 injections at weekly inter- vals. 2. CNS prophylaxis for AML: \200\223 ara-C 30mg/m2 (max 50mg), dosage schedule varies. 3. CNS treatment for ALL: Triple IT regimen viz: methotrexate 15mg/m2 (max 12.5 \200\22315mg). ara-C 30mg/m2 (max 50mg). hydrocortisone 15mg /m2. Usually given twice weekly until CSF clear of blasts then weekly to a maximum of 6 total co urses. Consider using folinic acid rescue. Technique 2 Standard contraindications to lumbar puncture apply \200\224alternatives will be needed in these situations. Cytotoxics should be made up freshly in smallest possible vo lume in a sterile drugstore. 2 Consider GA for children and IV sedation for adults. 2 Use special LP \200\230blunt \200 \231 needle or small gauge beveled LP needle. 2 Aim to remove the same volume of CSF as you are injecting intrathe- 576 cally (may be several mL if giving triple chemotherapy). 2 Take samples for CSF cytospin to determine blast cell concentration, microbiology for M/C/S, biochemistry for protein and glucose. 2 Check syringe cytotoxic dose carefully with another person before connecting. 2 Connect syringe and aspirate gently to confirm position in CSF. Inject slowly, drawing ba ck at intervals to reconfirm position. Disconnect syringe and connect other syringes in tur n if giving \200\230triple \200\231. 2 Follow standard post-LP precautions. Document procedure in notes. 2 Repeated IT chemother apy carries risk of CSF leakage and post-LP headache. Manometry pre-injection may help assess whether less CSF should be withdrawn pre- injection. 2 A syndrome of methotrexate-induced neurotoxicity occurs in a few patients presenting with features of meningo-encephalitis. Etiology is unknown. Treat with short pulse of high dose steroids. (cid:2) Do not give further IT methotrexate to these pat ients. 15-protocols.qxd 10.12.2003 04.32 PM Page 577 Protocols and procedures 577 15-protocols.qxd 10.12.2003 04.32 PM Page 578 Management of extravasation Inappropriate or accidental administration of chemotherapy into subcuta- neous tissue rathe r than into the intravenous compartment causes pain, erythema and inflammation which may le ad to sloughing of the skin and severe tissue necrosis. Appropriate early treatment can pre vent the most serious consequences of extravasation. All chemotherapy units should have a p rotocol with which all staff administering chemotherapy are familiar and a regularly update d extravasation kit for the management of extravasation giving first aid instructions and f urther directions. The risk of tissue damage relates to the drug \200\231s ability to bind to DNA, to kill rep licating cells, to cause tissue or vascular dilatation and its pH, osmo- larity, concentrat ion, volume and formulation components e.g. alcohol, polyethylene glycol. Drugs may be divided into three risk groups: Group 1: Vesicants Aclarubicin; amsacrine; car mustine; cisplatinum; dacarbazine; dactino- mycin; daunorubicin; docetaxel; doxorubicin; ep irubicin; idarubicin; mito- mycin; mustine; paclitaxel; plicamycin; treosulfan; vinblastine ; vincristine; vindesine. Group 2: Irritants (may cause local inflammation, pain and necrosis) Carboplatin; etoposide ; liposomal daunorubicin; methotrexate; mitoxantrone (mitozantrone). Group 3: Non-vesicants Asparaginase; bleomycin; cladribine; cyclophosphamide; cytarabine; f lu- darabine; fluorouracil; gemcitabine; ifosfamide; melphalan; pentostatin; raltitrexed; t hiotepa; aldesleukin (IL-2). Symptoms and signs 2 Burning, stinging or pain at the injection site. 2 Induration, swellin g, venous discolouration/erythema at injection site. 2 No blood return. 2 Reduced flow rate . 2 Increased resistance to administration. 578 Pre-extravasation syndrome 2 Severe phlebitis and/or local hypersensitivity. 2 Local risk f actors e.g. difficult cannulation and one patient symptom. 2 Withdraw IV therapy immediatel y to prevent progression to extravasa- tion. Type I extravasation 2 Bleb or blister with defined area of induration around site of extra vasa- tion. 2 Often due to rapid IV bolus injection with excessive pressure. Type II extravasation 2 Diffuse boggy tissue injury with dispersal into the intracellular s pace. 2 Associated with IV infusion or IV bolus into side arm port of infusion with dislodged cannula. 15-protocols.qxd 10.12.2003 04.32 PM Page 579 Protocols and procedures General treatment guidelines 2 Stop the infusion, disconnect the IV line but do not remove the cannula. 2 Mark the area of injury around the cannula tip. 2 Seek the help of a more experienced ind ividual if available. 2 Aspirate the site of extravasation to remove as much of the offendi ng drug as possible through cannula with a fresh 10mL syringe; this may be facilitated with SC injection of 0.9% saline. 2 Remove the cannula. 2 Administer 100mg hydrocortisone intravenously at another site. 2 Ad minister a further 100mg hydrocortisone locally by 6 \200\2238 SC injec- tions around the area of injury. 2 Administer SC injections of specific antidote where available. 2 Apply 1% hydrocortisone cream to the area and repeat bd whilst ery- thema persists. 2 Cover with gauze and apply heat to disperse the drug or cool to localize the extravasation. 2 Administer oral antihistamine (terfenadine 60mg/chlorpheniramine 4mg). 2 Administer analgesia if required (indomethacin 25mg tds). 2 Document site and extent of e xtravasation and treatment in case notes. 2 Photograph site if possible. 2 Complete a \200\230Green Card \200\231 to report the extr avasation episode. 2 Monitor injured site twice daily for erythema, induration, blistering or necrosis. 2 Photograph injured site weekly until healed. 579 15-protocols.qxd 10.12.2003 04.32 PM Page 580 Specific procedures following extravasation Group 1: Vesicant drugs All vesicants except vinca alkaloids & cisplatinum Apply cold pack instantly. SC dexamethasone 4mg around margins. Elevate limb but encourage movement. Reapply cold pack for 24h. Actinomycin D Infiltrate area with 1 \200\2233mL 3% sodium thiosulphate. Aclarubicin Daunorubicin Doxorubicin Epirubicin Idarubicin Mitomycin Topical DMSO painted every 2h followed by hydrocortisone cream and 30 mins cold compression . Repeated for 24h thereafter DMSO and hydrocortisone should be alternated every 3h; if bli stering occurs stop DMSO. Cisplatinum Infiltrate area with 1-3mL 3% sodium thiosulphate, aspirate off then administer 1500 units hyaluronidase and apply heat and compression. Carmustine Infiltrate area with 1 \200\2233mL sodium bicarbonate diluted to plicamycin 2.1%, avoid nor mal tissue at the margins, leave 2 mins then aspirate off. Docetaxel Paclitaxel Infiltrate area with 1 \200\2233mL of a mixture of 100mg hydrocortisone and 4mg chlorphenam ine (chlorpheniramine) as 0.2mL pin-cushion injections, followed by 1500U of hyaluronidase then warm compression alternated with topical antihistamine cream; hydrocortisone and antih istamine creams should be applied alternately for 3d. In severe cases administer 1g sodium cromoglicate PO as soon as possible. Chlormethine (mustine) Infiltrate area with 1 \200\2233mL 3% sodium thiosulphate then infiltrate with 100mg hydroc ortisone, apply cold compression intermittently for 12h. Vincristine, vinblastine & vindesine Infiltrate area with 1500 units of hyaluronidase as 0.2mL SC injections over and around the affected area; apply heat and compression for 24h then apply topical non-steroidal anti- i nflammatory cream to the area qds. 580 Group 2: Irritant drugs 2 Aspirate as much as possible. 2 Administer 100mg hydrocortisone I V. 2 Administer 100mg hydrocortisone SC at multiple sites around margins of extravasation. 2 Apply topical hydrocortisone. 2 Cover area with an ice pack. 2 Manage symptoms. Group 3: Non-vesicant drugs 2 Aspirate as much as possible. 2 Disperse extravasated drug wi th SC hyaluronidase injection around the area. 2 Apply heat and compression to aid dispersa l. 2 Manage symptoms. 15-protocols.qxd 10.12.2003 04.32 PM Page 581 Protocols and procedures 581 15-protocols.qxd 10.12.2003 04.32 PM Page 582 Splenectomy Splenectomy is an established procedure in management of selected hematological disorders. Removal of the spleen is usually required for one or more of the following reasons: 2 Extre me enlargement. 2 Hyperfunction. 2 Autoimmune activity. 2 Diagnostic and therapeutic purpos es. Indications include: 2 Lymphoproliferative disorders, e.g. CLL, mantle zone lymphoma, hairy cell leukemia. Reasons include massive organomegaly, occur- rence of autoimmune complicati ons and for diagnostic and/or thera- peutic purposes. 2 Myeloproliferative disorders \200\224commonly used in myelofibrosis to reduce transfusio n requirements, abdominal discomfort from massive splenic enlargement and may reduce consti tutional symptoms e.g. weight loss and night sweats. Occasionally used in the management of chronic myeloid leukemia. 2 Autoimmune conditions \200\224an accepted treatment in autoimmune thrombocytopenic purpura and autoimmune haemolytic anemia fol- lowing the failure of immuno suppression with corticosteroids and immunoglobulin (in the case of thrombocytopenic purpur a). The pro- cedure is not curative but may result in prolonged remissions and cer- tainly will have steroid-sparing effect. 2 Hereditary disorders \200\224reduces red cell sequestration and transfusion requirements in homozygous (cid:2)-thalassaemia. Recurrent, severe heredi- tary spherocytosis. Rare ind ications include pyruvate kinase deficiency and type 1 Gaucher s disease. Other circumstanc es where splenec- tomy may help include Felty s syndrome. 2 Staging splenectomy is no longer a routine procedure for non- Hodgkin \200\231s lymphoma or Hodgkin \200\231s disease. The clinician has to balance the risks and benefits of the procedure in an individual patie nt bearing in mind the long-term risk of post-splenectomy sepsis as well as immediate surgi cal factors. There are now established consensus guidelines for carrying out splenectomy. 582 Pre-operatively the need for the procedure is agreed with the patient and surgical team. At least 2 weeks pre-operatively immunization with pneu- mococcal and Haemophilus vaccine sho uld be given. Meningococcal vaccine may be offered but this covers sub-types A and C only a nd does not give long-lasting immunity. Peri-operative thromboembolic risks should be consi dered (e.g. standard surgical risks and those posed by the rebound thrombocytosis after spl enectomy). Low dose heparin may be appropriate peri-operatively followed by low dose aspiri n (may require modification in thrombocytopenia or if platelet dysfunction). Before dis- ch arge, patients must be given a leaflet/card which they carry. Life-long prophylaxis with pe nicillin V 250mg bd recommended or erythromycin 250mg bd if the patient is allergic to peni cillin. The patient and his/her 15-protocols.qxd 10.12.2003 04.32 PM Page 583 Protocols and procedures family must be advised to report urgently profound systemic symptoms, most promptly to thei r nearest local A&E department. Re-vaccination with pneumococcal vaccine every 5 years recommended. Asplenic patients trave ling to malarial areas must be meticulous in taking anti-malarial prophylaxis (greater risk of severe illness from Plasmodium falciparum). 583 Guidelines for the prevention and treatment of infections in patients with an absent or dys func- tional spleen. (2002) Clinical Medicine, 2, 440 \200\223443 (cid:27) www.bcshguidelines.com/pdf/spleen12.pdf 15-protocols.qxd 10.12.2003 04.32 PM Page 584 Plasma exchange (plasmapheresis) Plasmapheresis is the therapeutic removal of plasma from the peripheral blood usually carri ed out by a cell separator machine. The removed plasma is replaced isovolaemically usually by albumin/saline combinations depending on indication, plasma albumin level and frequency of exchange. Blood products may also be given as part of replacement which is useful in pat ients with fluid intolerance e.g. on renal dialysis. The exception to this is TTP where the replacement fluid is always FFP or cryosupernatant. 1 \200\2231.5 plasma volume is exc hanged in each procedure, i.e. 2.5 \200\2234L for average adult. Procedure takes 2 \200\223 4h depending on volume to be exchanged and the line flow rates. Procedure may need to be re peated daily until response e.g. TTP, or until a total volume exchange has been achieved e. g. 10 \200\22315L over 2 weeks (e.g. Guillain \200\223Barr syndrome), or monthly to contr ol hyperviscosity (e.g. Waldenstr m \200\231s macroglobuli- naemia). Indications \200\224generally accepted in: 2 Hyperviscosity syndromes. 2 Guillain \200\223B arr syndrome resistant to IVIg. 2 Myasthenia gravis: peri-operatively for thymectomy, and refractory disease. 2 Paraproteinaemic neuropathy. 2 Goodpasture \200\231s syndrome. 2 Thrombotic thrombocytope nia purpura. 2 Post-transfusion purpura. 2 Cold haemagglutinin disease. Efficacy contentious but may be indicated in: 2 Severe warm type AIHA. 2 Lupus, Wegener \200\231s and other vasculitides. 2 Rheumatoid arthritis. 2 Peripheral neuropathies other t han paraproteinaemic neuropathy. 2 Multiple sclerosis. 2 Chronic inflammatory demyelinating polyradiculopathy. 2 Eaton \200\223Lambert syndrome. 2 Renal transplant rejection. 584 Venous access If exchange is to be performed via peripheral veins, one large antecubital ve in is required sufficient to tolerate cannulation by a 16G butterfly needle as the drawing line (return line need only be 18G). If not possible, make arrangements for insertion of a central line prior to the planned exchanges inserting a double lumen renal dialysis type ca theter of 16G or larger. Regular medication due immediately prior to exchange may be best d eferred until immediately post-exchange particularly for drugs which are predominantly prot ein bound (see facing page). Problems with apheresis General \200\224patient anxiety, discomfort and boredom. Citrate toxicity \200\224parasthesiae, tremors, tetany. Vascular and cardiac \200\224poor venous access giving poor flow rates. 15-protocols.qxd 10.12.2003 04.32 PM Page 585 Protocols and procedures Extravasation, with haematoma at puncture sites, local vein thrombosis \200\224 during and after procedure, sepsis at puncture sites, hypo/hypervolaemia, vasovagal attacks, arrhythm ias. Metabolic and pharmacological \200\224hypoalbuminaemia, hypoglycaemia, removal of drugs (pl asma bound). Allergic reactions \200\224including anaphylaxis. Drugs>75% bound: If drugs on the list below are due immediately prior to exchange, delay ad ministration until after procedure. Beta blockers Propranolol Timolol Penbutolol Antipsychotics Chlorpromazine Haloperidol Thioridazine Ca2+ channel blockers Diltiazem Nifedipine Verapamil Antifungal agents Amphotericin B Ketoconazole Antihistamines Chlorpheniramine Anti-arrhythmics Amiodarone Propofenone Quinidine Digitoxin (Digoxin is OK) Antimalarials Mepacrine Pyrimethamine Antibiotics Cloxacillin Flucloxacillin Penicillin V Sulphonamide Doxycycline Diuretics Furosemide (frusemide) Metolazone Bendroflumethazide (bendrofluazide) Diazoxide A cetazolamide Anti-TB Rifampicin Hypolipidaemics Clofibrate 585 Anticoagulants Heparin Warfarin Gout drugs Probenecid Sulfinpyrazone Thyroid Drugs Thyroxine Tri-iodothyronine Propylthiouracil Analgesics NSAIDs (all) Aspirin Coproxamol Oestrogens and progestogens All Benzodiazepines All Hypoglycaemics Tolbutamide Glipizide Gliclazide Glibenclamide Chlorpropamide Antidepressants All Antiepileptics Carbamazepine Phenytoin Sodium valproate 15-protocols.qxd 10.12.2003 04.32 PM Page 586 Leucapheresis Leucapheresis is the removal from the peripheral blood of white blood cells, usually leukae mic blasts, via a cell separation machine. Procedure Usually now a standard computer controlled program on modern machines e.g. Cobe S pectra \204 or Fenwall CS \204 . May be performed manu- ally in an emergency (see p510). Indications In patients with high WBC e.g. AML, CML and with symptoms or signs of leucostas is, leucapheresis should be performed urgently. Leucostatic fea- tures are less common in l ymphoid than in myeloid malignancies. Leucostatic features 2 Confusion. 2 Decreased conscious level. 2 Fits. 2 Retinal hemorrhage s. 2 Papilloedema. 2 Hypoxia and miliary shadowing on CXR. 2 Bleeding and coronary ischaemi a. Should not be performed routinely just because of a high WBC. Leucostatic clinical features are the indication. Conversely, leucostasis may occur in some patients with AML without a very high blast count but these patients should be considered for leucapheresis. Chemotherapy should be started as soon as possible after leucapheresis as WBC will \200 \230rebound \200\231 quickly due to outpouring of cells from marrow. Leucapheresis may need to be repeated daily until chemotherapy has suppressed marrow. Other indications 2 Leucapheresis should be performed routinely at diagnosis of CML in pati ents <60 for stem cell cryopreservation which can be used in the future as a stem cell resc ue procedure. 586 2 Leucapheresis may be used as an alternative to chemotherapy in low grade hematological malignancies in pregnancy. 15-protocols.qxd 10.12.2003 04.32 PM Page 587 Protocols and procedures 587 15-protocols.qxd 10.12.2003 04.32 PM Page 588 Anticoagulation therapy \200\223 heparin For acute thrombosis DVT/PE start with heparin and warfarin simultane- ously. Essential to confirm diagnosis \200\224but start treatment whilst awaiting results of investigations. W hen warfarin stable \200\224stop heparin. Heparin Main advantage over oral anticoagulation is immediate anticoagulant effect and shor t t 1 \201\2042. Two main products: standard unfractionated heparin (UFH), a mixture of pol ysaccharide chains, mean MW 15,000, t 1 \201\2042 1.0 \200\2231.5h, and low molecular weigh t heparin (LMWH), fragments of UFH (mean MW 5000) with longer t 1 \201\2042 (3 \200\2236h) and greater bioavailability. LMWH has sig- nificant advantages: one daily SC injection, no monitoring, no dose adjust- ment, low risk of HITT. Heparins act by potentiating coagulatio n inhibitor antithrombin (AT) resulting in antithrombin and anti-Xa activity. Both UFH and LMWH depend on renal clearance. Therapeutic anticoagulation LMWH \200\224given SC once daily on basis of weight (see indivi dual products for dosage). Usually continued for 4 \200\2237 days until warfarin effect, IN R>2.0. Standard IV UFH \200\224initial IV bolus 5000iu in 0.9% saline given over 30 mins (lower lo ading dose for small adult/child). Follow with 15 \200\22325iu/kg/h using a solution of 25, 000iu heparin in 50mL 0.9% saline (= 500iu/mL) and a motorized pump, e.g. for 80kg adult do se is 80 25 = 2000iu/h. Monitor IVI with APTT ratio, aim for ratio of 1.5 \200\2232.5, c heck 6h after starting treatment. Adjust dose as shown opposite. Check APTT ratio 10h after dose change; daily thereafter. Use fresh venous sample \200\224d o not take from line. Continue heparin until INR in therapeutic range for warfarin \200 \224takes 5 days; massive ileo-femoral thrombosis and severe PE may require 7 \200\22310 d ays \200\231 heparin. Contraindications \200\224caution if renal, hepatic impairment, recent surgery, known bleed ing diathesis, severe hypertension. 588 Immediate complications of therapy Bleeding occurs even when APTT ratio within the therapeu tic range but risk 4 with 4APTT ratio. Treatment: Stop heparin until APTT ratio <2.5. In li fe-threatening bleeding use protamine sulfate: 1mg/100iu of heparin given in preceding hour . Thrombocytopenia \200\224Mild 5 platelets common early in heparin therapy; not significa nt. Severe thrombocytopenia less common (HITT); occurs 6 \200\22310d after therapy begun; m ay be associated thrombosis. Stop heparin. Give alternative antithrombin drug such as lep- irudin or danaparoid. Do not start warfarin until thrombocytopenia resolved. Prophylactic anticoagulation LMWH now used in preference to UFH. LMWH given at low dose SC once daily. Recommended dose usually greater for orthopedic surgery than general surgery. C ontinue until patient discharged and mobile. Moderate/high risk patients LMWH given 2h pre-op and once daily (see BNF for dosage). UFH S C 5000iu 2h before surgery and bd until patient is mobile. 15-protocols.qxd 10.12.2003 04.32 PM Page 589 Protocols and procedures Medical patients are also at risk of VTE and should be assessed for risk and considered for LMWH prophylaxis. Conclusions The increased convenience and proven efficacy means that for most clin- ical si tuations LMWH will now be preferred to UFH. Heparin infusion adjustment 2.5 \200\2233.0 TARGET <1.2 (1.5 \200\2232.5) APTR >5.0 4.1 \200\2235.0 3.1 \200\2234.0 1.5 \200\2232.5 5300U/h 5100U/h 550U/h No change 4400U/h 4200U/h DOSE Stop* 5500U/h Nil for 0.5 \200\2231.0h; check APTT ratio Doses and dose adjustments (UFH) should follow local guidelines. 589 Weitz, J.I. (1997) Low-molecular-weight heparins. N Engl J Med, 337, 688 \200\223698. 15-protocols.qxd 10.12.2003 04.32 PM Page 590 Oral anticoagulation Warfarin is the drug of choice; few side effects, well tolerated. A vitamin K antagonist, i t takes 72h to be effective; stable state takes 5 \200\2237d. t 1 \201\2042 35h. Circulat es mainly bound to albumin; free warfarin is active. Many drugs \206\221 warfarin effect b y displacing it from albumin. Monitored by PT using the international normalized ratio (INR ). Administration Given daily. Usually given with heparin on day 1. If massive thrombosis, del ay warfarin for 2 \200\2233d. Standard adult regimen = 10mg/d for 2d. Load with caution usi ng reduced dose if liver disease, interacting drugs, patient >80 years. Check INR <1.4 befo re loading. Check INR daily for first 4 days (see Appendix II, Guidelines on oral anticoagu lation: third edition, Brit J Haematol 1998, 101, 374 \200\223378) on Day 3, 16h after sec ond dose, and adjust as follows. Target INR usually 2.5 except for mechanical heart valves in mitral posi- tion when target is 3.0 or 3.5. Complications Hemorrhage. Easy bruising common within therapeutic range \200\224is patient on aspirin? Rate of major bleeds 2.7/100 treatment years, 4 age 4 INR. Rare side effects \200\224alopecia, warfarin-induced skin necrosis, hypersensi- tivity, purple toe syndrome. Management of over-anticoagulation: See p522 for details Asymptomatic patient INR >5.0 \200\224stop warfarin and reduce dose by at least 25%. Check INR within 1 week. INR >8.0 \200\224consider oral vitamin K 1 \200\2235mg. Symptomatic patient Moderate bleeding, INR 5.0 \200\2238.0, give vitamin K 1mg slowly IV. I NR >8.0: give vitamin K 1mg and FFP or factor concentrate. Severe bleeding: vitamin K 5mg I V, and concentrate containing factors II, VII, IX and X (e.g. beriplex). Observe in hospita l. Vitamin K reverses over-anticoagulation in 24h. Look for causes of over-anticoagulation e.g. heart failure, alcohol, drugs. 590 Kearon, C. & Hirsh, J. (1997) Management of anticoagulation before and after elective surge ry. N Engl J Med, 336, 1506 \200\2231511. 15-protocols.qxd 10.12.2003 04.32 PM Page 591 Protocols and procedures 591 15-protocols.qxd 10.12.2003 04.32 PM Page 592 Management of needlestick injuries Every doctor dealing with high risk patients is concerned to prevent expo- sure to blood an d body fluids, particularly a needlestick injury. The UK DoH published guidance on post-exp osure prophylaxis (PEP) for HIV in 1997 (tel 0203 9724385 for copy). Your hospital/GP surge ry should have a policy for the prevention and management of contamination incidents \200 \224 check this out. Risk to health care workers 2 types of injury \200\224sharps injury where intact skin is b reached by sharp object contaminated with blood/blood-stained body fluids or unfixed tissue , and contamination injury where blood/blood-stained body fluid comes into contact with muc ous membranes or non-intact skin. HBV and HIV are the 2 major concerns. All health care wor kers should be vacci- nated against HBV. Risk of contracting HIV from percutaneous exposure to HIV-infected blood is 0.3%. The amount of blood injected and a high viral load in the patient \200\231s blood increase the risk. General guidelines Prevention All health care workers must adopt universal precautions when handling blood/blo od stained fluids \200\224wear gloves, avoid blood spillage, use decon- tamination procedu res if spillage occurs, label high risk specimens, care with needles (do not resheath), dis posal in burn bins, etc. Immediate action in event of exposure 2 Encourage bleeding and/or wash under running water. 2 Contact Occupational Health/A&E departments for help. 2 Establish patient status re bloo d-borne viruses. 2 Take blood from patient/test for viruses (with consent). 2 Take blood fr om needlestick victim and store. Check HBV immunity/later tests if necessary. Treatment Decision to treat will be made by an experienced medical staff member. Treatment recommended for \200\230all health care workers exposed to high risk body fluids or tissue s known to be, or strongly suspected to be, infected with HIV through percutaneous exposure , mucous membrane exposure or through expo- sure of broken skin. \200\231 Zidovudine alone given as soon as possible 5 risk of seroconversion by 80% but failures are well described. Prophylaxis with triple therapy now recommended. Treat for 4 wks as soon as possible with: 2 Zidovudine 200mg tds/250mg bd + Lamivudine 150mg bd + Indinavir 800mg tds. A \200\230sta rter pack \200\231 should be available in an accessible place at all times. 592 2 Known exposure to hepatitis B \200\223 No immunity \200\224give HepB Ig 500mg IM; vaccinate immediately. \200\223 Known immunity with HepB Ab >100 IU/L in past 2 yr \200\224no action. \200\223 Immunity \200 \224HepB Ab status not known \200\224give booster dose. 15-protocols.qxd 10.12.2003 04.32 PM Page 593 Protocols and procedures Follow-up Occupational Health Department appointment for advice re further man- agement and tests. Counseling as required. 6 months after the incident a \200\223ve test indicates in fection has not occurred. Report incident to PHLS CDSC tel 0208 2006868. In Scotland to SCI EH tel 0141 9467120. 593 Cardo, D.M. et al. (1997) A case-control study of HIV seroconversion in health care workers after percutaneous exposure. Centers for Disease Control and Prevention Needlestick Survei llance Group. N Engl J Med, 337, 1485 \200\2231490. 15-protocols.qxd 10.12.2003 04.32 PM Page 594 Chemotherapy protocols VAPEC-B Vincristine, doxorubicin, prednisolone, etoposide, cyclophosphamide, bleomycin Indication Hodgkin \200\231s lymphoma stage IA or IIA only without B symptoms or bulky dise ase. Schedule: 6-week chemotherapy and radiotherapy regimen given once only. Days Drug Dose Route Comments 1 \200\22328 Prednisolone 50mg daily PO Take with food in morning; taper off after days 29 \200\22338; consider adding H2 antagonis t or PPI 35mg/m2 1 & 15 Adriamycin IV Bolus injection via fast-running drip or IVI in 100mL 0.9% saline over 15 min (doxorubicin) Cyclophosphamide 350mg/m2 1 IV IVI in 250mL 0.9% saline over 15min 100mg/m2 for 5 consec. days 15 \200\22319 Etoposide PT Take 1h before food on empty stomach 594 1.4mg/m2 (max 2mg) 8 & 22 Vincristine IV Bolus injection via fast-running drip; dilute in 20mL 0.9% saline as per national guideline 8 & 22 Bleomycin \200 10,000iu/m2 IV IVI in 250mL 0.9% saline over 60 min 36 IF radiotherapy \200 Prescribe hydrocortisone 100mg IV before bleomycin. Administration 2 Involved field radiotherapy is given in week 6, 2 weeks after last dose of chemotherapy. The dose is 30 \200\22340Gy to the initial volume of the disease. 2 Outpatient treatment. 2 Consider sperm banking in males (low risk of infertility). 15-protocols.qxd 10.12.2003 04.32 PM Page 595 Protocols and procedures 2 Oral systemic PCP prophylaxis is recommended for the first 6 weeks. 2 Oral systemic antif ungal prophylaxis is optional. 2 Antiemetic therapy for moderately emetogenic regimens on d ays 1 and 15. 2 Delay doxorubicin, cyclophosphamide or etoposide by 1 week if platelets <100 109/L or neutrophils <1 109/L. 2 Reduce cyclophosphamide to 75% dose if creatinine clearance 10 \200\22350mL/min, 50% dose if creatinine clearance <10mL/min. 2 Reduce doxorubicin, vincristine and etoposide to 50% dose if serum bilirubin 1.7 \200\223 2.5 upper limit normal and 25% if 2.5 \200\2234 upper limit normal. Caution with cycl ophosphamide if hepatic impairment. 2 All cellular blood components should be irradiated indefinitely. 2 Total regimen 6 weeks \200\231 treatment. 595 15-protocols.qxd 10.12.2003 04.32 PM Page 596 ABVD Adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine Indication Hodgkin \200\231s disease. Schedule 28 day cycle Day 1 (A) Day 15 (B) 25mg/m2 IV X X Doxorubicin 10,000iu/m2 IV Bleomycin X X 6mg/m2 IV (max l0mg) X X Vinblastine 375mg/m2 IVI in normal saline X X Dacarbazine Administration 2 Out-patient regimen. 2 Consider sperm banking in males. 2 Add allopurinol 300mg/day throughout first treatment cycle. 2 Antiemetic therapy for moderate emetogenic re gimens. 2 Consider doxorubicin dose reduction if significant liver impairment. 2 Repeat tre atment if WBC >3.5 109/L and platelet count >100 109/L. 2 25% dose reduction if WBC 2 .5 \200\2233.5 109/L or platelets 75 \200\223100 109/L. 2 Delay treatment 1 week if W BC <2.5 109/L or platelets <75 109/L. 2 Treat to complete remission + 2 cycles. 596 15-protocols.qxd 10.12.2003 04.32 PM Page 597 Protocols and procedures 597 15-protocols.qxd 10.12.2003 04.32 PM Page 598 ChlVPP Chlorambucil, vinblastine, procarbazine, prednisolone Indication Hodgkin \200\231s disease. Schedule 28 day cycle 6mg/m2 PO days 1 \200\22314 Chlorambucil 6mg/m2 IV (max. 10mg) Vinblastine days 1 & 8 100mg/m2 PO (max. 150mg) days 1 \200\22314 Procarbazine 40mg/m2 (max 60mg) PO Prednisolone days 1 \200\22314