od PO or erythromycin 250 mg od PO if penicillin allergic as prophy- laxis switching to hig h dose amoxicillin/cefotaxime if febrile. Post-SCT (see p294). 551 15-protocols.qxd 10.12.2003 04.32 PM Page 552 Guidelines for use of IV antibiotics in neutropenic patients Urgent action required if neutropenic patient develops 2 Single fever spike >38 C. 2 2 fev er spikes >37.5 C 1h apart. 2 Symptoms or signs of sepsis even without fever. Assessment 2 Search for localizing symptoms or signs of infection. 2 Full clinical examinat ion noting BP, pulse, mouth, chest, perineum, line sites, skin and fundi. 2 O2 saturation (pulse oximetry). 2 FBC, U&E, creatinine, LFTs, CRP, INR, APTT, fibrinogen. 2 Perform a septic screen: \200\223 3 sets of blood cultures (10mL per bottle optimizes organism recovery) if central line present, take paired peripheral and central samples. \200\223 Single further blood culture set if non-response at 48 \200\22372h or con- dition changes. 2 Swab relevant sites: wounds, central line exit site, throat. 2 Sputum culture. 2 MSSU. 2 Feces if symptomatic incl. C difficile toxin. 2 Viral serology if clinically relevant. 2 CX R. 2 Other imaging as relevant, consider sinus x-ray. 2 Consider bronchoalveolar lavage if chest infiltrates present. 2 Consider risk of invasive fungal infection: CT chest if high r isk. Empirical treatment Start IV antibiotics to provide broad spectrum cover. Stop prophylactic ciprofloxacin. Follow local protocol if available. 552 First line: Tazocin 4.5g tds plus gentamicin 6mg/kg/day. If patient has history of penicillin allergy use ceftazidime 2g tds instead of tazocin; if anaphylaxis with penicillin discuss with microbiologist. If suspected line infection (exit site inflammation) add vancomycin 1g bd and consider line removal. Vancomycin dose should be split and adminis- tered through each lumen. May be loc ked in the line for 1h then flushed. If there are signs of perianal sepsis, mucositis or intra-abdominal infection or if C diffi cile is suspected add metronidazole 500mg tds IV. 1. Patients on od gentamicin should have pre-dose level checked 24h after first dose then twice weekly if satisfactory. 2. Patients on vancomycin should have pre-dose levels checked immedi- ately before 3rd or 4 th dose (2nd if renal impairment) then twice weekly if satisfactory. 15-protocols.qxd 10.12.2003 04.32 PM Page 553 Protocols and procedures Reassess at 48 \200\22372h: If no response to antibiotics and negative blood cultures: Add vancomycin 1g bd. If already on vancomycin, consider line removal. Consider risk of invasiv e fungal infection. CT chest if high risk. Reassess after further 48 \200\22372h: If no response to antibiotics and negative blood cul tures: If high risk for invasive fungal infection: Stop above antibiotics. Commence amphotericin 1 mg/kg/day plus ciproflo- xacin 500mg bd PO/IV. Stop prophylactic fluconazole/itraconazole. If low risk for invasive fungal infection: Switch antibiotics to meropenem 1g tds plus gent amicin 6mg/kg/day. Reassess after further 48h: If no response to amphotericin, change ciprofloxacin to meropen em 1g tds plus gentamicin 6mg/kg/day. If not on amphotericin, consider switching to amphotericin 1mg/kg/day plus ciprofloxacin 50 0mg bd PO/IV. Stop prophylactic fluconazole/itra- conazole. Duration of therapy If temperature responds but cultures are negative, continue anti-infect ive treatment until apyrexial for 72h or minimum 5d course. If still neu- tropenic restart prophylactic anti-infectives. Amphotericin should be con- tinued until neutrophil regenerat ion or total dose of 1g administered. Positive cultures Antibiotic therapy may be changed on the basis of positive cultures. 553 15-protocols.qxd 10.12.2003 04.32 PM Page 554 Treatment of neutropenic sepsis when source unknown (cid:2)(cid:2) One of the commonest haemato-oncological emergencies. 2 May be defined as th e presence of symptoms or signs of infection in a patient with an absolute neutrophil count of <1.0 109/L. In practice, the neutrophil count is often <0.1 109/L. 2 Similar clinical picture also seen in neutrophil function disorders such as MDS despite normal neutrophil numbers. 2 Beware \200\224can occur without pyrexia, especially patients on steroids. Immediate action (cid:2)(cid:2) Urgent clinical assessment. 2 Follow ALS guidelines if card iorespiratory arrest (rare). 2 More commonly, clinical picture is more like cardiovascular shock respiratory embarrassment viz: tachycardia, hypotension, peripheral vasodilatation and tachypnoea. Occurs with both Gram +ve (now more common with indwelling central cathete rs) and Gram \200\223ve organ- isms (less common but more fulminant). 2 Immediate rapid infusion of albumin 4.5% or gelofusin to restore BP. 2 Insert central cat heter if not in situ and monitor CVP. 2 Start O2 by face mask if pulse oximetry shows satur ations <95% (common) and consider arterial blood gas measurement \200\224care with platelet counts <20 109/L \200\224manual pressure over puncture site for 30 mins. 2 Perform full septic screen (see p552). 2 Give the first dose of first line antibiotics im mediately e.g ureidopeni- cillin and loading dose aminoglycoside (ceftazidime or ciprofloxa cin if pre-existing renal impairment). Follow established protocols. 2 If the event occurs while patient on first line antibiotics, vancomycin/ ciprofloxacin or vancomycin/meropenem are suitable alternatives. 2 Commence full ITU-type monitoring chart. 2 Monitor urine output with urinary catheter if necessary \200\224if renal shut- down has already occurred, give single bolus of IV frusem ide. If no response, start renal dose dopamine. 554 2 If BP not restored with colloid despite elevated CVP, consider inotropes. 2 If O2 saturations remain low despite 60% O2 delivered by rebreathing mask, consider ventilation. 2 Alert ITU giving details of current status. Subsequent actions 2 Discuss with senior colleague. 2 Amend antibiotics according to cultur e results or to suit likely source if cultures negative. 2 Check aminoglycoside trough levels after loading dose and before second dose as renal imp airment may determine reducing or with- holding next dose. Consider switch to non-nephrotox ic cover e.g. cef- tazidime/ciprofloxacin. 2 Continue antibiotics for 7 \200\22310d minimum and usually until neutrophil recovery. 15-protocols.qxd 10.12.2003 04.32 PM Page 555 Protocols and procedures 2 If cultures show central line to be source of sepsis, remove immedi- ately if patient not responding. 555 15-protocols.qxd 10.12.2003 04.32 PM Page 556 Treatment of neutropenic sepsis when source known/suspected Central indwelling catheters Very common. Organisms usually Staph. epidermidis but can be o ther Staph spp. and even Gram \200\223ve organisms. May be erythema/exudate around entry o r exit sites of line, tenderness/erythema over subcutaneous tunnel or discomfort over line tract. Blood cultures must be taken from each lumen and peripherally and labeled individual ly. Add vancomycin 1g bd IV if not in standard protocol. Split dose between all lumens unle ss cultures known to be +ve in one lumen only. Lock and leave in line for 1h, then flush th rough. If no response or clinical deterioration, remove line imme- diately. Perianal or periodontal Both are common sites of infection in neutropenic patients. Periana l lesions may become secondarily infected if skin abraded. Add metronida- zole 500mg IV tds to standard therapy. Painful SC abscesses may form and may require surgical incision. Gum disease and localized tooth infec- tions/abscesses are frequently seen. Add metronidazole t o therapy as above, arrange OPG and dental review as surgical intervention may be required in non-responders. If possible, best delayed until neutrophil recovery in most cases \200 \224then do electively before next course of chemotherapy. Lung Atypical organisms Risk group HIV infection, HCL, post-SCT. Mycoplasma and other atypicals are commonly found and usually commu- nity acquired (except Legionella) \200\224typically occur shortly after return to hospital and in patients with chronic lung disease. 556 Treatment Azithromycin (or clarithromycin if IV preparation needed) is now treat- ment of c hoice \200\224well absorbed and fewer side effects than erythromycin. 5d rather than 3d cou rse may be needed. Pneumocystis carinii pneumonia Risk group Lymphoid malignancy long-term treatment esp. ALL, steroid usage, purine analogs e.g. fludarabine and 2-CDA. Treatment High dose cotrimoxazole IV initially \200\224watch renal function and adjust dose to creatinine. Give short pulse of steroid 0.5mg/kg at start of treat- ment. At-risk patie nts should remain on long-term prophylaxis until chemo finished and absolute CD4 lymphocyte count >500 \227 106/L. Use cotrimoxazole 480mg bd on Monday, Wednesday and Friday only, p ro- vided neutrophil count maintained >1.0 109/L. Otherwise use nebulised 15-protocols.qxd 10.12.2003 04.32 PM Page 557 Protocols and procedures pentamidine 300mg every 3 weeks with preceding nebulised salbutamol 2.5mg. Fungal Risk group Prolonged, severe neutropenia, chronic steroid and antibiotic usage, GvHD. Asper gillus and other molds increasingly common with intensive chemotherapy protocols and post-s tem cell transplant esp. MUDs. Treatment 2 Amphotericin IV (see p330). 2 Once neutrophil recovery has occurred, maintenanc e may be with oral itraconazole liquid 2.5mg/kg bd \200\224may also be used for prophylaxi s. Viral \200\224CMV Risk group Allogeneic SCT esp. MUDs where donor or recipient is CMV +ve. Disease usually du e to reactivation rather than de novo infection. Apart from pneumonitis, may cause graft su ppression, gastritis, oesophagitis, weight loss, hepatitis, retinitis, haemorrhagic cystiti s and vertigo. Treatment Ganciclovir or foscarnet (see CMV, p334) + IV immunoglobulin. Lack of response, s witch to the other drug. Viral \200\224HSV/HZV Risk group Rare causes of lung disease. SCT recipients at greatest risk esp. MUDs and inten sively treated lymphoid malignancy. Treatment High dose IV acyclovir 5 \200\22310mg/kg tds IV for minimum 10d. 557 Viral \200\224RSV Risk group Post-SCT recipients esp. MUDs. Treatment Consider ribovarin therapy. TB and atypical mycobacteria Risk group Prolonged T-cell immunosuppression e.g. chronic steroid or cyclosporin therapy, chronic GvHD, previous history and/or treatment for TB, HIV related disease. Treatment Often difficult to diagnose \200\224empirical treatment required with standard t riple therapy. 15-protocols.qxd 10.12.2003 04.32 PM Page 558 Prophylaxis for patients treated with purine analogs The purine analogs fludarabine and 2-CDA used in standard lympho- proliferative protocols i nduce neutropenia in all cases. Nadir 14d post- treatment initiation and neutrophil counts may fall to zero for several days or even weeks. They are therefore associated with the us ual neutropenic infections. In addition, purine analogs have a particular property of inhi- bition of T4 helper lymphocyte subsets within weeks of initiation of therapy (nadir at 3 m onths) and may last for >1 year following cessation of therapy. This profound T4 function i nhibition predisposes to fungal infection, as well as a higher incidence of Herpes zoster i nfection and PCP. \206\223 lymphocyte function also predisposes to transfusion associated GvHD in passenger lymphocytes of donor blood transfusions. The following preventive measures are recommended Recommended 1. Irradiation of cellular blood products (2500cGy) from day 1 of initia- tion of therapy and continue until 2 years post-treatment. 2. PCP prophylaxis from start of therapy \200\224usually cotrimoxazole 1 tablet bd Mondays, Wednesdays and Fridays. In patients who are already severely neutropenic, cotrimoxazole ma y be substituted by pentami- dine nebulisers 300mg 3-weekly with 2.5mg of salbutamol nebuli ser pre-treatment. PCP prophylaxis should continue until a year after the end of treatment. 3. HZV prophylaxis \200\224acyclovir 400mg qds is the minimum continuous dose required to prevent HZV reactivation. Most physicians will not wish to have patients continuously on th is dosage throughout the treatment cycle and for a year post-treatment so suggest: counsel patients about the risk of shingles and advised to contact the hospital immediately if shin gles suspected. Patients who have already had a zoster reactivation should be maintained co ntinuously on acyclovir 400mg qds and continuation of the purine analog reviewed. 558 Optional 1. Anti-bacterial prophylaxis \200\224consider use of ciprofloxacin 250mg bd PO from day 7721 of each course. 2. Anti-fungal prophylaxis: Patients with no history of fungal reactivation should perform nystatin suspension 1mL qds mouthcare from day 7721 of each course, taught symptoms of oral and genital thrush and supplied with fluconazole 200mg to be taken daily for 7d in the eve nt of thrush. 3. Patients with previous history of suspected fungal infection with a mold-type organism e .g. Aspergillus \200\224give itraconazole capsules 400mg daily or oral liquid 2.5mg/kg bd throughout treatment. 15-protocols.qxd 10.12.2003 04.32 PM Page 559 Protocols and procedures 559 15-protocols.qxd 10.12.2003 04.32 PM Page 560 Tumor lysis syndrome (TLS) Potentially from treatment-induced or spontaneous tumor necrosis causing renal, cardiac or neurological complications. Usually occurs in rapidly proliferating, highly chemosensitive neoplasms with high tumor load: leukaemias with high WBC counts (ALL >50 109/L; AML >100 109/L; CML blast crisis >100 109/L; CLL >200 109/L; PLL or ATLL >100 109/L) an d high grade NHL (particularly Burkitt lymphoma or high serum LDH). May occur before or up to 5 days (usually 48 \200\22372h) after initiation of chemotherapy. life threatening metabolic derangement resulting Pathophysiology and clinical features Rapid lysis of large numbers of tumor cells releases intracellular ions and metabolites into the circulation causing numerous metabolic abnormal i- ties to develop rapidly: 2 Hyperuricaemia due to metabolism of nucleic acid purines; (so lubility decreased by high acidity); may cause arthralgia and renal colic. 2 Hyperkalaemia due to rapid cell lysis; often earliest sign of TLS; aggra- vated by renal failure; may cause paraesthesiae, muscle weakness and arrhythmias. 2 Hyperphosphataemia due to rapid cell lysis,; precipitates calcium phos- phate in tissues (insolubility exacerbated by overzealous alkalinisation), 2 Hypocalcaemia secondary to hyperphosphataemia; may cause paraes- thesiae, tetany, carpo-p edal spasm, altered mental state, seizures and arrhythmias. 2 Acute renal failure predisposed by volume depletion and pre-existing dys- function; due t o uric acid nephropathy, acute nephrocalcinosis and pre- cipitation of xanthine; oliguria l eads to volume overload and pulmonary oedema; uraemia causes malaise, lethargy, nausea, ano rexia, pruritus and pericarditis; may require dialysis; usually reversible with prompt ther apy. Principles of management 1 Identify high risk patients, initiate preventative measures prio r to chemotherapy and monitor for clinical and laboratory features of TLS. 2 Detect features of TLS promptly and initiate supportive therapy early. 560 Prevention and management 2 Monitor daily weight bd, urine output, \202uid balance, renal function, serum potassium, phosphate, calcium, uric acid and ECG for 72h after initiation of chemothe rapy; monitor parameters at least three times daily in patients with TLS. 2 Ensure aggressive intravenous hydration: \200\223 Aim for urine output >100mL/h (>3L/d) and total input >4Ld (3L/m2/d) from 24 \200 \22348h prior to chemotherapy and in high risk patients, until 48 \200\22372h after complet ion of chemotherapy. \200\223 Frusemide (20mg IV) may be given cautiously to maintain adequate diuresis in well hydrated patients; may be used to treat hyperkalaemia or \202uid overloa d but may cause uric acid or calcium deposition in dehydrated patients; no proven bene \201t in initial treatment of TLS. 2 Prevent hyperuricaemia: \200\223 Allopurinol: xanthine oxidase inhibitor; 300 \200\223600mg/d PO for pro- phylaxis if renal function normal (100mg/d if creatinine >100mmol/L) up to max 500mg/m2/d f or treatment of TLS; may 15-protocols.qxd 10.12.2003 04.32 PM Page 561 Protocols and procedures be given IV if necessary (max 600mg/d); side effects: rash, xanthine urolithiasis; reduce d ose in renal impairment or mercaptopurine, 6-thioguanine or azathioprine therapy. \200\223 Rasburicase: recombinant urate oxidase; converts uric acid to water soluble metab olites without increasing excretion of xanthine and other purine metabolites; very rapidly 5 uric acid levels and simpli- fies management of high risk patients; dose 200mg/kg/d IVI o ver 30 mins for 5 \200\2237d; recommended in Burkitt lymphoma, high count leukemia and as r escue treatment in hyperuricaemia plus rapidly rising creatinine, oliguria, phosphate \211 2mmol/L or K+ \211 5.5mmol/L; side effects: fever, nausea, vomiting; less common: haemol ysis, allergic reactions or anaphylaxis; contraindicated in G-6-PD defi- ciency and pregnan cy. 2 Alkalinisation of urine: \200\223 Not routine; administer NaHCO3 PO (3g every 2h) or IV through central line (500mL 1.26% NaHCO3 over 1h; 1L 5% dextrose over 4h; 500mL 0.9% NaCl over 1h, repeated 6 hourly) to increase urinary pH to 7.0 and maximize uric acid solubility. \200\223 Risk of more severe symptoms or hypocalcaemia and increased calcium phosphate precipitation in tubules. \200\223 Requires close monitoring of urinary pH (test all urine passed), serum bicarbonate and uric acid; withdraw IV sodium bicarbonate when serum bicarbonate >30 mmol/L, urinary pH>7.5 or serum uric acid normalized. 2 Control of electrolytes \200\223 Hyperkalaemia: treat aggressively: 1 Restrict dietary K+ intake and eliminate K+ from IV fluids. 2 Use K+-wasting diuretics with caution. 3 Measure arterial blood gasses (c orrection more difficult if acidosis). 4 K+ >5mmol/L, start calcium resonium 15g PO qds and increase hydration; recheck K+ after 2h. 561 5 K+ >6mmol/L, check ECG; commence IVI of 50mL 50% dextrose with 20 U actrapid insulin over 1h. 6 ECG changes or K+ >6.5mmol/L, give 10mL calcium gluconate 10% or calcium chloride 10% IV cardioprotection. \200\223 Hyperphosphataemia: 1 Commence oral phosphate binding agent, e.g. aluminum hydrox ide 20 \200\223100mL or 4 \200\22320 capsules daily or Sevelamer 2.4 \200\2234.8g/d in divi ded doses; adjust dose according to serum phosphate. 2 Infuse 50mL 50% dextrose with 20 U actrapid insulin IV over 1h. 2 Dialysis \200\223 Seek renal and critical care consultations early if initial measures fail to control electrolyte abnormalities or renal failure. \200\223 Dialysis indicated if persistent hyperkalaemia (>6mmol/L) or hyper- phosphataemia (>3.33mmol/L) despite treatment, fluid overload, rising urea or creatinine (>880mmol/L), h yperuricaemia (>0.6mmol/L) or symptomatic hypocalcaemia. \200\223 Haemodialysis achieves better phosphate and uric acid clearance than peritoneal dialysis. 15-protocols.qxd 10.12.2003 04.32 PM Page 562 Management of chronic bone marrow failure Introduction Common hematological problem. Occurs as result of marrow infiltrated with dise ase e.g. MDS, or following chemotherapy or other causes of marrow aplasia. Extent of RBC, W BC and platelet production failure varies greatly in individual clinical situations. Produc tion failure may not affect all three cell lines equally. Management 2 Mainstay is supportive treatment with blood products and antibiotics. 2 Underl ying disease should be treated where possible. Red cell production failure 2 Where anemia is due solely to absence of RBC production, tran sfu- sion requirement should be 1 unit packed red cells/week. Suitable protocol is 3 unit transfusion every 3 weeks as day case. 2 If requirement is greater, investigate for bleeding and haemolysis. 2 If requirement is c hronic e.g. a young patient with MDS, consider giving desferrioxamine as long-term iron chelation (see p90). 2 Erythropoietin may be tried where some red cell production capacity remains and transfusion needs to be avoided or minimized e.g. Jehovah \200\231s Witnesses. White cell production failure 2 Mainstay of treatment is with antibiotics. 2 Prompt treatme nt of fever in neutropenic patient with combination IV antibiotics is lifesaving . 2 Simple mouthcare with Corsadyl or similar mouthwash, plus nystatin suspension orally redu ces risk of bacterial and fungal colonization in oropharynx. Dietary modifications may also be helpful. 2 Role of prophylactic antibiotics remains controversial as resistance generation is an increasing problem. 562 2 Ciprofloxacin 250mg bd PO is probably the best single agent. 2 Patients with recurring fo ci of infection may have prophylaxis targeted to their usual or most likely organisms. 2 Patients with neutropenia and low Igs who have developed bronchiec- tasis may benefit from regular infusions of IVIg 200mg/kg every 4 weeks rotating antibio tic courses. 2 WBC infusions are not generally useful except in rare situations \200\224they are toxic and cause HLA sensitisation. 2 Haemopoietic growth factors should not be used routinely. 2 Life-threatening infections d espite IV antibiotics and anti-fungals can be considered for trial of G-CSF or GM-CSF at 5 g/kg/d SC. Platelet production failure Where low platelets are due solely to absence of platelet produ ction, transfusion requirement should be 1 \200\2232 adult dose packs/week. Tranexamic aci d 1g qds PO may reduce clinical bleeding episodes and transfusion requirement. Thrombopoiet in (TPO) is a potent in vitro 15-protocols.qxd 10.12.2003 04.32 PM Page 563 Protocols and procedures platelet growth and maturation factor but its clinical role remains to be defined. 563 15-protocols.qxd 10.12.2003 04.32 PM Page 564 Venepuncture Blood samples are best taken from an antecubital vein using a 21G needle and a Vacutainer \204 system or syringe. If a large volume of blood is required a 21G butterfly may be inse rted to facilitate changing the vacutainer sample bottle or the syringe. A tourniquet should be gently applied to the upper arm and the antecu- bital fossa inspecte d and palpated for veins. In an obese individual antecu- bital veins may be more easily pal pated than seen. The skin over the vein should be \200\230sterilized \200\231 (alcohol swa b or Mediswab \204 ) and allowed to dry. The needle should then be gently introduced along the line of the chosen vein at an angle of 45 to the skin surface. It may be helpful to a ttempt to penetrate the skin with the initial introduction of the needle and then slowly pe netrate the vessel wall by continuing the forward movement of the needle. The tourniquet on the upper arm should be loosened once the needle has been inserted into the vein to reduce haemoconcentration. If a syringe is used the piston should be withdrawn slowly to prevent col- lapse of the vein. Once an adequate sample has been obtained, the tourni- quet should be completely removed, a dry cotton wool ball applied gently above the site of venepuncture and gentle pressure increased as the needle is removed. Firm pressure should be directly a pplied to the venepuncture site for 3 \200\2235 minutes to ensure haemostasis and prevent e xtravasation and bruising. A small elastoplast or if allergic, suitable light dressing, sho uld be applied to the venepuncture site. In patients in whom it is difficult to obtain a sample, the arm should be kept warm, a sphy gmomanometer cuff inflated on the upper arm to the diastolic pressure and the vein may be d ilated by smacking the overlying skin. With patience it is rarely impossible to obtain a ve nous sample. In very obese individuals or those in whom iatrogenic thrombosis or scle- rosi s has occurred in the antecubital veins, the dorsal veins of the hand may be used for sampl ing, though a smaller gauge needle (23G) or but- terfly is often necessary. 564 15-protocols.qxd 10.12.2003 04.32 PM Page 565 Protocols and procedures 565 15-protocols.qxd 10.12.2003 04.32 PM Page 566 Venesection Aim of venesection or phlebotomy is the removal of blood for donation to the Blood Transfus ion Service or as a therapeutic maneuver for a patient with haemochromatosis or polycythaem ia rubra vera or for a patient who requires an exchange transfusion. In patients with haemo chromatosis or PRV the therapeutic effect of the venesection pro- gramme to date should be assessed on a full blood count sample taken prior to venesection. Procedure 2 Patient or donor is best placed lying on a couch with the chosen arm placed comfortably on a supporting pillow. 2 A large gauge needle attached to a collection pack containing anticoag- ulant is inserted in an antecubital vein or forearm vein after application of a sphygmomanometer cuff to the upper arm (inflated to diastolic pressure) and sterilization of the skin. It is widespread practice to infil- trate the skin over the chosen vein with local anesthetic (1% lidocaine (lignocaine)) prior to insertion of the large bore needle. 2 Inflation of the sphygmomanometer cuff is maintained until the desired volume of blood is collected. 2 The patient may assist the flow of blood by squeezing a soft ball or similar object in the hand of the arm from which the blood is drawn. 2 Blood is allowed to drain into the collection pack until the desired volume has been obtained (usually 500mL). 2 The volume collected may be monitored by suspension of the pack from a simple spring measuring device. 2 The positioning of the collection pack below the patient \200\231s (or donor \200\231s) level facilitates blood flow into the bag. 2 Once the desired volume has been collected the cuff is deflated, the line should be clamped and the needle removed and a dry cotton wool ball used to apply pres sure to the venesection site. 2 Direct firm pressure should be applied for 5 minutes and the site inspected for haemostas is prior to application of a firm bandage. 2 The patient should slowly adopt the erect posture and should remain seated for several mi nutes if symptoms of lightheadedness occur. 566 2 Patients should not be permitted to drive after venesection. 2 The collected blood from a therapeutic venesection should be dis- posed of by incineration. Note: for patients with PPP/PRV isovolaemic venesection is recommended to minimize volume d epletion whilst still reducing Hct. 15-protocols.qxd 10.12.2003 04.32 PM Page 567 Protocols and procedures 567 15-protocols.qxd 10.12.2003 04.32 PM Page 568 Tunneled central venous catheters A tunneled central venous catheter is required in all patients undergoing intensive cytotox ic chemotherapy and those undergoing bone marrow or peripheral blood stem cell transplantat ion. Also indicated for some patients on long-term regular transfusion programs. Catheter type A double or triple lumen catheter preferred, and essential for patients under going transplantation procedures. Hickman catheters are available from Vygon UK and the Gro shong lines (Bard) are available for use in all patients except those needing stem cell col lections who will require apheresis catheters (Kimal). Requirements An x-ray screening room with facility for aseptic procedures or an oper- ating theater is required. A trained radiographer must be available for x- ray screening through out the procedure. In addition a minimum of two staff are required for the safe execution o f this procedure. One should be a member of medical staff (radiologist/surgeon/anesthetist/ haemato- oncologist) to insert the catheter and administer sedation and antibiotics and the other to generally assist. The second person can be an IV trained nurse. Patient assessment Assess for fitness for sedation and the ability to lie flat. Plan positi on of central venous catheter in advance. The first choice is the right subclavian vein, fo llowed by the left subclavian vein. Check FBC and clotting screen. Platelets should be avai lable if platelet count is less than 50 109/L. Patient preparation The patient should be well hydrated (5 CVP makes procedure difficult), and fasting for 6h prior to the procedure as sedative drugs will be admin- istered. Good pe ripheral venous access must be established (with Venflon \204 ) before commencing central v enous cannulation, for the administration of sedative drugs and prophylactic antibiotics as well as for emergency venous access. 568 Technique Follow manufacturer \200\231s instructions. Sequence of stages during insertion i s as follows: 1. Cannulation of the central vein, placement of guide wire and creation of the upper central wound. 2. Creation of lower peripheral wound, formation of subcutaneous tunnel and threading of th e catheter through subcutaneous tunnel with cuff buried. 3. Placement of the vessel dilator/sheath in the central vein over the guide wire. 4. Placement of the catheter into the sheath. 5. Careful removal of the sheath whilst retai ning position of catheter. 6. Suturing of the upper and lower wounds with suture around the body of the catheter close to the exit site to hold the catheter in position. 7. Manipulat e catheter so tip lies in SVC above right atrium. Patency must be confirmed by easy aspirat ion of blood, and the catheter flushed with heparinised saline. Check position with standar d PA chest radiograph. 15-protocols.qxd 10.12.2003 04.32 PM Page 569 Protocols and procedures Sedation and analgesia IV sedation is used if the patient is particularly anxious before or during the procedure. Prophylactic antibiotics 2 Teicoplanin 400mg is administered by peripheral vein immediately prior to central venous cannulation. 2 400mg teicoplanin is also administered into the central venous catheter immediately after the insertion procedure (200mg is locked into each lumen for 1h and then the catheter is flushed with heparinised saline). Catheter aftercare 2 Catheter may be used immediately after above procedures. All patients should be educated in the care of their indwelling tunneled intravenous catheter. This may include self-flushing of the catheter. Catheter should be flushed after each use w ith saline and locked with heparinised saline. Flush twice weekly when not in use. 2 Urokinase may be used if line blockage occurs, insert urokinase and leave for 4 \200\22312h and remove. 2 Clindamycin roll-on lotion may be applied to the exit site to minimize local infections. 2 Upper wound suture is removed 7d post-insertion. 2 Lower exit site suture can be removed at 2 weeks post-insertion for most lines and 3 weeks for apheresis lines to ensure SC embedding of the cuff. 569 15-protocols.qxd 10.12.2003 04.32 PM Page 570 Bone marrow examination Bone marrow is the key investigation in hematology. It may prove diag- ostic in the follow- up of abnormal peripheral blood findings. It is an impor- tant staging procedure in definin g the extent of disease, especially lymphoproliferative disorders. It is a helpful investig ative procedure in unexplained anemia, splenomegaly or selected cases of pyrexia of unknown origin (PUO). Preferred site for sampling7posterior iliac crest; aspirate and biopsy mater ial can easily be obtained from this location. The anterior iliac crest is an alternative. The sternum is suitable only for marrow aspiration (see below for contraindications). 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