393 CHAPTER 23.2 Anemia in critical care the overall number of transfusions an individual patient receives. However, single unit tra nsfusions are easier to give in patients with brittle cardiorespiratory function. There is a reduced risk of smaller volumes tipping the patient into or exacerbating pulmonary oedema . The number of blood donors is continuing to fall, and should the blood supply become limi ted this assumption will be challenged. role of erythropoietin in reducing the need for red cell transfusions. Despite resulting in a modest increase in hae- moglobin, erythropoietin has not been shown to reduce the incide nce of red cell transfusion in the critically ill. There is a role in those patients who de cline red cell trans- fusion and those patients who have previously established renal failu re. Conclusion Anemia is very common in the critically ill. Recent research has shed new light on the etiology of the anae- mia in critical illness and its management. Transfusion remain s very safe, but whenever possible measure should be taken to try to minimize excessive phl ebotomy and critically evaluate the need for transfusion in individual patients. Measures to minimize blood loss in the ICU An effective measure to reduce blood loss includ es where possible trying to restrict phlebotomy and minimize blood wastage. It has been est imated that blood gas (ABG) sam- pling and routine phlebotomy account for 40 \200\22380ml o f blood loss daily. This equates to 300 \200\223600ml of blood a week. A large part of thi s volume (up to 50%) can be accounted for with regular ABG testing. New in-line blood conse rvation pressure transducer systems for blood gas monitoring reduce blood wastage as there is no dead space loss. These systems reduce the need for transfusion and are theoreti- call y safer for both staff and patients, with less risk of cath- eter-related infections and po tential needle stick injuries. They may be applied to venous sampling in the future. Post-o perative strategies for optimizing the appropriate use of anti \201 brinolytics, FFP and p latelets can reduce blood loss. Where possible, elective surgery should be delayed in anemi c patients. Surgery in these patients is associated with an increased mortality. Treating a nemia before sur- gery has been shown to reduce mortality. Further reading Corwin HL, Gettinger A, Pearl RG, et al. The CRIT Study: anemia and blood t ransfusion in the critically ill \200\224current clinical practice in the United States. Cr it Care Med 2004; 32: 39 \200\22352. Ganz T. Hepcidin and its role in regulating systemic iron metabo- lism. Hematology 2006; 29 \200\22335. H bert PC, Wells G, Blajchman MA, et al. A multicentre, ran- domised, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999; 340: 409 \200\22317. Hill SR, Carless PA, Henry DA, et al. Transfusion thresholds and other strategies for guidi ng allogeneic red blood cell transfusion. Cochrane Database Syst Rev 2002; (2): CD002042. Vincent JL, Baron JF, Reinhart K, et al. Anemia and blood transfu- sion in critically ill patients. JAMA 2002; 288: 1449 \200\223507. Erythropoietin Given the deleterious effects associated with red cell transfusion, there ha s been considerable interest in the Vincent JL, Piagnerelli M. Transfusion in the intiensive care unit. Crit Care Med 2006; 34: S96 \200\223101. 394 A RETTER & BJ HUNT Sickle cell anemia Sickle cell disease (SCD) is the group of disorders associ- ated with the abnormal sickle h emoglobin. Homozygous sickle cell anemia (HbSS) is the most common form, whilst the double heterozygote conditions of HbSC, HbS thalassaemia and HbS/Punjab also cause sickling dis- ease. The sickle gene is estimated to be present in 8% of African-Americans. There are an e stimated 15 000 patients in the UK. Whilst the life expectancy is improving, many patients are dying in their early forties. The leading cause of death is acute chest syndrome, which is also the most fre- quent cause precipitating ICU admission. between HbSS, HbSC and HbS thalassaemia. A reticulo- cyte count is useful to exclude aplas tic crises. The HbA/ HbS% should be measured. The urine should be examined for proteinuria. CXR is mandatory, and an echocardiogram should be considered. Management \200\230general principles \200\231 Morphine is the drug of choice for pain rel ief and can be given IV. In the ICU, patient-controlled analgesia (PCA) or intermitted SC i njections are appropriate. PCA has been shown to provide superior pain relief, although the re are concerns that patients may receive increased doses of morphine leading to respirator y depression and the poten- tially increased risk of a chest crisis. Pethidine should not b e used because of its greater addictive potential and asso- ciated risk of seizures. Consti pation should be pre-empted with the use of regular laxatives. When pain control is improve d, the morphine should be weaned and converted to an equivalent oral dose. NSAIDs are effec tive at reduc- ing deep bone pain when used in conjunction with strong opiates. IV \202 u ids should be given to correct any dehydra- tion, which will promote HbS polymerization. Al l sickle cell patients should be regarded as asplenic and receive broad-spectrum antibiotic s if an infection is sus- pected. Penicilllin prophylaxis daily should be continued through out life. As a general principle, SCD patients should be immunized against hepatitis B and Pneumococcus, men- ingitis and Haemophilus. Hydroxyurea (HU), now known as hydroxycarbamide (HC), increases the production of fetal hemoglobin (HbF). This reduces the rate of sicklin g. HC can produce reversible myelosupression and we routinely suspend its use in those pati ents who are admitted with severe illness. The HC is restarted immediately prior to dischar ge. Pathogenesis SCD is an autosomal recessive disorder where substitution of valine for glutam ic acid in position 6 of the -globin chain results in the abnormal hemoglobin. There is p olym- erization of HbS molecules within the red cell as a result of hypoxia. These polymers distort the erythrocyte, causing it to acquire the classical sickle shape with a marked re duc- tion in \202 exibility. This leads to microvascular occlusion and hence a sickle cel l crisis. SCD causes a chronic haemolytic anemia. The sex distribution is equal. In the UK, universal neonatal screening is being implemented and so most British-born cases are ident i \201 ed early. Clinical approach The clinical manifestations of the disease vary amongst patients. Painful vaso-occlussion is the most common clini- cal feature. Visceral sequestration crises can a ffect any organ system, resulting in chest crises, splenic sequestra- tion, and hepatic and girdle sequestration. Painful vaso- occlusive crises may cause infarcts in the bones, lung s and even the brain. The most serious manifestation is stroke, which can be either haemorr hagic or ischaemic. Stroke warrants an immediate exchange transfusion. SCD can also present with aplastic crisis due to an infection (classically parvovirus) causing transient red ce ll aplasia. Due to the shortened red cell survival in SCD, this may lead to a pre- cipitous drop in the hemoglobin level. The heart may be involved, with chronic anemia and microinfa rcts leading to haemosiderin deposition within the myocardium, leading to ventriclular dila tation. Cholelithiasis may be asympto- matic or require acute surgical intervention. The ki dneys lose concentrating capacity, which results in the loss of large volumes of \202 uid further exacerbating the dehydra- tion. Proteinuria is common in older patients. Renal fai lure may ensue. The spleen undergoes repeated infarction, and over time becomes \201 brot ic and shrinks. Hence patients with SCD are regarded as asplenic. Pneumococcal infec- tions are common. Attention must be paid to antibiotic prophylaxis and regular vaccination. Pulm onary hyperten- sion has recently been reported as a common complica- tion in SCD and is as sociated with a high mortality. Transfusion in sickle cell anemia Although anemia is a constant feature in SCD, the patient s tolerate the anemia well. The indications for an emer- gency transfusion include: Top up transfusion: (aims to raise Hb by 2 \200\2233g/dl) \200 \200 Aplastic crisis Acute splenic sequestration Exchange transfusion \200 \200 \200 \200 \200 \200 Acute stroke Acute chest syndrome Severe sepsis Hepatic sequestration Priapism (if surgical treatment has failed) Acute multi-organ failure Despite profound anemia, the amount of blood that can be given as a \200\230top up \200 \231 is limited due to concerns over pos- sible hyperviscosity. HbS-containing cells are hy perviscous and have poor \202 ow characteristics which are exacerbated by the transfusion of HbA-containing red cells. Practically, the post-transfusion hemoglobin should not excee d 10g/ dl. Exchange blood transfusion produces rapid and some- times dramatic improvements in biological and oxygena- tion parameters. By removing red cells, the concerns over hyperv iscosity are circumvented. The proportion of HbA/ HbS red cells should be measured pre- and post-exchange. The major disadvantage of exchange transfusion is the Examination There are no speci \201 c exam \201 ndings. The patient is often icteric, th e mucus membranes are pale and a systolic mur- mur is sometiems present. The spleen may be enlarged in younger patients. Evaluation must be undertaken for pul- monary hypertension as this may be present in as many as 60% of patients. Investigations If a diagnosis of SCD is in question, hemoglobin electro- phoresis will rapi dly con \201 rm the diagnosis and delineate 395 CHAPTER 23.3 Sickle cell anemia \201 nding at autopsy, and may be present in as many as 60% of patients with SCD. Symptom s tend to be absent until irre- versible damage has occurred and the patient complains of s hortness of breath. Patients with SCD and pulmonary hypertension have been successfully tre ated with infusions of prostacyclin or sildena \201 l. Echocardiography should be consider ed on all patients with SCD admitted to the ICU to exclude the presence of occult pulmonary hyperten- sion. increased donor exposure, with a greater risk of infection and alloimunization. To try to p revent immunization, patients with SCD should be transfused ABO-compatible blood with match ing of their Rh C, D, E and Kell antigens. This approach reduces the probability of alloant ibody for- mation. The exchange can either be performed manually or with an apheresis machi ne. In the critically ill, an auto- mated exchange is preferable as it is relatively quick, taking 2h, and provides more control, achieving a target \201 nal Hb, %HbS and \202 u id balance. There is less \202 uctuation in the cir- culating volume and it is probably s afer in patients with haemodynamic compromise. However, there is no evi- dence directly com paring an automated exchange with a manual exchange. The major advantage of a manual exchan ge is that less training is required without the need to use an apheresis machine. For both techniques, a 1.5 red cell volume exchange is regarded as the best volume to achieve a max imum reduction in HbS red cells. The patient \200\231s red cell volume is equal to the pre- transfusion haematocrit multiplied by the estimated blood volume (70ml/kg for an adult Surgery There is a high risk of post-operative complications and an 1% mortality among SCD patients undergoing elective surgery. In these patients, an elective exchange transfusion may be undertaken in an attempt to try to reduce this mortality. However, in patients with a low hemoglobin, top up transfusion has been shown to be as good as a red cell exchange. E xtrapolating this to critically ill patients, it would appear reasonable to consider an exc hange transfu- sion in any critically ill SCD patient prior to a surgical pro- cedure. Post -operatively, scrupulous care must be taken to monitor oxygenation and hydration in an atte mpt to pre- vent a crisis. A series of patients undergoing elective chole- cystectomy with SCD received CPAP for the \201 rst 24h post-operatively. Only one patient developed a che st crisis. The remaining patient responded well to a prolonged course of CPAP. Incentive sp irometry has also been shown to reduce the incidence of chest crises. Dehydration increases the relative concentration of the abnormal HbS within the red cell, increasing the chances of polymeriza- tion. SCD patients have a prothrombotic pro \201 le and thus should receiv e thromboprophylaxis when acutely ill and perisur- gery. The acute chest syndrome This is a common complication and the most frequent cri- sis requi ring ICU support. It may be precipitated by infec- tion, hypoventilation and atelectasis, p ulmonary oedema or bonchospasm. Acute chest syndrome may present post- operatively, and is the most common cause of post-opera- tive death in SCD. Careful perioperative management is required. Acute chest syndrome is diagnosed when a new pulmonary in \201 ltrate is detect ed on a CXR involving at least one complete lung segment with the addition of either chest pain, fever >38.5 C, tachypnoea or hypoxaemia with a pO2 <9mm Hg. Life-threatening respira tory compromise can occur. The acute treatment of acute chext syndrome is supportive. In ad dition to the general measures mentioned above, patients with acute chest syndrome should r eceive treatment with inhaled bronchodilators. NIV has been a signi \201 cant step forward in the management of acute chest syndrome, reducing the requirement for mechanical venti- lation, and should be started early if possible in the man- agement of an acute chest crisi s. The primary treatment remains prompt exchange transfusion. There is no evi- dence for th e routine use of anticoagulation. Conclusion Patients with SCD present speci \201 c challenges when criti- cally ill. Howeve r, with the development of improved trans- fusion strategies and the use of NIV, the progno sis is continuing to improve in this challenging patient group. Successful care is reliant on close communication between the critical care and hematology teams. Further reading Howard J, Gabriel I. Pulmonary complications of sickle cell disease. Pulmonary hypertension This is de \201 ned as a raised pulmonary artery pressure of >25mm Hg on catheterization. This roughly equates to a tricuspid regurgitant jet velocity of 2.5m /s on echocardiog- raphy. Haemolysis results in the release of free haemo- globin which sca venges NO and catalyzes the formation of reactive oxygen species. Asplenia increases the ci rculation of platelet-derived mediators which promote pulmonary microthrombosis and adhesio n of red cells to the pulmo- nary vasculature. Repeated episodes of regional pulmonary hypo xia produce progressive tissue damage and alteration of the pulmonary vasculature, ultimate ly leading to pulmo- nary hypertension. Pulmonary hypertension is a frequent Airways J 2005; 3: 001. Hoffbrands AV, Pettit JE, Moss PAH. Essential hematology. Oxford: Blackwell Science. Mak V, Davies SC. The pulmonary physician in critical care * Illustrative case 6: acute che st syndrome of sickle cell anemia. Thorax 2003; 58: 726 \200\2238. Platt OS, Brambilla DJ. Mortality in sickle cell disease. Life expect- ancy and risk factor s for early death. N Engl J Med 1994; 330: 1639 \200\22344. Vichinsky EP, Haberkern CM, Neumayr L, et al. A comparison of conservative and aggressive t ransfusion regimens in the periop- erative management of sickle cell disease. The Preoperat ive Transfusion in Sickle Cell Disease Study Group. N Engl J Med 1995; 333: 206 \200\22313. 396 A RETTER & BJ HUNT Haemolysis The normal red cell survives for 120 days in the circulation. If the bone marrow is healthy , then red cell survival can be reduced by as much as 8-fold without developing signi \201 - cant anemia. However, if red cell survival is <15 days, anemia is inevitable. Premature destruction occurs due to abnormal red cell structure, excess physical trauma to the cells or because the cells have become abnormally rigid, or via immune mechanisms \200\224complem ent can punch large holes in the membrane, or IgG-coated cells are removed by the reticu- l oendothelial system. Constant haemolysis results in splenomegaly. The diagnosis is made by demonstrating decreased levels of G-6-PD. Immune haemolysis Alloimmune haemolysis IgM antibodies \201 x complement and cause intrav ascular haemolysis, as seen with blood transfusion of an ABO mis- match. Pre-formed anti-A or anti-B will bind to transfused red cells causing instantaneous intravascular haemolysis, with shock and renal failure. Over 20% of patients with ABO incompatibility die. IgG antib odies bind to red cells, and red cell destruction occurs in the spleen (extravascular), e.g . if a patient devel- ops anti-D or anti-Kell antibodies. Due to the time taken to develop these antibodies, this occurs 7 \200\22310 days after trans- fusion. General approach to haemolysis 1 Is there increased red cell production? \200 Blood \201 lm \200\224polychromasia, macrocytosis Raised reticuloyte count Autoimmune haemolysis These may be \200\230warm \200\231 due to the presence of antibodies active at 37 C or cold when the antibodies are active at 40 C. Both are uncommon and sho uld be referred to a hematologist. 2 Is there increased red cell destruction? \200 \200 \200 Elevated bilirubin level Elevated LDH Elevated fecal and urinary urobilinogen Reduced hapto globins 3 Is the haemolysis intravascular? Elevated plasma hemoglobin Methaemoglobin presen t Haemoglobinuria Urinary haemosiderin if a chronic condition Non-immune Damage to red cells due to oxidative stress is common in patients in critical ca re, brought about by drugs, physical damage such as burns, and infection. Fragmentation of red cells by mechanical trauma occurs either with \200 \200 \200 \200 Cardiac haemolysis \200\231, when foreign material is in contact with the blood such as hae mo \201 ltration, the intra-arotic balloon pump and the ventricular assist device, or when there is a para valvular leak. Microangiopathic haemolytic anemia. When blood vessels are partially blocked by \201 brin strands of platelets, arteritis, \201 briniod necrosis o r malignant cells. (see Table 23.4.1) 4 Why are the cells being destroyed? Genetically determined \200 Morphology looking for sickle cells, sphero- cytes, etc. Haemoglobinopathy analysis Enzyme de \201 ciency, glucose-6-phosphate dehydro- genase (G-6-PD) being most common in UK \200 Acquired \200 Immune \200\224do a Coombs test, if clinical suspicion high, repeat if negative. Non-immune \200\224trauma, valve prosthetic leak, liver disease, parasitic disorder, bacterial infect ion, physi- cal agents, Hypersplenism, microangiopathic haemolytic anemia. Table 23.4.1 Microangiopathic haemolytic anemia Disease Underlying Pathology Malignant hypertension Fibrinoid necrosis Haemolytic \200\223uraemic syndrome Renal microthrombi Thrombotic thrombocytopenia purpura Platelet aggregates Haemolytic conditions particularly relevant to critical care Glucose-6-phosphate dehydrogen ase de \201 ciency This X-linked de \201 ciency makes red cells vulnerable to oxi- dative damage. It is widely distributed and has a high preva- lence in Africa, Southern Europe, t he Middle East, Asia and Oceana. Most individuals are asymptomatic but risk haemolytic anem ia with 1 Drugs (antimalarials, sulfonamides, aspirin, cipro \202 oxacin, Disseminated intravascular coagulation Microthrombi The vasculitides (polyarteteritis, Wegeners, SLE) Meningoccocal sepsis Microthrombi/DIC Homograft rejection Microthrombi Pre-eclampsia Fibrinoid necrosis DIC etc.) 2 Infections 3 Fava beans The anemia is largely due to intravascular haemolysis; the blood \201 lm shows the features of acute haemolysis along with \200\230bite cells \200\231 (b its of cell bitten away) and Heinz bodies (denatured hemoglobin). Haemolytic \200\223uraemic syndrome (HUS) is a triad of throm- bocytopenia, haemolysis and renal failure. There may be associated multi-organ disease including enterocolitis, neurolo gical complications, liver, pancreatic and cardiac dysfunction. The epidemic form (D+) is a ssociated with a prodromal illness, bloody diarrhea and verotoxin 397 CHAPTER 23.4 Haemolysis enterococcal (verocytotoxin-producing Escherichia coli (VTEC)) infection. Rare sporadic or atypical cases have no prodrome and may be associated with HIV, CMV or bacterial infection. Secondary cases of HUS include post- solid organ or bone marrow transplantation, drug expo - sure (pentostatin, cyclosporin, mitomycin C, heroin and quinine), malignancy, pregnancy a nd familial complement factor H de \201 ciency or other complement defects. Early stool cu lture is essential for the diagnosis of VTEC- associated HUS. Other investigations are as f or TTP. Management involves meticulous \202 uid and electrolyte bal- ance, and blood pres sure control, with renal dialysis as required. Antimotility drugs and antibiotic treatment adversely affect the outcome and should be avoided. At present there is no conclusive evide nce that either FFP or plasma exchange improves outcome. Adjuvant treatment with antiplatel et agents, anticoagulation, anti- \201 brinolytics or IVIG is not recommended. A panel of investigations required in a suspected case of TTP includes: \200 \200 \200 \200 \200 \200 \200 \200 \200 FBC and \201 lm Reticulocyte count Clotting screen including \201 brinogen and D-dimers Urea and electrolytes Liver function tests Lactate dehydrogenase Urinalysis Direct antiglo bulin test HIV and hepatitis serology Single volume daily plasma exchange should be com- menced immediately. Theoretically plasma exchanges using cryosupernatant or solvent \200\223detergent prepared FFP (both de \201 cient in high MW von Willebrand factor multimeric forms hence less likely to stimulate furt her thrombosis) may be more ef \201 cacious than using standard fresh frozen although ther e is no clinical data to support this currently. Daily plasma exchange should continue for a minimum of 2 days after complete remission. Adjuvant pulsed methylprednisolone 1g IV dail y for 3 days can be considered. Low dose aspirin (75mg daily) should be commenced on platel et recovery (platelet counts > 50 x 109/l). Red cell transfusion according to clinical need . Folate supplementation is required. Platelet transfusions are contraindicated unless ther e is life-threatening hemorrhage. In refractory disease intensi- \201 cation of plasma ex change should be considered. The use of Ritoximab is emerging as a major advance in the man age- ment of acquired TTP. TTP Thrombotic thrombocytopenic purpura (TTP) is a clinical diagnosis characterized by thro mbocytopenia, microangio- pathic haemolytic anemia, \202 uctuating neurological signs, re nal impairment and fever. Excessive platelet aggregation results in platelet microvas- cula r thrombi, which particularly affect the cerebral circu- lation. This is mediated by ultra- large von Willebrand factor (vWF) multimers due to a de \201 ciency of vWF cleaving protea se (vWF-CP), also known as ADAMTS13. De \201 ciency of vWF-CP activity may be; \200 \200 genetic \200\224absence of the enzyme acquired \200\224presence of an autoantibody to vWF-C P. Coagulation pro \201 les are usually normal. Secondary DIC due to prolonged tissue isch emia is an ominous prognostic indicator. Specialized units CAN measure levels of vWF-CP and its inhibitor to con \201 rm the diagnosis of TTP, but results are not available quickly. IF TTP is suspected they must be treated immediately and the diagnosis must be con \201 r med or refuted retrospectively. Delay in treatment may result in sudden death due to thromb otic occlusion of the coronary arteries. References Allford SL, Hunt BJ, Rose P, Machin SJ; Haemostasis and Thrombosis Task Force, B ritish Committee for Standards in Hematology. Guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anaemias. Br J Haematol. 2003 Feb;120(4):556 \200\22373. Hoffman PC. Immune hemolytic anemia \200\223selected topics. Hematology Am Soc Hematol Educ Program. 2006:13 \200\2238. 398 A RETTER & BJ HUNT Disseminated intravascular coagulation disorder. Once the triad of DIC, hypoxia and acidosis has developed, the prognosis is poor, and so aggressive man- agement is required to prevent this stage. Plasma and platelet subs titution therapy, anticoagulation and the resto- ration of anticoagulant pathways are also bene \201 cial in experimental and clinical studies. Management of DIC is to replace the m issing haemostatic factors: \200 \200 \200 DIC is not a disease or a symptom but a syndrome which is always secondary to an underlying disorder. It is charac- terized by a systemic activation of the blood coagulation system, which results in the generation and deposition of fibrin, leading to microvascular thrombos is in various organs and contributing to the development of MOF. Consumption and subsequent exhaustion of platelets and coagulation proteins may result in severe bleeding compli- cat ions. In the UK, bacterial sepsis, trauma and obstetric calamities are the common causes of DIC. Worldwide, snake bites are the major cause. If aPTT and/or INR >1.5 of normal give FFP 15ml/kg If \201 brinogen <1.5 g/dl give cryopr ecipitate If platelets <50 x 109/l give a pool of platelets Pathogenesis of DIC Tissue factor, dysfunctional physiological anticoagulant pathways and i mpaired \201 brinolysis all contribute to wide- spread \201 brin deposition. In sepsis, the generation of TNF and IL-1 lead to expression of tissue factor on monocytes and endoth elial cell activation. In meningococcal sepsis, it has been shown that the level of tissue factor present on monocytes is predictive of outcome. PAI-1 gene polymor- phisms which prod uce poor \201 brinolysis are associated with increased mortality. DIC is a clinicopatholo gical diagnosis. It cannot be made in the haemostasis laboratory as several other condition s such as liver disease will produce the same haemostatic picture \200\224prolongation of a PTT and INR, and low \201 brino- gen and platelet count (all due to consumption), and ele - vated D-dimers. In liver disease, this same picture re \202 ects lack of production of h aemostatic factors, as in patients with massive blood loss, where the mechanism is loss of haemostatic factors. Hyper \201 brinolysis can also tend to produce a similar picture, alt hough the fall in platelet count tends to be less severe. A scoring system that uses simple laboratory assays is a strong independent predictor of outcome in intensive care patients (see Taylor et al.). The keystone of management is the speci \201 c and forceful treatment of the underlying Constant repeated monitoring of haemostasis with coagu- lation screen and FBC is indicated. Anti \201 brinolytics are contraindicated as the lysis of thrombus is essential for resol ution of DIC. In profoundly prothrombotic DICs such as meningococcal sepsis, there is a the oretical argument to give an anticoagu- lant to switch off the prothrombotic effect of tiss ue factor on the monocytes. Options include giving supplementary antithrombin, APC and IV h eparin. A hematologist should be consulted for advice as there are no clinical trials in th is area. Further reading Bernard GR, Vincent JL, Laterre PF et al. Ef \201 cacy and safety of re- c ombinant human activated protein C for severe sepsis, N Engl J Med 2001; 344: 699 \200\2237 09. Hermans PW, Hazelzet JA. Plasminogen activator inhibitor type 1 gene polymorphism and sepsi s. Clin Infect Dis 2005; Suppl 7: S453 \200\2238. Levi M. Current understanding of disseminated intravascular coagu- lation. Br J Haematol 2004; 124: 567 \200\22376. Osterud B, Bjorklid E. The tissue factor pathway in DIC. Semin Thromb Haemost 2001; 27: 605 \200\22317. Taylor FBJ, Toh CH, Hoots K, et al. Towards a de \201 nition, clinical and laboratory crit eria and a scoring system for disseminated intra- vascular coagulation. Thromb Haemost 2000 ; 86: 1327 \200\2231330. This page intentionally left blank 400 A RETTER & BJ HUNT Neutropenic sepsis A fever of >38 C in a neutropenic patient is a medical emergency. Immediate assessment wit h prompt initiation of broad-spectrum antibiotic therapy is essential. Neutropenic sepsis r emains the most common life-threat- ening complication of treatment with chemotherapy, and the most frequent reason for patients receiving chemo- therapy to require ICU admission. Al though improving, critically ill patients with neutropenic sepsis continue to have poorer o utcomes when compared with matched patients without malignancy. Access to ICU care may be r estricted because of the perceived increased mortality and poor outcomes. A multi-disciplin ary approach is required to optimize management. Initial treatment It is imperative that broad-spectrum antibiotics are started promptly. Th e UK national service framework requires that all such patients should receive antibiotics in <1h following admission. In practice, most units would aim to have initiated treatment w ithin 20min. Obtain the appropriate cultures prior to the initiation of antibiotic therapy, but antibiotic therapy must not be overly delayed. Microbiological approach Infection control measures These patients are at extremely high risk of contracting other infections. Scrupulous atten tion must be paid to hygiene and, if possible, they are best managed in side rooms preferab ly where high ef \201 ciency particulate air (HEPA) \201 lter units are installed. De \201 nition A diagnosis of neutropenic sepsis is made when a patient has a neutrophil c ount <1.0 x 109/l, and either a single oral temperature >38.5 C, or 38 C sustained for \211 1h. For prac- tical purposes, unexplained hypotension without fever, or new onset conf usion should also require urgent evaluation and treatment. Bacterial infection Look for previous micriobiological history and any prior colonization w ith MDR organisms. This may lead to altera- tion of the empiric treatment protocol. Getttin g the antibi- otic choice right \201 rst time improves outcome \200\224choosing the wrong antibiotics in this patient group may be rapidly fatal. Prior to the 1980s, Gram-negative bacilli were the predom- inant organisms causing infection in neutropenic patients. Now Gra m-positive infections account for up to 60 \200\22370% of identi \201 ed bacteraemias. Emp iric treatment is with an antipseudomonal penicillin and an aminoglycoside. Single daily do sing of aminoglyco- sides is favored since it is more ef \201 cacious and associated with less ototoxicity and nephrotoxicity. Some authors argue that the addition of aminoglycoside therapy only increases the incidence of side effects, but the addition of an aminoglycosid e to ceftazadine monotherapy gives better Gram-negative cover. Carbapenems have very broad- spectrum activity and can be used as \201 rst-line mon- otherapy but are generally held a s second line. There are no RCTs of one antibiotic regimen compared with another, and the p recise regimen used should be decided locally. Vancomycin is frequently used as second-line agent; how- ever, if the risk for MRSA is high, it should be initiated as \201 rst line. A response to \201 rst-line antibiotics should occur within 48h. If not, they should be changed to second-line antibiotics. If pyrexia persists after 96h, consideration must be gi ven to antifungal therapy. There are no \201 rm rules as to the dura- tion of antibiotic therapy; however, many centers continue antibiotics until the neutrophil count has recovere d to >0.5 \200\2231.0 x 109/l. Prolonged courses of broad-spectrum antibiotic increase the chances of developing multi-resist- ant organisms. If a speci \201 c organism with known s ensitivi- ties is cultured, it is appropriate to narrow the antibiotic spectrum to minimize the chances of producing multi- resistant organisms. This approach is controversial as neu tropenic patients may be infected with more than one organism; infection with two organis ms is reported in up to 19% of patients. No attempt should be made to de-esca- late therapy if the patient has mucositis; the risk of multiple infections is too high. Pathogenesis Chemotherapy has a direct toxic effect on the bone mar- row, causing pancytope nia. Many hematological malignan- cies infiltrate the bone marrow compromising haematopoies is. Both chemotherapy and malignancy cause disordered T-cell and B-cell function, further c ontributing to immune dysfunction. Clinical approach History \200 The type of malignancy, disease state (active/remission), recent chemotherapy, presence of graft vs host disease (GvHD) must be documented. These factors have all been shown independ ently to affect outcome and may lead to signi \201 cant alterations in care. Patients from Eastern Europe, the Middle East, Far East or the Indian subcontinent should be considered at risk of TB especially if they have not received TB prophylaxis with chemotherapy Examination \200 Identify the site of infection to guide evaluation and treatment. Neutropenic patients dete riorate rapidly and are susceptible to unusual infections presenting in an atypical fashion . Look for signs of infection around tunneled venous catheters, the mouth for mucositis and dental abscesses, the perianal area for infection. Rectal examinations risk introducing fu rther infection and are not recom- mended. Hypotension without fever or general malaise can still be due to severe sepsis. Investigations \200 Blood cultures should be taken from all the lumens of a tunneled venous line, and in additi on peripheral cultures taken; sputum and urine culture, and CXR are all essential. A high r esolution CT (HRCT) of the chest and sinuses (HRCT remains the most sensitive and speci \201 c way of diagnosing fungal chest infections in neutropenic patients.) Ultrasound of th e abdomen looking for hepatosplenic candidiasis 401 CHAPTER 23.6 Neutropenic sepsis Blood product support Patients with hematological malignancies require exten- sive blood pr oduct support. Each patient receiving chemo- therapy who has special transfusion requiremen ts should have a record of their transfusion status stored with their local blood bank. Fungal infection This remains a considerable diagnostic and therapeutic challenge in neutro penic patients and a major cause of morbidity and mortality. Autopsy studies suggest that i nva- sive fungal infections are found in up to 40% of haematol- ogy patients. The most comm on fungal infections are Candida and Aspergillosis. Invasive candidiasis in the neutropenic patient is usually associated with well de \201 ned risk factors including, a pro- longed duration of neutropenia, mucositis, corticosteroids, prolonged use of broad-spectrum antib iotics and the pres- ence of a central venous line. The overall mortality for Candida infec tions approaches 60%. Treatment involves removal/replacement of any in-dwelling lines (incl uding tunneled lines) and treatment with either a lipid formula- tion of amphotericin B or either voriconazole or caspos- fungin. The data regarding caspofungin are encouraging, and it may well become the \201 rst line. Treatment should continue for a minimum of 14 days, and should only be stopped if the neutrophil count has recovered. Invasive aspergillosis i s probably the most serious infection in neutropenic patients, occasionally proving excepti onally dif \201 cult to treat. In bone marrow transplant recipients, the mortality is repo rted to be >80%. The use of high dose steroid or other immunosuppression and GvHD are well de \201 ned risk factors. Recovery of bone marrow function is critical for survival, and u ltimately antifungal agents are temporary holding measures awaiting immune regenera- tion; granulocyte colony-stimulating factor (G-CSF) should be used. The traditional treatment has been high dose lipososmal amphotericin B. Voriconazole was found to have an increased resp onse rate with a lower mortality rate and a reduced incidence of adverse reactions, and som e centers recommend voriconazole as \201 rst-line treat- ment. Liposomal amphotericin has a broader spectrum of action. Caspofungin has been used as salvage therapy or when patient s are intolerant of the other medications. Antifungal therapy should continue until all sig ns and symp- toms of the infection have resolved for at least 2 weeks and the neutrophil co unt has recovered. Given the high mortality rate of invasive fungal infection there has bee n considerable interest in the use of combi- nation therapy, with potential synergy between antifungal agents to enhance fungal killing. The cost of such therapy is extremely high an d has not been studied in an RCT. Thrombocytopenia Thrombocytopenia presents many practical dif \201 culties in a critical c are environment. For a \200\230severe sepsis patient \200\231 the platelet count should be maintained above 20 x 109/l. Below this level there is a progressive and substantially inc reased risk of spontaneous bleeding. Many patients will require daily platelet support and some become refractory to platelet transfusion. Pethidine 50mg SC is an excellent antipyret ic agent which can be used to cover mild febrile reactions; with platelets, however, there is a risk of seizures related to the accumulation of its metabolites. In ICU, chlo- rphenir amine is probably the safest agent to cover platelet reactions. Frequently platelet transfu sions are co-adminis- tered with hydrocortisone; this should not be used rou- tinely in the ICU, since patients are already profoundly immunosuppressed and additional doses of steroi d further impair immunity as well as exacerbating problems with gly- caemia and adrenal sup pression. Invasive procedures It is not always practical to aim for a platelet count of 100, and a co unt of 50 should be acceptable for most proce- dures (CVP line placement, Hickman line remo val, para- centesis, NG tube insertion, bronchoscopy). A platelet count >100 is required fo r major surgery. Irradiated blood products are needed for all bone marrow transplant recipi ents, patients with Hodgkin \200\231s disease and those who have received purine analogs or alemtuzu- mab. There have been no reported cases of transfusion- associated GvHD since the initiation of leucodepletion, but care must be taken as transfusion-associated GvHD is reg arded as universally fatal. FFP and cryoprecipitate are not cellular products and therefore do not need to be irra- diated. CMV-negative blood products should be requested for all po tential candidates or recipients of a bone marrow trans- plant who are CMV negative prior t o transplant. There is no need for CMV-negative products if the patient was seropositive pr ior to their transplant.