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. Viral infections Viral infections are also an important cause of morbidity and mortality in neutropenic patients. The difference in the incidence and outcome of viral infections vari es widely between patient groups. The most vulnerable group of patients are those who have received bone marrow trans- plants and require ongoing immunosuppression. CMV, HSV, varicel la-zoster virus, respiratory syncytial virus and in \202 u- enza viruses are the more freq uent pathogens. CMV infec- tion is a frequent complication following a bone marrow transpla nt \200\224reactivation of latent infections in patients who were seropositive prior to the ir transplant. Pre-emp- tive therapy based on PCR screening is conducted by bone marrow tra nsplant units. Indications for treatment include a high CMV or rising CMV titres; treatment is with either foscarnet or ganciclovir. Waiting for the emergence of symptoms is frequent ly fatal. Treatment should continue until two consecutive negative CMV blood PCR results ar e obtained. Granulocyte-colony stimulating factor G-CSF is given once daily as an SC injection, stimula ting the production of WBCs. It accelerates recovery from neutro- penia after chemotherapy, reducing the frequency of infec- tions and the duration of neutropenia. There is no eviden ce to suggest a substantial bene \201 t in the critically ill. One study showed no differe nce in the depth or duration of neutropenia, or survival with the use of G-CSF. As there is no evidence to suggest that G-CSF causes additional harm and there is a potential theoreti cal bene \201 t, most haema- tologists support its use. Dosage Theoretically (no evidence and costly) there is potentiallly reduced adsorption of G -CSF in patients receiving vaso- pressors so in patients receiving either adrenaline or nor e- pinephrine the dose of G-CSF should be doubled. G-CSF can be stopped when the neutrophil count is >1.0 x 10 9/l for two consecutive days. G-CSF should be restarted if the count dr ops below this level. 402 A RETTER & BJ HUNT Nutritional support Enteral nutrition should be considered early. Patients with malignant d isease and who have received chemotherapy are frequently malnourished and have lost a signi \201 cant pro- portion of their body weight. Inadequate nutritional sup- port contributes signi \201 cantly to mortality. Mucositis makes oral feeding extremely dif \201 cult, an d it is virtually impossible to maintain a satisfactory calori \201 c intake. appears infected the device should be removed. Multiple studies have reported the use of an tibiotics to treat infected long-term catheters. These studies generally exclude neutropeni c patients and report success rates of 60 \200\22390%. As a general rule, the tunneled line of any neutro- penic patient should be removed if they are admitted to ICU with severe sep sis. This should be mandatory if there is bacteraemia, or evidence of MRSA or fungal (in pa rticular candidal) colonization of the line. Organ-supportive therapy Mechanical ventilation and intubation has been shown to impact neg atively on the survival of critically ill haematol- ogy patients. The reported mortality of ventilated neutro- penic patient \200\231s ranges from 85 to 94%. The major cause of death in ventilated patients is septic shock and MOF rather than hypoxaemia. These poor outcomes must be tempered by the fact that several studies have now shown improved overall survival in patients requiring ventilatory support. The cause of this improved survival is attribut able to the increased use of NIV and the use of lung protective ventila- tory strategies. E ach patient needs to be evaluated on a case-by-case basis, with close liaison between the a ttend- ing intensivist and hematologist to ensure patients with limited chances of survival are not inappropriately treated. Renal replacement therapy is also associated with an incr eased mortality rate of 67% when used in neutropenic patients. In patients requiring combin ed RRT and mechani- cal ventilation, the mortality is extremely high. The data on this pati ent group are limited, but one study reports a 5% survival Conclusion There will continue to be an increasing demand for critical care resources for t hese patients. Currently neutropenic patients with severe sepsis have poor outcomes, but th ere is much scope for further improvement in the treatment of this challenging patient grou p. Further reading Azoulay E, Alberti C, Bornstain C, et al. Improved survival in cancer patie nts requiring mechanical ventilatory support: impact of non- invasive ventilatiory support. Crit Care Med 2001; 29: 519 \200\22325. Benoit D, Depuydt P, Peleman RA, et al. Documented and clinically suspected bacterial infection precipitating intensive care admis- sion in p atients with hematological malignancies: impact on out- come. Intensive Care Med 2005; 31: 934 \200\22342. Bow E. Of yeasts and hyphae: a hematologist \200\231s approach to antifun- gal therapy. Hematology 2006; 361 \200\2237. Brunet F, Lanore J, Dhainaut JF, et al. Is intensive care justi \201 ed for patients with hematological malignancies? Intensive Care Med 1990; 16: 291 \200\2237. Donovitz G, Makii D, Crnich CJ, et al. Infections in the neutropenic patient \200\224new vi ew of an old problem. Hematology 2001; 113 \200\22339. Hilbert G, Gruson D, Vargas F, et al . Noninvasive ventilation in im- munosupressed patients with pulmonary in \201 ltrates, fe ver and acute respiratory failure. N Engl J Med 2001; 344: 481 \200\2237. Tunneled venous lines Reliable venous access is essential, and the majority of patients hav e tunneled venous lines. These devices are associated with a signi \201 cant potential for iatrogenic bacter- aemia and candidaemia. The two main causes of line infec- tion are inad equate insertion technique resulting in early infection and poor handling/manipulation of t he line. Colonization can also develop from haematogenous spread from an established infect ion. Suspicion of line sepsis must always be high in neutropenic patients. If in doubt of t he source, the line should be removed and a fresh catheter placed at a new site. If the tun nel of a long-term catheter Pene F, Aubron C, Azoulay E, et al. Outcome of critically ill alloge- neic stem-cell transp lant recipients: a reappraisal of indications for organ failure supports. J Clin Oncol 2006 ; 24: 643 \200\2239. Rebulla P, Finazzi G, Marangoni F, et al. The threshold for prophylac- tic platelet transfu sions in adults with acute myeloid leukemia. N Engl J Med 1997; 337: 1870 \200\2235. Wade J. Viral infections in patients with hematological malignancies. Hematology 2006: 368 \200\22374. This page intentionally left blank 404 R RAO BAIKADY Hematological malignancies in the ICU Patients with hematological malignancies may present to ICU due to disease-related complica tions or treatment issues. Over the last few decades therapeutic interventions for leukaemi as and lymphomas have evolved and pose new challenges to clinicians. Though the management of patients with hematological malignancies with acute complications is similar to any crit ically ill patient, it is important to discuss the following key issues before intensive ca re admission. \200 \200 \200 Mechanical complications SVC syndrome, as a result of impaired venous return through the SV C to the right atrium, is seen in lymphomas. Pericardial effusion and cardiac tamponade may spontane- ously develop in patients with leukemia and lymphoma. Epidural cord compression with neurological affects is a rare but serious complication seen in patients with lym- pho ma and myeloma. Principles of management \200 The type of the malignancy including staging. Severity of the illness and immediate managem ent. Is the symptom related to malignancy or a side effect of treatment? Further treatment options for the disease and prognosis. Communication with the patient and family regarding their wishes. Profound neutropenia necessitates prophylaxis with antibacterial, antifungal and antiviral agents. Adjunctive measures include early intervention with G-CSF to hasten haemopoietic ce ll recovery. If vascular catheter- related infection is suspected the catheter should be re moved. Septicaemic shock and MOF should be treated aggressively with sepsis treatment strat egies. Individual units may follow their own antibiotic guide- lines. Respiratory failure r equiring tracheal intubation and mechanical ventilation have very poor outcome. Recent stud ies have shown that early intervention with NIV reduces the need for intubation with better ITU out- come. Management of TLS includes allopurinol, to inhibit xanthine oxidase and uri c acid crystal formation, aggres- sive IV \202 uid hydration and alkalization of urine. P atients with metabolic derangements need monitoring and optimization of electrolyte imbalan ce. Patients with acute renal failure will bene \201 t from early haemo \201 ltra- tion. Regular transfusion of blood and clotting products are indicated in patients with haemorrha gic complica- tions. The management of patients with thrombocytope- nia depends on the seve rity of the underlying defect, the extent of bleeding, the type of invasive procedures, and the risks associated with treatment. Platelet transfusion should be limited to severe thro mbocytope- nia with complication in order to avoid platelet refracto- riness. Leucopheresis is indicated in severe leucostasis to decrease the tumor cell burden without inducing lysi s. Chemotherapy may have to be instituted during acute critical illness to control the acti ve disease. High dose methylprednisolone is the primary therapy of acute GvHD. The initial course is 2mg/kg/day for 14 days and, if the symptoms are controlled, steroid weaning shoul d be considered. Chronic GvHD patients need long-term steroid therapy with or without immun osup- pressants. The management of mechanical complications depends on the etiology, the se verity of symptoms and the disease prognosis. Chemotherapy is the treatment of choice for S VC syndrome. Cardiology intervention with pericardiocentesis may be indicated in acute car- diac tamponade. Therapeutic options for epidural cord compression include corticosteroids, surgery and radiation. Regular consultation with hematology and oncology teams to discuss appropriateness of the treatments and also prognosis \200 Complications of hematological malignancies Neutropenia and infection Neutropenia is one of the most common complications due to underlying disease or cytotoxic treatment. These pati ents are susceptible to infections with Gram-negative bacteria, staphylococci and fungi. As a consequence, patients may present with septicaemic shock and MOF. Metabolic complications Hyperuricaemia, hyperkalaemia, hyperphosphataemia and hypocalcaemia are consequences of tumor lysis syndrome (TLS), which is due to the release of intracellul ar purines, phosphates and potassium from rapidly proliferating tumor cells. TLS is commonl y observed in solid tumors. This may occur spontaneously or with the initiation of chemothe rapy. Other metabolic complications include hypercalcaemia and hyponatraemia. Haemorrhagic complications Thrombocytopenia and abnormal coagulation, including DIC seconda ry to disease process or treatment, may lead to severe bleeding, e.g. acute GI and cerebrov ascular hemorrhages. Thrombocytopenia is a common complica- tion with platelet count <10 00 0/mm3. Haemorrhagic com- plications may occur due to platelet dysfunction rather than actua l platelet count. Leucostasis A serious complication with a leucocyte count >100 000/ l. The high count may lead to capillary stasis and tissue hypoxia. Chemotherapy-induced toxicity Chemotherapy for leukaemias and lymphomas can be toxic and le thal, with myelosuppression, metabolic compli- cations, immunosuppression and cardiac dysrh ythmias. All chemotherapy drugs have distinct side effect pro \201 les. Haemopoietic cell transplantation (HCT) and GvHD An increasing number of hematological mali gnancies receive HCT. Failure of allogenic HCT may result in graft rejection or GvHD, with serious consequences. GvHD results from donor-derived T cells that react with recipient tis sue antigens. The clinical presentation of acute GvHD involves skin rashes, liver dysfuncti on and various GI symptoms. Patients are also susceptible to respiratory infections and sep sis. 405 CHAPTER 23.7 Hematological malignancies in the ICU Outcome and prognosis Despite the recent advances in ITU management, mortality and morbidit y in this group of patients are relatively high. The factors associated with poor outcome i nclude respiratory failure requiring mechanical ventilation, MOF needing vasopressors and h aemofiltration, established GvHD, persistent neutropenia and high APACHE II score. Overall mortality and outcome are likely to depend on the severity of the organ dysfunction rather than the type of the disease. Montgomery BR, Thompson JA. Oncologic emergencies In: Irwin RS, Rippe JM, eds. Intensive ca re medicine, 5th edn. Philadelphia, PA: Lippincott Williams & Wilkins, 2003: 1302 \200\2231 3. Negrin RS, Blume KG Allogenic and autologous hematopoietic cell transplantation. In: Beutle r E, Lichtman MA, Coller BS, Kipps TJ, ed.s Williams hematology, 6th edn. New York: McGraw- Hill, 2001: 209 \200\22347. Pawson H, Jayaweera A, Wigmore T. Intensive care management of patients following haematopo ietic stem cell transplantation. Current Anesthesia and Critical Care 2008; 19(2): 80 \200 \22390. Further reading Sekeres MA, Stone RM. Acute leukemias In: Irwin RS, Rippe JM, eds. Intensiv e care medicine, 5th edn. Philadelphia, PA: Lippincott Williams & Wilkins, 2003: 1295 \200 \223302. 406 J UPRICHARD AND S BRETT Coagulation monitoring Coagulation screen Anticoagulant Test for Therapeutic window monitoring Prothrombin Time (PT) is prolonged in de \201 ciencies of factors II, V, X, VII. UFH APTT 2 \200\2233 times normal control Activated Partial Thromboplastin Time (APTT) is prolonged in de \201 ciencies of factors I I, V, X, VIII, IX, XI, XII. It is also prolonged in the presence of heparin and in patients with a lupus anticoagulant. LMWH Anti-Xa Prophylactic: 0.2 \200\2230.4 IU/ml Therapeutic: 0.4 \200\2231.0 IU/ml Danaparoid Anti-Xa 0.5 \200\2230.8 IU/ml Lepirudin APTT 1.5 \200\2233 times normal control Thrombin Time (TT) is prolonged in hypo- and dys \201 brino- genaemia, in the presence of heparin, and in the presence of \201 brin degradation products. Heparin contamination can be con \201 rmed if the prolonged thrombin time is corrected by the addition of reptilase . The Bleeding Time has been largely superseded by the PFA-100 . This test indicates globa l platelet function in a high-shear environment. Interpretation of prolonged times must be made in the light of the clinical situation and other coagulation tests. The test should on ly be requested fol- lowing liason with a hematologist. Normal screening tests may not mean that patient has normal haemostasis in vivo (e.g. mild hemophilia A). Conversely, abnormal tests may not mean that there is a risk of clinical hemorrhage (e.g. lupus anticoagulant). Bivalirudin ACT > 350 seconds appears to be resistant to heparinisation. Testing should be performed three hours after th e injection. Near patient testing devices are available. Dif \201 culties with heparin management Acute phase response Fibrinogen, von Willebrand f actor and FVIII are acute phase proteins. They will be raised in in \202 ammatory conditio ns. This can result in a resistance of the APTT to prolongation by therapeutic dose unfract ionated heparin. In this case, moni- toring of anticoagulation by anti-Xa levels is appropr iate. Antithrombin de \201 ciency In antithrombin de \201 ciency states (e.g. severe sepsis), t rue heparin resistance may occur and adequate anticoagulation may require replacement with antithrombin concentrate or fresh frozen plasma in addition to heparin. Note that some anti -Xa assays are sensitive to the amount of anti- thrombin in patient plasma. Hematological a dvice will be necessary. Speci \201 c factor assays (e.g. monitoring hemophilia A) For major operations, factor lev els should be maintained at 50-100% for 7-10 days. This can be achieved by an initial bolus to bring the level to 100% and then either continu- ous infusion or twice daily dosing (on ce daily for haemo- philia B) with the appropriate factor concentrate. Factor assays should be performed to guide dosage. Near-patient testing ACT Whole blood clotting time is used for monitoring high doses of hep arin (e.g. when on cardiopulmonary bypass). It is likely to be inaccurate if the patient ha s an inhibitor (e.g. lupus anticoagulant). ACT needs to be interpretated with caution in th e presence of aprotinin and in critically ill patients Anemia Erythrocytes facilitate the interaction of platelets with the vessel wall, so increa sing the haematocrit can correct an increased bleeding tendency. Thrombocytopenia Increased bleeding is unlikely to occur until the platelet count falls to 50 x 109/l, unless there is concurrent anti- platelet therapy. There is an increased risk o f spontaneous life-threatening bleeding at counts below 10 x 109/ L. In the presence of sep sis, the transfusion threshold should be raised to 20 x 109/l. PT and APTT devices These are designed to test patients on anticoagulants (e.g. Coaguchek ). Thromboelastography This is seen as a global test of coagulation as it uses whole blood rather than plasma. The thromboelastogram works on the principle that the physical proper ties of a blood clot indicate whether under, over, or normal activity of the hae- mostatic system is present. Clot formation is recorded graphically. Parameters of the trace indicate activity of platelets, coagulation factors, and \201 brinolysis and so can aid appropria te product transfusion. It is used primarily in liver and cardiac surgery. The time to comm encement of \201 brin formation is meas- ured as the r-time. An increased r-time has been used as an indication for FFP infusion. A decrease in the maximal clot strength (MA) is us ed to guide platelet transfusion. A reduc- tion in the -angle suggests the need for cryop recipitate. The additional use of heparinase in the system may guide protamine dosage. Laboratory control of oral anticoagulants Warfarin anticoagulation is monitored using the I NR (international normalized ratio). For the majority of indica- tions an INR of 2.0 \200 \2233.0 is effective. It is usually suf \201 cient to stop warfarin three days prior to in vasive surgery and restart the usual maintenance dose on the evening of the surgery. The th ree day period usually needs to be covered by heparin anticoagulation. Laboratory control of parenteral anticoagulants (heparin, danaparoid, lepirudin, bivalirudi n) Anti-Xa This is used primarily to monitor LMWH (low molecular weight heparin) as LMWH do es not affect the APTT. It is the test of choice for monitoring UFH (unfractionated heparin ) if a lupus anticoagulant is present or if the APTT 407 CHAPTER 23.8 Coagulation monitoring -angle MA r-time Coagulation Fibrinolysis Time Fig. 23.8.1 Thromboelastogram trace. The r-time (normal range 4 \200\2238minutes), A-angl e (normal range 47 \200\22374 ), and MA (maximal ampli- tude, normal range 55 \200\22373mm) are shown. References Anderson JA, Saenko EL. Heparin resistance. Br J Anaesth 2002; Hayward CP, Harrison P, Cattaneo M, Ortel TL, Rao AK. Platelet func- tion analyzer (PFA)-10 0 closure time in the evaluation of platelet disorders and platelet function. J Thromb Haem ost 2006;4(2): 312-9. 88(4):467-9. Baglin T, Barrowcliffe TW, Cohen A, Greaves M. Guidelines on the use and monitoring of hepa rin. Br J Haematol 2006;133(1): 19-34. Rochon AG, Shore-Lesserson L. Coagulation monitoring. Anesthesiol Clin 2006;24(4):839-56. Luddington RJ. Thrombelastography/ thromboelastometry. Clin Lab Chee Y, Crawford, JC, Watson HG, Greaves M. Guideline on the assessment of bleeding risk pr ior to surgery or invasive proce- dures. BCSH; 2007. www.bcshguidelines.com/pdf/ Coagscreen 200107.pdf Haem 2005;27:81-90. This page intentionally left blank 409 Chapter 24 Metabolic disorders Chapter contents Electrolyte disorders 410 Hyponatraemia 414 Hypernatraemia 416 Categorizin g metabolic acidoses 418 Metabolic acidosis etiology 420 Metabolic alkalosis 422 Glycaemic control in the critically ill 426 Diabetic ketoacidosis 428 Hyperosmolar diabetic emergenci es 430 Thyroid emergencies: thyroid crisis/thyrotoxic storm 432 Thyroid emergencies: myxoed ema coma 434 Hypoadrenal crisis 436 410 P O NEIL & N WEBSTER Electrolyte disorders The physiology, etiology, clinical features and management of potassium, magnesium, calcium and phosphate disorders in the critically ill. exceed 20mmol/h, although rates as high as 60mmol/h have been used in emergency situations. Rapid infusion is dangerous as it can lead to VF. In patients with renal impairment, the d ose should be halved, and serum levels checked to assess response to therapy. Potassium sho uld not be diluted in dextrose as it can increase intracellular potassium shift by stimulat ing insulin release. Potassium-sparing diuretics can be used in the preven- tion of hypokal aemia, but are of limited use in the acute setting. If hypomagnesaemia co-exists with hypok alaemia, it should be corrected as it can cause refractory hypokalaemia. Potassium 98% of total body potassium (K+) is intracellular, with only 2% located in the ex tracellular \202 uid. The potassium ratio between intracellular and extracellular \202 uid is the major determinant of resting membrane potential. Potassium concentration in plas ma is maintained within tight limits, between 3.5 and 5.0mmol/l. Potassium is mostly absorb ed by diffusion from the GI tract. It is excreted by the kidney. A smaller amount (10%) is excreted through the GI tract. Control of extracellular potassium is achieved by: \200 \200 \200 \200 Hyperkalaemia Hyperkalaemia is defined as a serum potassium level >5.0mmol/l, and may be li fe threatening if >6.5mmol/l. Insulin \200\224drives K+ into cells via Na/K ATPase B2-Adrenoceptor agonists \200\224drive K+ into cells Acid \200\223base status \200\224exchange of H+ for K+ Osmolality \200\224in crease causes K+ to be dragged extracel- lularly Mineralocorticoids \200\223 drive K+ into cells Causes \200 \200 Increased K+ intake: iatrogenic Extracellular shift: acidaemia, hyperosmolality, B2-adren- oceptor antagonists, insulin de \201 ciency, succinylcholine, digoxin overdose, rhabdomyol ysis. Decreased renal excretion \200 \200 Hypokalaemia Hypokalaemia is de \201 ned as a serum potassium concentra- tion <3.5mmol/l, and is severe if <2.5mmol/l. renal failure mineralocorticoid de \201 ciency (Addisons disease, iso- lated aldosterone d e \201 ciency, renin de \201 ciency, drugs, e.g ARBs, ACE inhibitors, NSAIDs) mineralocor ticoid resistance (spironolactone, tri- methoprim, tubulointerstitial disease) Causes \200 \200 Inadequate K+ intake: if <1g/day Intracellular shift of K+: metabolic alkalosis, B2 agonist s, insulin, theophyllines Increased K+ loss: drugs (loop/thiazide diuretics, corti- costero ids, aminoglycosides, amphotericin B), hypomag- nesaemia, RRT, GI losses (diarrhea, fistula e, NG suctioning), hyperaldosteronism. Pseudohyperkalaemia: release of intracellular K+ during phlebotomy or storage of blood, hae molysis, thrombo- cytosis, leucocytosis. Clinical features Hyperkalaemia is often asymptomatic at levels <6.5mmol/l, and may \201 rst be detected on routine blood sampling. The symptoms are related to muscle and cardiac d isturbances. Generalized weakness, muscle twitching, cramping and ascending paralysis can o ccur. Arrhythmias occur, which can include bradycardias, VF and asystole. ECG changes inclu de peaked T waves, PR interval prolongation, QRS complex widening, QT interval shortening, leading eventu- ally to the sine wave which precedes VF. Clinical features Mild hypokalaemia is often asymptomatic. Hypokalaemia <2.5mmol/l patients can develop generalized weakness, nausea, vomiting and constipation. Some patients can dev elop an ascending paralysis. Rhabdomyolysis can also occur. Cardiac arrhythmias are the mos t worrying effect of hypokalaemia, and are more common in patients with underlying heart di sease and those on digoxin. ECG changes seen in hypokalaemia can vary, with U waves, ST dep ression, T wave \202 attening or inversion all seen. Management The management of hyperkalaemia is dependent on the presence of symptoms and on the presence of ECG changes. In asymptomatic patients with no ECG changes, the initial mana gement is to stop exogenous sources of potassium and all drug therapies which may increase potassium. Serum potassium should be rechecked. In a symptomatic patient, or those with ECG changes, therapies can act in several ways. \200 \200 \200 \200 Potassium levels s hould be monitored at least every 6h in patients with hyperkalaemia. Management Potassium replacement is the mainstay of treatment. As a guide, a 0.3mmol/l fall in serum potassium corresponds to a 100mmol total body de \201 cit. This is unreliable wh en hypokalaemia has been caused by intracellular shift of K+. Potassium chloride can be adm inistered orally or through a nasoenteric tube in divided doses up to 100mmol/day. Potassiu m phosphate and potassium bicarbonate are alter- natives in the presence of hypophosphataem ia and acidae- mia, respectively. Oral potassium supplementation has an unpleasant taste, a nd may cause GI erosion. IV potassium supplementation will rapidly correct hypoka- laemia. When administering potassium through a periph- eral vein, the concentration should not exce ed 80mmol/l, as it may cause pain and thrombophlebitis. Adminstration through a central ven ous line allows higher concentrations to be used. The rate of infusion of potassium should not Membrane stabilization Increase intracellular shift of K+ Increase K+elimination GI binding of K+ 411 CHAPTER 24.1 Electrolyte disorders Treatment Dose Mechanism of action Plasma Ca2+ 2.50mmol/l Calcium gluconate 10% 10ml over 5 \200\22310min Membrane stabilization Insulin 10U in 50ml 50% dextrose Intracellular shift Protein bound 1.16mmol/l Diffusible 1.34mmol/l Sodium bicarbonate 50 \200\223100mmol Intracellular shift Salbutamol 5mg nebulized Intracellular shift Ionized Ca2+ 1.18mmol/l Complexed 0.16mmol/l Globulins 0.24mmol/l Albumin 0.92mmol/l Furosemide 20 \200\223250mg IV Increased elimination Haemodialysis Increased elimination Sodium polystyrene sulfonate 30g oral or rectal, then 15mg 3x day GI binding Causes \200 \200 Iatrogenic End-stage renal disease. Magnesium The majority (99%) of magnesium is found intracellularly in bone, muscle and soft tissue. Normal serum levels are 0.7 \200\2231.05mmol/l. It acts as a physiological antagon ist to cal- cium and is a cofactor in all ATP reactions and numerous other enzyme reactions . Absorption of magnesium is through the small intestine. It is reabsorbed by the kidney, s o that only 1% of \201 ltered magnesium is excreted in the urine. Parathyroid hormone inc reases GI absorption and reduces renal excretion, whereas renal excretion is increased by a ldos- terone. Magnesium is used therapeutically in acute severe asthma, torsades de pointes , digoxin toxicity, atrial and ventricular arrhythmias, pre-eclampsia and eclampsia. Its us e following AMI is debatable. Clinical features Usually well tolerated, but it can cause nausea and vomit- ing. Deep tend on re \202 exes are lost, and at higher levels res- piratory paralysis can occur. Cardiova scular symptoms are of hypotension, bradycardia and increased PR interval and/ or QRS durat ion on the ECG. Management Stop magnesium administration. If necessary, systemic effects can be antagonized in severe cases by IV calcium (e.g. calcium chloride 0.5 \200\2231mg over 5 \200\22310min) . Its excretion can be increased by \202 uid administration, loop diuretics or haemodialy sis. Calcium Calcium is integral to excitation \200\223contraction coupling in myocardial, smoot h and skeletal muscle. It is also essential in bone metabolism, cardiac automaticity, coagu lation, hor- mone secretion and nerve conduction. 99% of the body \200\231s calcium is skel etal, <1% is in the plasma. Total plasma calcium level is 2.5mmol/l, and 40 \200\22350% is bound to plasma proteins. Calcium binding to plasma pro- teins is reduced by metabolic acid osis. Calcium is absorbed from the GI tract in a process regu- lated by 1,25-dihydroxychole calciferol. Parathyroid hor- mone and 1,25-dihydroxycholecalciferol promote Ca2+ release fr om bone stores. It is excreted in the kidneys, where it is \201 ltered then 99% reabsorbe d. Hypomagnesaemia Hypomagnesaemia is de \201 ned as a serum Mg2+ <0.7mmol/l, although serum levels do not correlate well with intracellular levels. It may occur in up to 65% of critic ally ill patients, and has been associated with an increased mor- tality. Causes \200 \200 Inadequate intake: malnutrition, alcoholism Excess GI losses: NG tube, small intestine dise ase, mal- absorption, diarrhea Renal loss: aminoglycosides, amphotericin, dopamine, diureti cs Chelation: citrate in blood transfusion Redistribution: refeeding syndrome, catecholamin es. Hypocalcaemia Falsely low plasma calcium levels can occur in the pre- sence of hypoalbumina emia, therefore ionized Ca2+ or corrected serum Ca2+should be used. Hypocalcaemia is de \201 ned as a serum calcium <2.0mmol/l or an ionized Ca2+ <1.1mmol/l. Corrected Ca2+(mmol/l ) = measured x [40 \200\223 albumin(g/l)] x 0.02 \200 Clinical features Cardiovascular features of hypomagnesaemia include hypertension, angina a nd arrhythmias (typically torsades de pointes). The neuromuscular signs are of stridor, dys phagia, myoclonus and tetanus. Seizures and coma can also be seen. Hypomagnesaemia is assoc iated with hypokalaemia, and hypocalcaemia Causes \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Septic shock Renal insuf \201 ciency Hypomagnesaemia, hyperphosphataemia Malignancy Pancre atitis Rhabdomyolysis Hypoparathyroidism Pseudohypoparathyroidism Post-parathyroidectomy Vi tamin D de \201 ciency Management Oral or IV supplementation; oral magnesium is poorly tol- erated \200\224GI upse t. IV doses of 8 \200\22364mmol can be used, at a maximum infusion rate of 8mmol/h in asymp tomatic patients. In severe symptomatic hypomagnesaemia, 8mmol can be given over 5min. Smal ler doses may be necessary in renal failure. Hypermagnesaemia Hypermagnesaemia is a plasma concentration >1.05mmol/l. It is usually iatr ogenic. 412 P O NEIL & N WEBSTER Clinical features Neuromuscular features predominate, with paraesthesia, muscle cramps, tet any, laryngospasm and seizures. Cardiovascular features include hypotension, bradycardia an d prolongation of the QT interval. Reduce bone resorption: bisphosphonates will reduce Ca2+ levels over days \200 \200 Tre at underlying disease: parathyroidectomy in hyper- parathyroidism Other treatments: glucoco rticoids, plicamycin, calcitonin and gallium nitrate have been used. Etidronate 7.5mg/kg/day over 4h for 3 \200\2237 days Pamidronate 60 \200\22390mg over 4h Management Chronic hypocalcaemia is treated with oral calcium supplementation. In severe hy pocalcaemia or sympto- matic patients, rapid correction is indicated. This is achieved usin g IV calcium gluconate 10% 10ml (94mg Ca2+) or calcium chloride 10% 10ml (272mg Ca2+) over 10min. It should be remembered that calcium salts are irritant to veins, so should ideally be given through central venous access. Calcium salts can precipitate if infused with sodiu m bicarbonate. Calcium administration to patients on digoxin may cause toxicity, so extra m onitoring is needed. Other considerations are to check and correct hypomag- nesaemia, and t o correct hypocalcaemia prior to correct- ing acidosis. Hyperphosphataemia may occur with h ypocalcaemia, and administration of calcium can lead to precipitation of calcium phosphate in tissues. Therefore, if hyperphosphataemia is present, a phosphate binder should be given . Phosphorus Phosphorus is found predominantly (85 \200\22390%) in the skele- ton. It is a vi tal constituent of ATP, cAMP and 2,3-diphos- phoglycerate. In serum, phosphorus is mostly p resent as phosphate, and normal levels are 0.8 \200\2231.4mmol/l. GI absorp- tion of phosph orus is increased by 1,25-dihydroxycholecal- ciferol. Phosphorus is filtered through glomer uli, and 85 \200\22390% reabsorbed in the proximal tubule. This process is inhibited by par athyroid hormone.