terlipressin (initially 0.5 \200\223 1mg/4 \200\223 6h IVI). Bene \201 ts: d SCr, i UO, i MAP, and improved early survival. Physiological bene \201 ts seen early and often persis t. Repeat courses can be effective. 1 Side effects: ischaemia, e.g. digital, cardiac, mesen tery. Terlipressin is not available in the USA. Noradrenaline (0.5 \200\223 3mg/kg/h) is an alternative. \200 Midodrine (7.5 \200\223 1 2.5mg PO tds), a selective A 1 agonist, may be given in combination with the somatostatin a nalog octreotide (100 \200\223 200 micrograms SC tds). Aim to i MAP by 15mmHg. Bene \201 ts include improved survival although probably less effective than vasopressin analogs. MANAGEMENT OF HRS 159 Transjugular intrahepatic portosystemic shunts (TIPS) may improve SCr in selected patients (esp. those with refractory ascites and variceal bleeding). Howeve r, there is a 5% incidence of de novo AKI post-TIPS. N-acetylcysteine may have additional bene \201 ts and remains under study. Renal replacement therapy \200 1 RRT does not improve outcome in HRS and should be viewed as a bridge to liver transplantation in this context. 2 However, AKI in a cirrhotic patient is not always s to HRS and may 6 be reversible. Dialy sis treatment should not be withheld in these circumstances. Standard indications apply ( b p. 172), although volume overload is the usual precipitant in this group. Continuous RRT techniques ( b p. 174) may be better tolerated (less haemodynamic instability, slower correction of d Na + , and less \202 uctuation in intracranial pressure) than intermittent HD. It has been hoped that arti \201 cial hepatic assist devices can be developed, following t he same general principles as dialysis for renal failure; for exam- ple, the molecular adso rbent recirculating system (MARS) is an extracor- poreal technique in which dialysate is ci rculated through charcoal and anion exchanger columns (removing potential HRS mediators, e. g. TNF, IL-6, and NO). Unfortunately, the diverse metabolic functions of the liver have pro ved dif \201 cult to replicate, and results have been disappointing. Technologies under cu rrent development are based on the use of various hepatocyte cell lines to deliver syntheti c liver capacity. Liver transplantation The most (only?) effective therapy of HRS, although many patients die before transplantation is possible. Organ allocation differs between countries, but, in ma ny scoring systems (e.g. MELD), HRS patients are afforded high priority. 7 40% patients admitted for liver transplantation have AKI by RIFLE criteria, and 7 70% dev elop AKI post-operatively (the majority of these will require renal replacement therapy). improves outcomes post-transplantation, although patients with pre-transplant renal impairm ent have d long-term survival, compared with those with a normal GFR. Treatment of HRS pre-transplantation Most patients will have improved renal function after they have recov- ered from surgery, a lthough the majority do not regain a normal GFR ( 7 10% incidence of ESRD at 11 years). Combined liver kidney transplantation is an option in selected patients. CHAPTER 2 Acute kidney injury (AKI) 160 Tumor lysis syndrome Tumor lysis syndrome (TLS) usually occurs at initiation of treatment ( chemo- or radiotherapy, or even corticosteroids) of lymphoproliferative (and, less commonly , solid) malignancies but may occur spontaneously, with a large tumor burden, or at later s tages of treatment. Classically, it is a complication after chemotherapy for high-blast cou nt acute lymphocytic leukaemias, lymphoma, myeloma, or germ cell tumors. It results from treatment-induced necrosis of large numbers of purine-rich (actively prolif erating) malignant cells, with intracellular and membrane products released abruptly into t he circulation. Uric acid, in particular, causes AKI. (See Table 2.10.) Table 2.10 Criteria for laboratory and clinical diagnosis The Cairo \200\223Bishop de \201 nition (2004) \211 476 mol/L (8mg/dL) or 25% increase Uric acid \211 6.0mmol/L or 25% increase Potassium \211 1.45mmol/L or 25% increase Phosphate Calcium <1.75mmol/L or 25% decrease \211 2 of these features between 3 days pre- and 7 days post-tumor treatment encompasses the laboratory de \201 nition. A clinical diagnosis of TLS can be made if AKI, arrhythmias, or seizures occur in conjuncti on with the laboratory features. Cairo MS, Bishop M (2004). British Journal of Hematology , 127 (1), 3 \200\223 11. Acute uric acid nephropathy Uric acid is freely \201 ltered and, in excess, precipitates in the tubular lumen to form obstructing crystalline casts. This is more likely in volume-d eplete patients with low urinary \202 ow rates or if u-pH d . Clinical \201 ndings In the context of recent cancer therapy, symptoms and signs are due to electrolyte abnormalities ( 3 i K + and dysrhythmias) and AKI. TLS usu- ally occurs with in 24 \200\223 48h of treatment. Nausea, vomiting, anorexia, mus- cle cramps, and \202 a nk pain may also be present. Investigations Measure the following pre- and 4 \200\223 6h post-therapy and serially 6 \200\223 12h. \200 i K + : often rapid i to >7mmol/L. \200 i PO 4 and d Ca 2+ : phospha te avidly binds calcium, precipitating hypocalcaemia and calcium phosphate deposition in the vasculature, myocardium, and kidney. d Mg 2+ . \200 i uric acid: purine nucleotides are metabolized to hypoxanthine, xanthine, and then uric acid, often rising to >1000 mol/L ( 18mg/dL). i SCr. \200 i LDH. \200 Urinary urate measurement and microscopy for crystals rarely ne eded. tumor LYSIS SYNDROME 161 Prevention \200 Identify at-risk patients. Algorithms to assist this risk assessment have been developed. These are based on tumor type, disease burden, and presence or absence of r enal impairment. They stratify patients to low, intermediate, or high risk. Local protocols may vary. Pre-hydration: 0.9% NaCl or glucose saline 2 \200\223 3L/m 2 ( 7 4 \200\223 5L/d) for 48h pre- and post-therapy. Aim for UO >3L/d (preferably >2mL/kg/h). 1 Beware volume overload i f renal or cardiac impairment. Diuretics may be used cautiously to maintain urine \202 ow unless persistent hypovolaemia. Prevent uric acid formation: If risk low to moderate: allopurinol PO 100mg/m 2 8-hourly (max 800mg/d) from 2 days prior to therapy ( 1 reduce dose by 50% if renal impairment). Inhibits xanthine oxidase and preve nts the metabolism of hypoxanthine to xanthine (and then uric acid and its salt urate). IV allopurinol is available if oral medication not possible (200 \200\223 400mg/m 2 /day in 1 \200\223 3 divided doses \200\224 maximum 600mg/day). If high-risk for TLS, pre-emptive rasburicase (see below). Treatment of established tumor lysis \200 Laboratory tests every 4 \200\223 6h. Cardiac monitor. Consider ITU transfer. \200 2 Beware i K + . \200 2 Beware d Ca 2+ induced by i PO 4 . Correct i PO 4 \201 rst to avoid systemic calcium phosphate precipitation. Parenteral calcium should only be administered if evidence of neuromuscular instability and then with extreme caution. Continue volume expansion with 0.9% NaCl, and maintain high UO. \200 Continue allopurinol . \200 X Alkalinize the urine: 50mL 8.4% NaHCO 3 in 1L 0.45% NaCl or 5% glucose (dependin g on sodium load and serum Na + ), aiming for u-pH >7.0. i u-pH converts uric acid l more s oluble urate salt, although simply maintaining adequate UO may be as effective. 1 In additi on, alkalosis may promote systemic calcium phosphate deposition (shifts ionized calcium to non-ionized form), so many have abandoned this practice (unless severe concomitant metaboli c acidosis). Rasburicase: A recombinant form of the enzyme urase oxidase that occurs in most species but not higher primates. \200 Oxidizes uric acid to soluble allantoin. \200 Rapidly d uric acid levels (within 4h; often to undetectable). \200 Effective at preven ting tumor lysis syndrome. \200 Usually given as 200 micrograms/kg IVI over 30min daily f or 5 \200\223 7 days, although shorter protocols (including single dose) have been developed (it is expensive). 1 Avoid if G6PDH-de \201 cient. No adjustment required in renal impairment. \200 SE: rashes, GI upset, headache. Institute intermittent haemodialysis early if oliguric or uncontrolled electrolyte abnormal ities. Aim for high dialysis clearances with daily treatments. Continuous techniques may be preferred ( b p. 174). CHAPTER 2 Acute kidney injury (AKI) 162 Abdominal compartment syndrome (ACS) Introduction An important cause of AKI in a critical c are setting. Intra-abdominal pressure (IAP) is the pressure enclosed within the abdomen and usually corr elates with BMI. Intra-abdominal hypertension (IAH) is de \201 ned as a persistent IAP of \211 12mmHg (with various grades of severity as IAP rises). Increased IAP l d blood \202 ow to abdominal viscera l organ dysfunction. It strongly predicts adverse outcomes in critically ill patients. Abdominal compartment syndrome (ACS) describes the syndrome of organ (including renal) dysf unction s to IAH. It is most often seen in an HDU/ICU setting where it may be dif \201 cul t to diagnose amongst the com- plications of a primary disease. Causes \200 p ACS: disease/injury within the abdomen (e.g. trauma, surgery, ascites, bowel distension, intraperitoneal bleeding, liver transplantation, retroperitoneal disease \200\224 including AAA, pancreatitis). s ACS: disease/injury outside the abdomen (e.g. sepsis, burns, aggressive \202 uid resuscitation). Estimates of prevalence vary widely, e.g. 1 \200\223 15% in the context of traumatic injur y. Consequences \200 ACS can affect virtually organ system: CV: d venous return l reduced cardiac output. \200 Respiratory: d chest compliance l resp iratory compromise and i infection. GI: d mesenteric blood \202 ow l bowel ischaemia. Venous congestion l gut oedema. Bacterial translocation l sepsis. Liver dysfunction l lactic acidosis. Renal \200 Renal vein compression l venous congestion. \200 d cardiac output l SNS and RAS activation l renal vasoconstriction. Both of these l d RBF l glomerular perfusion l oliguria l AKI. Clinical presentation Abdominal pain, tenderness, bloating and distension, breathlessness ( or i ventilatory requirements), i pulse, d BP, i JVP, d UO, peripheral oedema, lactic acido sis. Diagnosis Diagnosis requires recognition of at-risk patients and situations with appropriat e measurement of the IAP. ABDOMINAL COMPARTMENT SYNDROME (ACS) 163 IAP can be measured indirectly, using intra-gastric, intra-colonic, IVC, or intra-vesical ( most common) catheters. The World Society of the Abdominal Compartment Syndrome recommends the latter (see Fig. 2.15). Commercial devices are available, although a pressure trans- du cer connected to a standard Foley catheter is often used. Imaging is non-diagnostic. Management \200 Supportive care 9 surgical decompression: Supportive care: adequate analgesia, sedation, and muscle paralysis (with ventilatory suppo rt); consider NG and rectal decompression; accurate \202 uid management; nurse in supine position. Surgical decompression: early intervention as IAP rises (and prior to development of ACS) i s increasingly advocated. The most common technique is midline decompression, leaving an op en abdomen. Patients should be screened for IAH/ACS risk factors upon ICU admission and with new or pro gressive organ failure. \200 If two or more risk factors are present, a baseline IAP meas urement should be obtained \200 If IAH is present, serial IAP measurements should be perf ormed throughout the patient \200\231s critical illness. Risk factors for IAH/ACS 1. Diminished abdominal wall compliance \200 Acute respiratory f ailure, especially with Patients has TWO or more risk factors for IAH/ACS upon either ICU admission or in the prese nce of new or progressive organ failure elevated intrathoracic pressure Abdominal surgery with primary fascial or tight closure Major trauma/burns \200 Prone positioning, head of bed >30 degrees \200 High body mass index (BMI), central obesity Measure patient \200\231s IAP to establish baseline pressure 2. Increased intra-luminal contents \200 Gastroparesis \200 Ileus \200 Colonic pseudo -obstruction IAP measurement should be: 1. Expressed in mmHg (1mmHg = 1.36cmH O) 2. Measured at end-expiration 3. Performed in the supine position 4. Zeroed at the iliac crest in the mid-axillary line 5. Performed with an instillation volume of no greater than 25mL of saline (1mL/kg for children up to 20kg) (for bladder technique) 6. Measured 30 \200\22360 seconds after instillation to allow for bladd er detrusor muscle relaxation (for bladder technique) 7. Measured in the absence of active abdominal muscle contractions 3. Increased abdominal contents \200 Haemoperitoneum/pneumoperitoneum \200 Ascites/live r dysfunction 4. Capillary leak/fluid resuscitation \200 Acidosis (pH <7.2) \200 Hypotension \200 H ypothermia (core temperature <33 C) \200 Polytransfusion (>10 units of blood/24 hours) \200 Coagulopathy (platelets <55,000/mm3 OR Prothrombin time (PT) >15 seconds OR partial thromboplastin time (PTT) >2 times normal OR i nternational standardized ratio (INR) >1.5) Sustained IAP \211 12mmHg? Massive fluid resuscitation (>5L/24 hours) \200 Pancreatitis \200 Oliguria \200 Sepsi s \200 Major trauma/burns \200 Damage control laparotomy YES NO Patient does not have IAH Patients has IAH IAH grading IAP 12 \200\22315mmHg IAP 16 \200\22320mmHg IAP 21 \200\22325mmHg IAP \211 25mmHg Grade I Grade II Grade III Grade IV Notify patient \200\231s doctor of elevated IAP. Proceed to IAH/ACS management algorithm. Observe patient. Recheck IAP if patient deteriorates clinically. Abbreviations IAH - intra-abdominal hypertension ACS - abdominal compartment cyndrome IAP - intra-abdomin al pressure. Fig. 2.15 IAH assessment algorithm. Used with the kind permission of the World Society of t he Abdominal Compartment Syndrome. M http://www.wsacs.org CHAPTER 2 Acute kidney injury (AKI) 164 AKI in the developing world Introduction The etiology (and 6 presentation) of AKI may be di fferent from that seen in developed countries, particularly in more rural areas. This may v ary down to a regional level, depending on socio-economic and environmental factors. Howeve r, basic pathophysiological and management principles still apply. Epidemiology Cases are underreported, so accurate epidemiological data are scarce. However, community-acquired AKI is more common (estimate 7 150 pmp) and affects a younger age group (mean age 37 in one study from south- ern India). Mortality rates are also higher and more dependent on local resources. There may be less access to RRT in some areas, with peritone al dialysis more commonly employed for this purpose ( b p. 188). Overall, \200\230medical \200\231 causes of AKI, such as sepsis, predominate; how- ever, cases related to surgery are rising, as increasing numbers of pro- cedures are undertaken i n older, more comorbid patients. Fortunately, obstetric-associated AKI is in fairly rapid d ecline in most areas. Causes Infective causes of AKI \200 Diarrhoeal disease: Common cause of pre-renal AKI and ATN (and HUS \200\224 see further in list). Children with diarrhea are much more susceptible to AKI (diarrhea causes 7 50% of dialysis-requiring AKI in Indian children). Viral causes: rotavirus and Norwalk agent. \200 Bacterial causes: E. coli , Shigella spp. , Salmonella enteritides, Vibrio cholera , Campylobacter jejuni , Pseudomonas aeruginosa , Klebsiella pneumoniae. Treatment is supportive ( l directed at \202 uid and electrolyte imbalances) 9 antimicrobials for speci \201 c infections. Diarrhea-associated (D+) haemolytic uraemic syndrome ( b p. 578) is common in pediatric practice internationally. It is most commonly associated with Shigella dysenteriae serotype 1 but has many other precipitants. Malaria ( b p. 702). \200 Leptospirosis: Leptospira interrogans is a spirochaete that infects many mammalian species and is shed in urine. Illness classically follows a biphasic course, with an initial febrile illness, followed by more fulminant disease with liver involvement. AKI occurs in 7 50% of severe cases. \200 Associated AKI may be pre-renal/ATN, but an int erstitial nephritis (with marked urinary K + wasting) is also common. Diagnose with serology (late) or antigen detection via PCR (early). \200 Treatment is sup portive, plus penicillin, doxycycline, or 3rd-generation cephalosporin (e.g. ceftriaxone). AKI IN THE DEVELOPING WORLD 165 HIV ( b p. 676): AKI usually s to HIV-associated infection or HAART-related nephrotoxicity, but many other r enal lesions are recognized. Melioidosis: Organism: Burkholderia pseudomallei . \200 Area: South East Asia and Northern Australia. \200 Illness: pneumonia, visceral and cutaneous micro-abscesses, septicaemia. AKI in >50%. Renal micro-abscesses are common. Viral haemorrhagic fevers: Severe multisystem illnesses (including Dengue, Yellow, Ebola, Marburg, and Lassa fever) ca used by 12 RNA viruses from four families ( \202 avi-, arena-, bunya-, and \201 lovirus) . Haemodynamic instability and increased vascular permeability l ATN. Also rhabdomyolysis. Proteinuria is common. Hantavirus is discussed on b p. 73. Non-infective causes \200 Herbal or traditional medicines are a common part of healthcare in many developing countries ( b p. 901). Surgical AKI: Incidence steadily increasing with the growth of surgical specialties and facilities across the globe. Includes perioperative AKI and post-operative complications. Trauma. \200 Obstructive uropathy is increasing (ageing population, particularly \231 \202 ). \200 Pregnancy-related AKI is declining, with fewer illegal abortions and better access to good antenatal care. \200 Glucose-6-phosphate de \201 ciency (G6PD): Affects several hundred million people worldwide, mainly in the Mediterranean, Africa, Middle and Far East. Intravascular haemolysis occurs, following signi \201 cant oxidative stress (e.g. infections, drugs). Haemoglobinuric AKI results ( b p. 155). Toxins: Snake bites (e.g. from Elapidae, Viperidae, Colubridae, and Hydrophidae species) cause an astonishing 70% of AKI in Myanmar although much less in India (3%) and Thailand (1.2%). Venom l haemoglobinuric and myoglobinuric AKI ( b pp. 152 \200 \223155), as well as ATN s to circulatory compromise and DIC (and occasional direct nephrot oxicity). Early administration of anti-venom (monovalent preferable to polyvalent) may prev ent renal injury. Scorpion, spider, centipede, and jelly \201 sh bites or stings. \200 Mushroom ingestion (of Amanita , Galerina , and Cortinarius genera), associated with liver and renal failure in severe cases. Chemicals: The incidences of AKI s to poisoning with copper sulfate (leather industry), formic acid (r ubber industry), and paraquat (agriculture) are now falling. CHAPTER 2 Acute kidney injury (AKI) 166 AKI in sepsis What is the sepsis syndrome? Sepsis accounts for 2% of all hospital admission s but 25% of admissions to ITU. AKI is a frequent complication of the sepsis syndrome, incr easing in incidence as the severity of sepsis increases. Patients whose renal failure is se psis-related have a mortality of up to 75%. With sepsis, there is evidence of (usually loca l) infection, with systemic signs of in \202 ammation ( i temp, i HR). This progresses to the sepsis syndrome if organ dysfunction ensues \200\224 typically, confusion, oliguria, h ypoxia, and acidosis. Full-blown septic shock implies hypotension, despite adequate volume resuscitation, with signs of organ dysfunction. Causes of signi \201 cant sepsis \200 Gram +ve organisms: Staphylococci (incl. S. aureus , MRSA, and S. epidermidis ) 20 \200\223 35%. \200 Strept ococcus pneumoniae 10%. \200 Other Gram +ve 10 \200\223 20%. Gram \200\223 ve organisms: \200 E. coli 10 \200\223 25%. \200 Other Gram \200\223 v e (commonly Pseudomonas ) 5 \200\223 20%. Others: Fungi ( Candida ) 3%, viruses 3%, parasites (malaria) 1 \200\223 2%. How sepsis becomes shock Engulfed pathogens are lysed, liberating membrane products (includ ing lipopolysaccharide (LPS) and exotoxin), proteins, and DNA. These frag- ments are recogn ized by speci \201 c cellular receptors (Toll-like receptors) which l NF -B-dependent c ell activation. Activated cells then release proin \202 ammatory mediators (e.g. IL-1, TNF, IFN), stimulating local and systemic host defense networks. Systemically activated leucocytes now orchestrate the immune response, with local leucocyte recruitment into in \202 amed tissue encouraged. At the same time, anti-in \202 ammatory and resolution pathways (nega- tive feedback) are induced; inappropriate regulation of these pathways often leads to a deleterious prolongati on of systemic in \202 ammation. Within in \202 amed tissue, and eventually systemically, the endothelium upregulates cellu lar adhesion molecules and tissue factors to encourage recruitment of effector cells. Induc ible nitric oxide synthase generates large quantities of NO, and the integrity of intracell ular tight junctions is compromised. The consequences are reduced microvascular \202 ow and mitochondrial dysfunction, leading to organ failure. AKI IN SEPSIS 167 Clinically, this translates into \200 d systemic vascular resistance (NO is a potent vaso dilator and renders angiotensin II and adrenaline less ef \201 cacious). \200 i capillary leakiness (tight j unctions impaired). \200 Local tissue injury (neutrophil recruitment with elastase releas e and oxidant burst). i sympathetic activity. \200 RAS activation: A2 l vasoconstriction. \200 Aldosterone l Na + retention ( b pp. 456 \200\2237). Non-osmotic ADH (vasopressin) release l vasoconstriction. \200 Vascular smooth muscle bec omes less sensitive to vasoconstrictors, so, despite high circulating levels of adrenaline, angiotensin, and endothelin, the circulation remains (maximally) vasodilated. The kidney in sepsis \200 Noradrenaline l afferent arteriolar vasoconstriction l d transglomerular perfusion pressure l d GFR and Na + retention. \200 i systemic NO l downr egulation of intrarenal NO production l further d RBF (particularly in the metabolically vu lnerable outer medulla). In \202 ammatory cells produce oxidants and proteases that injure renal endothelium (remem ber 20% of cardiac output is to the kidney) l local coagulopathy with intra-glomerular thro mbus formation l d capillary blood \202 ow. The end result is d O 2 delivery and ATN ( b p. 108). Vasopressor therapy \200 Treatment with noradrenaline (NADR) acts to counteract the generalized vasodilation and sepsis associated d SVR. However, NADR may d RBF through the mechanism just described, thus potentiating AKI. In fact, available studies suggest that NADR affects renal outcome differently, depending o n whether d RBF is s to sepsis-induced vasodilation or hypovolaemia. \200 In sepsis, NADR has a greater effect on arteriolar resistance and can normalize renal vascular resistance, maintaining transglomerular perfusion pressure. NADR l i SVR l d renal sympathetic tone l i renal perfusion. \200 The key point is that \200\230adequate \200\231 \202 uid resuscitation must take place before (or at least sim ultaneously with) vasopressor administration. CHAPTER 2 Acute kidney injury (AKI) 168 Managing septic shock and AKI De \201 nitions Systemic in \202 ammatory response syndrome (SIRS) \200 Temperature >38.5 or <36.0 . \200 HR >90. \200 RR >20, pCO 2 <4.2kPa, or the need for ventilation. \200 WCC >12 or <4 (or blasts >10%). Sepsis \200\224SIRS and: \200 Positive cultures or focus of infection identi \201 ed (e. g. cellulitis/ pneumonic changes on CXR). Severe sepsis \200\224sepsis + one of: \200 Skin mottling. \200 Capillary re \201 ll \211 3s. \200 UO <0.5mL/kg/h or the need for dialysis. \200 Lactate >2mmol/L. \200 A ltered mental status (or abnormal EEG). \200 Plt <100 or DIC. \200 Acute lung injury (A RDS). \200 Impaired cardiac function. Shock \200\224severe sepsis + one of: \200 MAP <60 (80 if known hypertensive) after 40 \200\223 60mL/kg 0.9% NaCl or 20 \200\223 30mL/kg colloid, i.e. does not respond to volume resuscitation. Calculating MAP Mean arterial pressure is expressed as: DBP + (SBP \200\223 DBP)/3. Septic shock bundle 3 Start immediately, and complete within 6h. Resuscitation of these pat ients should be subject to a locally agreed protocol that can be initiated as soon as these patients are identi \201 ed. \200 Antimicrobial therapy: 3 Culture blood and other sites, and institute broad-spectrum antibiotics within 1h. Antiviral and antifungal cover may be necessary, depending on the clinical scenario. Reassess antimicrobial regimen daily. \200 Further diagnostic measures should not delay r esuscitation. Image possible sites of infection as early as possible. Consider surgical tre atment of localized source. In the event of d BP and/or lactate >4mmol/L, administer a minimum bolus of 30mL/kg of crystalloid within 1h. Apply vasopressors for d BP unresponsive to initial \202 uid resuscitation. Aim to maintain MAP \211 65mmHg. MANAGING SEPTIC SHOCK AND AKI 169 If persistent d BP, despite volume resuscitation (septic shock), and/or initial lactate >4m mol/L, consider invasive monitoring ( b p. 13). \200 Aim for CVP >8mmHg and central venou s oxygen saturation (ScvO 2 ) of >70%. If ScvO 2 70% (or SvO 2 equivalent of 65%) persists, despite adequate \202 uid resuscitat ion, then consider transfusion of packed red blood cells to achieve a haematocrit of 30% 9 dobutamine infusion (to a maximum of 20 micrograms/kg/min). During the \201 rst 6h of resuscitation, the goals include all of the following: \200 CVP >8mmHg. \200 MAP \211 65mmHg. \200 UO \211 0.5mL/kg/h. \200 Central venous (superior vena cava) oxygen saturation \211 70% (or mixed venous oxygen saturation \211 65%). Aim to normalize serum lactate (a marker of tissue hypoperfusion) as quickly as possible. Fluid therapy: Give an initial \202 uid challenge of \211 1000mL crystalloids (to achieve a minimum of 30mL/kg in the \201 rst 4 \200\223 6h). More rapid administration and larger amounts of \202 uid may be necessary in some patients. Continue incremental \202 uid boluses as long as there is haemodynamic improvement, as evidenced by either dynamic (e.g. stroke volume variation) or static (e.g. CO, BP, heart rate) variables. Consider adding albumin to the initial \202 uid resuscitation regimen if serum albumin is low. Avoid sodium bicarbonate therapy for the correction of hypoperfusion-induced lactic acidaem ia with pH \211 7.15. Vasopressor therapy: Use vasopressor therapy to target an initial MAP of \211 65mmHg. \200 Noradrenaline is \201 rst-line. \200 Adrenaline can be added or substituted if an additional agent is required to maintain BP. Vasopressin (0.03 units/min) can also be added to, or substituted for, noradrenaline. Dopamine is an alternative to noradrenaline in selected patients at low risk of arrhythmias who have low CO 9 low heart rate. Do not use low-dose dopamine for \200\230renal protecti on \200\231 . Consider early placement of an arterial catheter in all patients receiving vasopressor therapy. Inotropic therapy: Add dobutamine to vasopressor therapy (if administered) in the presence of: (i) myocardial dysfunction (as suggested by elevated cardiac \201 lling pressures and low CO); or (ii) o ngoing signs of hypoperfusion despite adequate intravascular volume and MAP. Corticosteroids: If patients require persistent high doses of vasopressors for maintenance of adequate BP despite adequate \202 uid resuscitation. CHAPTER 2 Acute kidney injury (AKI) 170 Consider a continuous infusion of IV hydrocortisone (200 \200\223 300mg daily \200\224 no higher) for a minimum of 5 days. Do not base the need for corticosteroid therapy on ACTH stimulation testing. Hydrocortisone is now recommended alone, rather than in combination with \202 udrocortisone. Blood product administration: Transfuse to maintain Hb >7.0g/dL. \200 Do not administer FFP to correct laboratory clott ing abnormalities unless bleeding or planned invasive procedures. Antithrombin administration is no longer recommended in the treatment of severe sepsis. Consider platelet administration if: \200\224 Counts are <5000/mm 3 (5 x 10 9 /L), regardless of bleeding. \200\224 Counts are 5000 \200\223 30,000/mm 3 (5 \200\223 30 x 10 9 /L) and bleeding risk. \200\224 Surgery or invasive procedures is required: counts \211 50,000/mm 3 (50 x 10 9 /L) are recommended. Glucose control: Hyperglycaemia impairs leucocyte function 9 less well-understood effects. Commence insulin when two consecutive blood glucose levels are \211 10mmol/L (180mg/dL), and aim to keep blood glucose levels \211 10mmol/L. All patients receiving IV insulin should receive a glucose calorie source. Blood glucose values should be monitored every 1 \200\223 2h until glucose values and infusion rates have stabilized and then at least every 4h ( 1 point-of-c are testing of capillary blood should be interpreted with caution, as they may overestimate plasma glucose concentration). Renal priorities in the ITU \200 Maintain independent renal function, if possible. \200 No convincing data to suggest any particular volume expander or vasopressor is better or w orse for the kidneys, although balanced crystalloid solutions are increasingly recommended (hydroxyethylstarch has also previously been implicated in i AKI). Avoid renoprotective strategies that lack an evidence base, e.g. low-dose dopamine is NOT recommended ( b p. 144). X There is no measurable superiority of either intermittent HD (IHD) or CVVHDF, including o utcomes for renal recovery, in critically ill AKI patients, although management of \202 u id balance is often easier with continuous therapies. X \200\230High-dose \200\231 CVVHF (aiming for an UF rate of 45mL/kg/min over 25mL/kg/min) does not demonstrably improve outcomes. \200 X A larger delivered IHD dose ( e.g. daily treatment) may not improve outcomes but may have bene \201 ts over thrice weekly HD in terms of \202 uid an d electrolyte management. MANAGING SEPTIC SHOCK AND AKI 171 CHAPTER 2 Acute kidney injury (AKI) 172 Renal replacement therapy in AKI Introduction X Opinions differ regarding indications, timi ng, what technique to use, what \200\230dose \200\231 to give, and when to stop. Indications Since evidence is currently lacking, it is principally a matter for clinical ju dgment, based on the patient s clinical condition, trends in laboratory tests, and the pote ntial for swift recovery of renal function. The indications are distinct from those applied to CKD. In general, the clinician must care fully consider what goals they want to achieve with RRT in an individual patient with AKI. Absolute indications \200 3 Hyperkalaemia: There is no universally agreed K + concentration. A helpful rule: consider urgent dialysis if K + \211 6.5mmol/L or rapidly rising, regardless of ECG changes (particularly if not responding to other interventions, such as insulin and glucos e). 3 Volume overload: Pulmonary oedema in an oligo-anuric patient with an inadequate response to diuretics. Volume status is an important determinant of outcome in AKI and should be afforded a high priority in this setting. The remaining indications for dialysis are urgent , rather than emergent. This can be an im portant distinction \200\224 depending on local resources, it may be preferable to delay d ialysis and perform it as a planned daytime procedure under adequate supervision and with m ultidisciplinary support. When to start RRT \200 There is limited evidence to support an earlier start to RRT in AK I, e.g. at lower values of urea (<25 \200\223 30mmol/L or 70 \200\22385mg/dL), the onset o f oliguria, and certainly well before \200\230classical \200\231 indications supervene. However, the bene \201 ts of this practice (in terms of survival, duration of AKI, and renal recovery) are not clear-cut. Clinicians have a general tendency, perhaps extrapolated from their CKD care, to wait as long as possible before dialysis initiation. \200 The recent KDIGO g uidelines sensibly recommend a pragmatic approach and to \200\230consider the broader clinical context, the presence of conditions that can be modi \201 ed with RRT, and trends of laboratory tests \200\224 rather than si ngle Ur or SCr thresholds alone \200\231 . RENAL REPLACEMENT THERAPY IN AKI 173 Relative indications \200 Acidosis (pH <7.2), especially if haemodynamically unstable, or where volume overload precludes IV bicarbonate administration. \200 There is evidence tha t myocardial enzymes are dysfunctional with pH <7.2 l higher risk of arrhythmia. Critically unwell patients (usually in an HDU/ITU setting): To maintain \202 uid balance and allow safer administration of \202 uid, feeding, blood and blood products, antimicrobials, and drugs. Uraemic complications: Rare for these to be a signi \201 cant factor in AKI. If you are waiting for these before initiating dialysis, then you are waiting too long! Uraemic pericarditis or encephalopathy. \200 Uraemic symptoms, especially once Ur >40mmol /L (112mg/dL) ( 1 there is no absolute \201 gure that equates with \200\230uraemia \200 \231 , and there is considerable interpatient variation in \200\230biochemical tolerabilit y \200\231 ). Diuretic-resistant cardiac failure. \200 Poison or toxin removal (lithium, ethylene glyco l, etc.) ( b p. 906). \200 Hyperthermia. Why delay RRT \200\224the potential complications \200 Complications of dialysis access i nsertion ( b p. 180). \200 Haemodynamic strain or overt hypotension in an already sick pa tient ( X which may then perpetuate AKI). Electrolyte imbalances, e.g. rapid reduction of K + ( 1 l arrhythmias). \200 Complication s of anticoagulation ( b p. 182). \200 Dialysis disequilibrium ( b p. 177). When to stop RRT \200 Requires regular (at least daily) assessment. \200 Average durati on of RRT in AKI is 7 12 days. \200 Assessment of underlying renal function during RRT ca n be dif \201 cult. It is often particularly uncertain for intermittent haemodialysis (IHD ) where variable rebound in Ur, SCr, and electrolytes may occur between treatments. An increase in urine output is particularly helpful, although the use of diuretics will need to be factored in (routine administration of diuretics to i UO and faci litate earlier cessation of RRT is not recommended). Trends in SCr, Ur, and electrolytes need to be carefully considered (and allowance made for non-renal confounding factors, such as the patient s catabolic state and volume status). Theoretically, serial measurements of urinary Cr excretion might be helpful but are very rarely undertaken in practice. Cessation of RRT does not have to be an absolute. It might be prudent to initially adjust the duration and frequency of treatment or to consider a modality chang e (e.g. step down from CRRT on ITU to IHD on a renal unit). On occasion, particularly in a critical care setting, more fundamental issues concerning th e futility of further treatment will need to be included in the decision-making. CHAPTER 2 Acute kidney injury (AKI) 174 RRT in AKI: modalities Introduction The ideal modality of RRT in AKI is unknown. In practic e, the choice will be based primarily upon: (i) the availability of different treatments an d (ii) a patient s haemodynamic status and overall clinical condition. PD use in AKI is inf requent, except in pediatric practice and in areas where resources are constrained ( b p. 1 88). The treatments are not mutually exclusive, with changes between them dictated by clini cal circumstances. Modalities Generally, intermittent haemodialysis (IHD) is preferred on renal units whilst c ontinuous techniques (CRRT), such as continuous veno-veno hae- mo \201 ltration (CVVHF), c ontinuous veno-venous haemodialysis (CVVHD), continuous veno-veno haemodia \201 ltration ( CVVHDF), and sustained low-ef \201 ciency dialysis (SLED), are more often encountered in h igh dependency and critical care environments. Intermittent haemodialysis (IHD) (see Fig. 2.16 ) \200 Solute clearance mainly by diffusi on across semi-permeable membrane. \200 Pores in the membrane allow small molecules (e.g. Ur (MW = 60Da), Cr (113Da)) and electrolytes but not larger ones (e.g. plasma proteins (al bumin 60,000Da, IgG 140,000Da) or blood cells) to pass through. Dialysate (physiological solution of electrolytes) is required. \200 Concentration differ ences across the membrane allow molecules to diffuse down a gradient. This allows waste pro ducts to be removed and desirable molecules or ions (e.g. HCO 3 \200\223 ) to be replaced. \200 Diffusion is maximized by maintaining high- \202 ow rates of blood and dialysate a nd by pumping the two through the dialyser in countercurrent or opposite directions. Usually administered intermittently (e.g. 4h, 3 x /week), although the delivery in AKI may differ from this ( b see chapter 4). Water can be driven through the membrane by hydrostatic force (ultra \201 ltration or UF). The pressure gradient across the membrane (transmembrane pres sure or TMP) can be controlled to vary the amount of water removed (but usually <3 \200 \223 4L in a 4h treatment). Haemo \201 ltration (HF) (see Fig. 2.16 ) \200 Solute clearance by convection (mainly), i.e. \202 uid shifts across the dialysis membrane also allow solutes to cross ( \200\230 solute drag \200\231 ). Achieved by generating a TMP across the membrane. \200 Large volumes need to be \201 lt ered to achieve adequate solute clearance. This would cause hypovolaemia, unless replacement \202 uid is administered \200\224 usually pre-prepared 5 \200\223 10L bags (during IHD, HF is used to remove \202 uid that has accumulated between treatments 6 no \202 uid replacement is necessary). No dialysate is required. Removes larger MW (30 \200\223 50kDa) molecules (e.g. vitamin B12 and B 2 microglobulin) m ore ef \201 ciently than dialysis. X May also remove pro- (and anti-) in \202 ammatory cy tokines. Delivered as a continuous, rather than intermittent, technique. RRT IN AKI: MODALITIES 175 IHD modi \201 cations (e.g. SLED) \200 This essentially refers to treatments using stand ard dialysis equipment but for a longer treatment than the \200\230traditional \200\231 4h. Both IHD and CRRT machines can be adapted easily for this purpose. \200 Sustained low-ef \201 ciency dialysis (SLED) uses extended (e.g. 6 \200\223 12h) treatments with blood and dialysate \202 ows of between 100 \200\223 300mL/min. The aim of SLED is to improve tolerability over IHD. \200 The \200\230low-ef \201 cienc y \200\231 tag is misleading \200\224 it is often commendably ef \201 cient. Hemofiltration Hemodialysis Predilution replacement fluid blood flow blood flow effluent dialyzate Mid-dilution replacement fluid filtrate fresh dialyzate blood flow blood flow Postdilution replacement fluid Convective blood purification Diffusive blood purification