Intra-renal ischemia Cardiogenic shock Systemic sepsis Hepatorenal failure Anaphlyactic sho ck Nephrotic syndrome Abdominal compartment syndrome Page kidney Renal vein thombosis Drugs COX-1 and -2 inhibitors \200 ACEIs and ARBs \200 Calcineurin inhibitors However, in cases of established AKI, rapid \202 uid administra- tion may well result in pulmonary edema. Review of clinical \202 uid balance charts and daily weights aids assess ment along with history of \202 uid losses and reduced \202 uid intake. Young patients can compensate for volume depletion to a far greater extent than the elderly, and may well maintain a \200\230normal \200\231 brachial arterial pressure with no demonstrable postura l hypotension. However, the pulse pressure may be narrowed due to increased sympathetic ner vous activity. CHAPTER 10.1 Clinical approach to acute kidney injury 321 Table 10.1.4 Causes of intrinsic AKI Table 10.1.5 Causes of post-renal (obstructive) AKI Small vessel vascular disease Occlusion Intrinsic Intraluminal \200 Calculus \200 Blood clot \200 Sloughed papilla Cholesterol emboli \200 Cryoglobulinemia \200 HUS/TTP \200 DIC \200 Plasmodium mala ria \200 Sickle cell crisis \200 Eclampsia Intramural \200 Ureteric malignancy \200 Ureteric stricture (TB) \200 Post-irradiatio n \201 brosis \200 Bladder cancer \200 Prostatic hypertrophy Vasculitis Microscopic polyangiitis Wegeners granulomatosis Extrinsic Extramural SLE \200 Henoch \200\223Sch nlein purpura \200 Hyperacute renal transplant rejection Retroperitoneal \201 brosis \200 Pelvic malignancy \200 Ureteric ligation Hypertension Malignant hypertension \200 Scleroderma Acute glomerulonephritis Crescentic rapidly progressive GN density >10% suggests that the patient will be preload responsive). Volume loading in patie nts with CVP >12 mmHg is unlikely to increase cardiac output. During mechanical ventilation , the variation in cardiac stroke volume, or \201 nger pulse pressure variability during the venti- latory cycle, can also predict preload responsiveness. In patients predicited to be volume responsive, a \202 uid bolus of 2 mL/kg of colloid or 3 mL/kg of crystalloid o ver 10 min should be given, and then the patient should be reassessed. Anti-GBM disease \200 Postinfectious GN \200 Idiopathic Interstitial nephritis Drug-ass ociated \200 Antibiotics \200 NSAIDs Post-infection Leptospirosis \200 Epstein \200\223Barr virus Drug toxicity Aminoglycosides \200 Tenovir Investigations All patients should have urine stick testing performed to detect blood, prot ein, glucose and nitrites. Depending upon the history and physical examination other invest iga- tions may be required (Table 10.1.7). Toxins Radiocontrast media \200 Myoglobin \200 Hemolysis \200 Myeloma/light chains \200 Sn ake/spider venom Urinary electrolytes Urinary electrolytes may be helpful in determining those patients with reversible prerenal AKI. Heavy metals \200 Cisplatin Spot urinary sodium Urinary sodium excretion can be affected by pre-existing CKD and prior treatment with diuretics. Urinary sodium concentration on a spot urine sample may not be di scriminant if normal or increased, but would suggest possible volume responsive in AKI if: \200 \200 Poisons \200 Plant \200 Drugs \200 Chemical (e.g. ethylene glycol) Crystals \200 Urate \200 Indinavir \200 Oxalate In \201 ltration \200 Sarcoid \200 Lymphoma <10 mmol/L in a healthy young adult; <20 mmol/L in an elderly patient. Importantly, following relief of urinary obstruction, the patient may be intravascularly vo lume-depleted but still have a normal or increased spot urine sodium concentration. Infection Acute pyelonephritis \200 Bacterial infection Spot urine osmolality Spot urine osmolality may be increased in volume respon- sive AKI, bu t is also normally increased in the immediate postsurgical period, due to changes in vasopr essin release and renal free water clearance. Immunological Renal transplant Cellular rejection A. DAVENPORT 322 Hemodynamic (and volume) assessment of the patient with AKI Is the patient hemodynamically stable? YES NO Is patient preload (volume) responsive? monitor YES NO give fluids and reassess Is there reduced vasomotor tone? YES NO add vasopressor and consider further fluid add inotrope Fig. 10.1.4 Clinical approach to volume and vasopressor management in the patient with AKI. After each step, reassess patient. Typical vasopressor: noradrenaline. Typical inotrope: d obutamine. Vasomotor tone typically assessed invasively as SVR (systemic vascular resistanc e). Table 10.1.6 Assessment of tissue perfusion FEUrea <35%. Other causes of a FENa <1% include: \200 \200 \200 Measured variable Desired range cardiac failure; contrast nephropathy; heme pigment nephropathy. Mean arterial blood pressure SVO2 mixed venous oxygenation SCVO2 central venous oxygenation Arterial/venous lactate >65 mmHg >70% sat. (4 \200\2236 kPa) >65% sat. <2 mmol/L(A) or <2.5 mmol/L (V) 2 mmol/L <2 s <100 beats/min The FEUrea is a better discriminant of prerenal AKI than FENa, as even when patients have b een given diuretics the FEUrea will be <35%, whereas the FENa is often >2%. In established AKI, both are elevated. In the hepatorenal syndrome the FEUrea is low, and the urinary sodi um concentration is typically 10 mmol/L. Metabolic acidosis \200\223 base excess Capillary re \201 ll time Tachycardia Novel biomarkers of AKI Traditionally urea and creatinine have been used to assess renal fu nction. However, following AKI, serum creatinine does not increase for some 24 \200\22372 h , and similarly there is a delay between the recovery of residual renal function and a fall in serum creatinine. This has led to the search for other biomarkers to detect AKI at an e arlier stage. For example, cystatin C tends to increase \211 24 h prior to cre- atinine ri ses. Other urinary biomarkers investigated include: \200 neutrophil gelatinase-associated lipocalin; \200 IL-18; \200 kidney injury molecule-1; N-acetyl-B-(D)-glucosinidase. \200 Fractional excretion of sodium and urea To try and improve the diagnostic accuracy of urine biochemistry in AKI, ratios of sodium and urea excretion relative to creatinine have been evaluated. The fractional excretion of sodium (FENa) and fractional excretion of urea (FEUr ea) are useful parameters. FENa = urinary Na \227 plasma Cr \227 100 plasma Na \227 urin ary Cr The normal FENa is >1% and FEUrea is >45%. In those patients with prerenal AKI: \200 FENa <1%; CHAPTER 10.1 Clinical approach to acute kidney injury 323 Table 10.1.7 Investigation Comment Urine Urine stick testing Renal or lower urinary tract in \202 ammation/myoglobin Glomerular or renal tubular protei nuria Urinary infection Urinary infection Red cell casts in glomerulonephritis and vasculit is Oxalate/indinavir/uric acid stones Malignant cells Eosinophiluria in interstitial nephri tis Blood Protein Nitrites Urine culture Microscopy/cytology Biochemistry Serum Urea, creatinine, cystatin C raised in AKI Hyperkalemia and metabolic acidosis Hypocalcemia and hyperphosphatemia in rhabdomyolysis Hypercalcemia in myeloma, sarcoid, malignancy Hypo albuminemia in nephrotic syndrome, cirrhosis Bilirubin raised in liver disease, leptospiros is LDH raised in malignancy and hemolysis CPK raised in rhabdomyloysis, sickle cell crisis Haptoglobins reduced in hemolytic uremic syndrome ACE raised in sarcoid CRP raised in in \202 ammation and sepsis Uric acid raised in tumor lysis syndrome, sickle cell crisis Fract ional excretion of sodium and urea Proteinuria; quantitation: protein/creatinine ratio Urine Hematology Full blood count Eosinophilia in vasculitis, cholesterol emboli Thrombocytopenia in hemolytic uremic syndrom e Red cell fragments in hemolytic uremic syndrome Malaria Disseminated intravascular coagul ation in sepsis, burns, fat embolism, eclampsia, amniotic \202 uid embolism, severe heat stroke, liver failure and neoplasia Blood \201 lm Coagulation studies Immunology Immunoparesis, paraprotein/light chains in myeloma ANA and dsDNA in SLE RhF in cryoglobulim emia ANCA in vasculitis, WG, MPA Proteinase 3 (PR-3) in WG, MPA Myeloperoxidase (MPO) in WG , MPA Antiglomerular basment membrane in Goodpasture \200\231s syndrome Immunoglobulins Autoantibodies Low C3 and/or C4 in SLE Low C4 in cryoglobulinemia Low serum complement activity (CH50) acu te post-streptococcal GN, type II MPGN, subacute bacterial endocarditis, \200\230shunt \200\231 nephritis, and cryoglobulinemia Complement Cryoglobulin in hepatitis C, SLE and lymphoma Cryoglobulins Serum amyloid A protein in AA amyloid Serum amyloid A Bence Jones protein/free light chain in urine in myeloma and AL amyloid Urine free light chain Microbiology Blood Speci \201 c infections Virology Cultures to exclude bacteremia Leptospirosis, legionella, viral hemorrhagic fevers HIV (FSG S, increased risk of prerenal AKI in patients taking HAART) HBV/HVC (cryoglobulinemia and G N, also risk of transmission on hemodialysis) Investigations to consider in the patient with AKI. The investigations required will vary i n individual cases depending upon history and physical examination: systemic lupus erythema tosis (SLE); Wegener \200\231s granulomatosis (WG); membranoproliferative glomerulonephriti s (MPGN); microscopic polyangiitis (MPA); human immunode \201 ciency virus (HIV); hepatiti s B and C viruses (HBV/HCV); glomerulonephritis (GN); HAART (highly active antiretroviral t herapy). A. DAVENPORT 324 Renal vascular imaging Color Doppler USS may be helpful in assessing major renal arterial a nd venous \202 ow, but MRI with contrast may be required. However, gadolinium contrast me dia may occasionally cause nephrogenic \201 brosing dermopathy. In AKI, renal function ma y not be suf \201 cient for nuclear medicine imaging. Occasionally formal renal angiography is required in cases of larger vessel vasculitis, suc h as polyartertis nodosa (Fig. 10.1.5). Indications for renal biopsy Renal biopsy should be performed when the history, examination , or laboratory tests suggest the possibility of an underlying systemic disorder amenable t o speci \201 c treat- ment. It may also be indicated in those cases where there is doubt a s to the cause of AKI (no convincing history or documentation of vasomotor renal injury), w hen renal recovery has been unusually delayed, or when there is the possibility of a second pathology, such as a drug-induced interstitial nephritis. Treatment Speci \201 c measures to reverse AKI Despite years of research, no speci \201 c pharmacological treatment has been proven to prevent or shorten AKI. Loop diuretics and do pamine should not be routinely administered. Patients with prerenal AKI should be appropria tely resusci- tated with \202 uids and/or vasopressors as outlined above. Nephrotoxic dru gs should be discontinued. Renal obstruction and abdominal tamponade should be relieved. Th e abdominal compartment syndrome should be consid- ered in postoperative patients, and in t hose with a distended abdomen. The intra-abdominal pressure (IAP) can be measured by transd ucing the intravesical pressure. A com- partment syndrome is present when the absolute IAP is \211 20 mmHg, or the difference between the mean systemic arterial pressure and the IAP is <60 mmHg. Speci \201 c pharmacological treatments are appropriate in special circumsta nces to prevent or reduce AKI, including rasburicase in tumor lysis syndrome, and fomepizol e in ethylene alcohol poisoning. Mannitol and sodium bicarbo- nate have been advocated in t he management of rhab- domyolysis, but there is no evidence to support any additional benef it from aggressive fluid resuscitation alone. More recently, in the intensive care setting, it has been suggested that strict blood glucose control can reduce the incidence of AKI. P otential nephrotoxins, such as aminoglycosides, should be avoided, and iodine-based contras t studies minimized. If contrast studies are necessary then potential nephrotox- icty shoul d be minimized by using the smallest volume of hypo-osmolar contrast required for the study . There may be an additional bene \201 t of using sodium bicarbonate proph- ylaxis. Recent ly phosphate-containing enemas have been described causing AKI due to acute nephrocalcinosi s. Sepsis should be actively sought and aggressively treated. Fig. 10.1.5 Renal angiogram showing intrarenal aneurysms due to polyarteritis nodosa. Some of these biomarkers can increase within 24 h of AKI, and similarly some have been show n to predict require- ment for dialysis. However, in adult practice these biomark- ers are not as helpful as in pediatric practice, as many adult patients have underlying CKD. Renal imaging Ultrasound Ultrasound scanning (USS) is a key investigation and pro- vides va luable information on renal size and intrarenal echogencity. Small kidneys suggest pre-exis ting CKD. USS can help to exclude obstruction by detecting blad- der, prostate and pelvic pathology, and hydronephrosis. In acute obstruction, the renal pelvis may not have had time to dilate. CT scan CT-KUB (kidney ureters and bladder) scanning without contrast is now used to image renal/ureteric calculi, sloughed papillae. Contrast CT is used to investigate extrinsic obs truction. The risk of contrast nephropathy can be reduced by choos- ing a hypo-osmolar cont rast agent. Preloading the patient with isotonic bicarbonate (3 mL/kg/h for 1 h precontrast , and then 1 mL/kg/h for 6 h post CT scan) may also be bene \201 cial. Nephrostomy and contrast studies In cases of obstruction, it is often easier and quicker to relieve obstruction by antegrade nephrostomy, and then subsequently perform appropriate re trograde investiga- tions, and/or stenting. CHAPTER 10.1 Clinical approach to acute kidney injury 325 Drugs known to potentially reduce renal perfusion, includ- ing as NSAIDs, ACEIs, ARBs and c alcineurin inhibitors should be avoided if at all possible. As calcium does not affect the serum potassium concen- tration, other treatments are requir ed to reduce hyperka- lemia. These include: \200 IV insulin and glucose (10 U rapidly acting insulin + 50 mL 50% dextrose); salbutamol (10 m g via nebulizer); isotonic sodium bicarbonate (volume depending upon patient volume assessm ent); cation exchange resins (sodium or calcium polystyrene sulphonate 15 g by mouth 6-hour ly or 15 \200\22330 g per rectum 6-hourly, with lactulose 20 mL qds). Nutrition Nutritional support for patients with AKI must take into account not only the spe ci \201 c metabolic disturbances asso- ciated with AKI, but also the underlying disease pr ocess. Enteral nutrition is preferred, and as a general rule patients with AKI should recei ve 20 \200\22335 kcal/kg/day, with up to a maximum of 1.7 g amino acids/kg/day if catabolic and receiving continuous renal replacement therapy. The majority of enteral and parenteral supplements designed for patients with AKI are low in sodium. Electrolytes should be close ly monitored to avoid hyper- and hypokalemia, and hypophosphatemia. Trace elements and wate r-soluble vita- mins should be supplemented where appropriate. \200 In refractory cases dialysis is required. Pulmonary edema Salt and water overload in AKI leads to pulmonary edema. In some cases this is iatrogenic due to overzealous \202 uid administration. Patients should be treated wit h: \200 Treatment of the complications of AKI Hyperkalemia Hyperkalemia in AKI may lead to cardiac arrest, due to alteration in the cardiac action potential resulting in char- acteristic ECG changes (Fig. 10.1.6). ECG changes occur when the plasma potassium concen- tration increas es to 5.5 mmol/L or more. These include: \200 \200 supplemental oxygen (CPAP +5 to +10 mmHg, or a rebreathing mask may be required); opiates; parenteral nitrate infusion; loop diuretics (furosemide infusion 5 \200\22310 mg/h). \200 \200 In patients with oligoanuric AKI, dialysis may be required. \200\230tenting \200\231 of the T waves; prolongation of the QT interval. More severe hype rkalemia causes: \200 widening of the QRS complex; \200 suppression of the P wave; \200 lengthening of the PR interval. Postobstructive diuresis Following relief of renal obstruction, and also in the poly- uric phase of recovering AKI, \202 uid balance may be prob- lematic, due to the loss of water and electrolytes. As well as loss of sodium and potassium, patients may develop tetany and/ or fits due to profound hypocalcemia/ hypomagnesemia. Careful monitoring of daily weights a nd electrolytes is mandatory to determine appropriate replacement. Calcium administration (10 mL of 10% calcium gluconate, for patients aged >60 years) is the standard medical man- agement of hyperkalemia in patients with ECG changes beyond simple T -wave \200\230tenting \200\231. This should be repeated until the ECG changes reverse. Fig. 10.1.6 ECG changes of hyperkalemia. A. DAVENPORT 326 Table 10.1.8 Indications for renal replacement therapy in patients with AKI Biochemical indications Potassium Urea Creatinine Refractory hyperkalemia >6.5 mmol/L Serum urea >30 mmol/L \2273.0 \206\221 baseline serum creatinine or an absolute SCr >355 mol/l or acute \206\221 SCr >44 mol Refractory meta bolic acidosis pH \211 7.1 Refractory hypo- or hypernatremia, hypercalcemia Hyperuricemia and hyperphosphatemia Hyperammonemia, methylmalonic acidemia Metabolic acidosis Other electrolyte disturbances Tumor lysis syndrome Urea cycle defects and organic acidurias Clinical indications Urine output Urine output <0.3 mL/kg for 24 h or or absolute anuria for 12 h AKI with multiple organ fai lure Refractory volume overload Create intravascular space for plasma and other blood produ ct infusions and nutrition Pericarditis, encephalopathy, neuropathy, myopathy, uremic bleed ing Severe poisoning or drug overdose Severe hypothermia or hyperthermia Multiple organ failure Volume overload End-organ damage Poisoning Thermoregulatory disturbance Summary The incidence of AKI is increasing in the hospital setting, and is more common with increasing age, male sex, and pre-existing CKD. The majority of cases result from multi- p le insults: dehydration, drugs in conjunction with in \202 am- mation and/or sepsis. Patie nts should be appropriately resuscitated to achieve a mean arterial BP >65 mmHg, and \202 uids to maximize cardiac preload responsiveness, without overloading the patient. Dependin g upon the individual his- tory and examination, obstruction may need to be excluded by ren al imaging, and other investigations obtained to establish the cause of AKI. Initiation of renal dialysis The decision to start renal replacement therapy depends on the clinical assessment of the individual patient. However, general guidelines are set out in Table 10.1.8. Follow-up Earlier studies demonstrated that renal function may continue to improve followin g AKI, for up to 6 months or even longer in some cases, such as in scleroderma renal crisis . Thus following recovery of renal function from AKI, patients should have their renal func tion checked at 6 months. If the patient is left with CKD, continued follow- up is required as patients may progress to ESRD. Future prospects Changes in serum creatinine measurements are a relatively late feature of AKI. Although the introduction of urinary biomarkers has been shown, to precede changes in creati- nine, particularly in pediatric practice, the current biomar- kers cannot predict t he severity of the insult. However, newer biomarkers are being investigated, and in the fut ure we will probably use a panel of urinary biomakers to detect both glomerular and tubular injury. This will have impor- tant applications in cancer chemotherapeutic regimens, to ai d dose adjustments in those patients developing AKI. Biomarkers may also be used to predict the severity of renal injury, and thus the need for renal replacement therapy. Prognosis Survival and renal recovery following AKI For hospital inpatients an increase in serum creatinine is associated with a stepwise increased risk of mortality. The relative ri sk of mortality increases: \200 \2274 for a 27 mol/L rise in creatinine; \200 \2271 4 for a 180 mol/L increase in creatinine. Despite the increased risk of death associated with AKI, the overall survival of patients w ith AKI and of those requiring dialysis has improved over time. Mortality fell from 40% in 1988 to 20% in patients with AKI and to 27% in patients with AKI requiring dialysis in 200 2. Traditionally renal recovery following severe AKI with acute tubular injury takes around 21 days, although this varies according to the severity of the original insult, pre- exist ing kidney disease and subsequent clinical course. As more patients are surviving AKI, it i s now becoming clearer that renal recovery is often only partial. Some 7% of survivors beco me dialysis dependent within 3 years of the AKI event, and this rises to 28% in those patie nts with pre-existing CKD. Further reading Bellomo R, Kellum JA, Ronoc C. De \201 ning acute renal failure: physiological principles. Intens Care Med 2004; 30: 33 \200\22337. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P, and the ADQI workgroup. Acute renal fa ilure \200\223 de \201 nition, outcome measures, animal models, \202 uid therapy and in formation technol- ogy needs. The second international consensus conference of Acute Dialys is Quality Initiative (ADQI) Group. Crit Care 2004; 8: R204 \200\223R212. CHAPTER 10.1 Clinical approach to acute kidney injury 327 Mishra J, Ma Q, Prada A, et al. Identi \201 cation of neutrophil gelatinase- associated li pocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol 2003 ; 14: 2534 \200\2232543. Briguori C, Airoldi F, D \200\231Andrea D, et al. Renal Insuf \201 ciency Following Contra st Media Administration Trial (REMEDIAL). A randomized comparison of 3 preventive strategie s. Circulation 2007; 115: 1211 \200\2231217. Nash K, Hafeez A, Hou S. Hospital-acquired renal insuf \201 ciency. Am J Kidney Dis 2002; 39: 930 \200\223936. Cano N, Fiaccadori E, Tesinsky P, et al. ESPEN guidelines on enteral nutrition: adult renal failure. Clin Nutr 2006; 25: 295 \200\223310. Internet resources The Acute Dialysis Quality Initiative: Druml W. Nutritional management of acute renal failure. J Renal Nutr 2005; 15: 63 \200\22370. Feest TG, Round A, Hamad S. Incidence of severe acute renal failure in adults: results of a community based study. Br Med J 1993; 306: 481 \200\223483. http://www.ADQI.net The Acute Kidney Injury Network: Ho KM, Sheridan DJ. Meta-analysis of frusemide to prevent or treat http://akinet.org/index.php acute renal failure. Br Med J 2006; 333(7565): 420 \200\223425. See also Assessment of renal disease, p. 1 Urinary tract obstruction, p. 652 Crescentic glo merulephritis, p. 120 Antiglomerular basement membrane disease, p. 124 Systemic vasculitis, p. 168 Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, Levin A. AKIN: acute kidne y injury network: report of an initiative to improve outcomes in acute kidney injury. Ind J Nephrol 2007; 17: 1 \200\2233. Metcalfe W, Simpson M, Khan IH, et al. Acute renal failure requiring renal replacement ther apy: incidence and outcome. Q J Med 2002; 95: 579 \200\223583. Kreymann KG, Berger MM, Deutz NEP et al. ESPEN guidelines on enteral nutrition: intensive c are. Clin Nutrition 2006; 25: 210 \200\223223. A. DAVENPORT 328 Renal replacement therapies in acute kidney injury Introduction There are many potential modes of renal replacement therapy (RRT) now availabl e for treating the patient with acute kidney injury (AKI) who has developed renal failure: \200 \200 \200 \200 Ultra \201 ltration Ultra \201 ltration occurs due to the high glucose content of the fre sh dialyzate causing an osmotic gradient: \200 \200 1.36% = 64 mmol/L glucose; 2.27% = 120 mmol/L glucose. peritoneal dialysis; intermittent hemodilaysis/hemo \201 ltration; continuous renal replac ement therapy; hybrid techniques. Considerations for PD treatment in AKI In patients with shock and in those on vasopressors, the mesenteric blood \202 ow may be reduced. This will affect sol- ute clearances and ul tra \201 ltration volumes. Higher glucose concentrations may then be required to obtain ef fective ultra \201 ltration. Glucose is absorbed, and this may result in hyperglycemia, pa rticularly in diabetic patients. In addition peritoneal dia- lyzates are hyponatremic, and therefore should be avoided in patients with brain injury and/or cerebral edema. Continuous \202 ow PD has recently been introduced, using one catheter for dialyzate in \202 ow, a nd a second for dialyzate out \202 ow in an effort to increase the ef \201 ciency of solu te clearances. Regeneration of the dialyzate using sorbents allows a limited volume of PD d ialyzate to be continuously recycled. Rather than trying to provide all possible modalities, units should become pro \201 cient in a limited number of options. When to initiate renal replacement therapy RRT is often initiated based on the clinical ass essment of the patient coupled with the most recent biochemical data. Over the years the tr end has been to start RRT earlier, particularly in those with multiple organ failure and se psis, compared to those with AKI alone. Peritoneal dialysis In patients with an intact abdominal cavity, peritoneal dialy- sis (PD) remains an option. PD catheter insertion Hard PD catheters have generally been superseded by silastic soft cat heters, which can still be inserted at the bed side under local anesthesia. Insertion tends to be \200\230blind \200\231, typically inserting the catheter in the midline, one-third of the distance from the umbilicus to the symphysis pubis. The peritoneal membrane should b e penetrated during inspiration, when tensed. Pre \201 lling the peritoneal cavity with PD \202 uid using a venous cannula introduced at McBurney \200\231s point reduces the risk of bowel perforation with the PD catheter insertion stylet. Vascular and intestinal injury remain a possible complication of insertion. Alternative methods of PD catheter insertion i nclude use of peritoneoscopy, full laparoscopy and open surgical insertion. The method chos en will depend on the local expertise and the clinical state of the patient. Intermittent hemodialysis/hemo \201 ltration The key to prescribing intermittent hemodialy sis (IHD) or hemo \201 ltration (IHF) to the patient with AKI is to avoid intradialytic hy potension and further renal injury. Intermittent hemodialysis Compared with regular IHD for the patient with ESRD the following changes should be made: \200 \200 \200 dialyzate cooled to 35 C or set at isothermic; dialyzate calcium of 1.35 \200\2231.5 mmol/ L; dialyzate sodium of 10 mmol/L above plasma sodium (up to a maximum of 150 mmol/L); dialy zate potassium highest possible; minimize ultra \201 ltration rate. \200 Each of the \201 rst three strategies has been independently shown to reduce intradialyti c hypotension. Similarly the highest possible potassium concentration should be cho- sen to minimize cardiac arrhythmias. As the rate of \202 uid removal during dialysis is also an important determinant of hypotension, then the ultra \201 ltration rate should be mini- m ized by extending the duration of the treatment session, above the standard 4 h treatment o f chronic dialysis patients, and increasing the frequency of treatments to alternate days o r daily. The minimum dose of intermittent HD should exceed a Kt/V > 12 per thrice weekly se ssion. With the development of dialysis technology, there are now HD machines capable of as sessing relative blood volume, as a surrogate of the difference between ultra \201 l- trat ion rate and plasma re \201 lling rate; the most sophisticated can vary the ultra \201 lt ration rate to maintain the relative blood volume. If at all possible the most sophisticate d HD machine should be used for the treatment of the patient with AKI. When IHD has been ca refully delivered to minimize intradialytic hypotension, then patient outcomes have been PD prescription in AKI Small solute clearance In cases of hyperkalemia, rapid cycles are re quired. Typically 1 L of dialyzate should run into the peritoneal cavity in 5 min, 2 L in 1 0 min. In severe hyperkalemia 30 min cycles may be required, although generally 1 h cycles will suf \201 ce. For an hourly cycle of 2 L, 10 min will be required for the in \202 ow, 12 \200\22315 min for the out \202 ow, limiting the dwell time to 45 \200\22348 min. To c ompensate for the shortened dwell times, the \201 ll volume has to be increased. For adul ts 2 \200\2232.5 L cycles with a dwell time of a 90 min may be required. In many studies th e clearances achieved with PD in AKI are similar to those of CKD patients regularly treated by PD, but are much less than other techniques. However, PD remains a viable option, parti cularly in infants and small children in whom vascular access problems preclude blood puri \201 cation techniques, and in those patients who are not hypercatabolic. CHAPTER 10.2 Renal replacement therapies in acute kidney injury 329 reported to be similar to those of continuous renal replacement therapies (CRRTs). During HF, the replacement/substitution fluid can be replaced pre, mid or post \201 lter ( Fig. 10.2.2). Small solute clearances are greater with: \200 Intermittent hemo \201 ltration Whereas the main driving force during IHD is diffusion alo ng concentration gradients, during hemofiltration, hydrostatic pressure drives a bulk water movement across the hemo \201 lter, known as convection (Fig. 10.2.1). Intermittent HD is much more effective in clearing small solutes such as potassium, urea and creatinine than IHF, but IHF preferentially removes larger molecular weight solutes, and also drugs such as vancomycin. post > mid > pre \201 lter \202 uid replacement. Conversely, middle molecular weight solute clearances, are greater with: \200 pre > mid > post \202 uid replacement. However, to achieve the same small solute clearances much more \202 uid (and therefore a higher cost) is required with pre and mid compared with postdilutional replacement. Dialysis Convection highly permeable membrane semi- permeable membrane dialysis fluid blood blood filtrate Fig. 10.2.1 Dialysis and convection. Dialysis occurs by diffusion down a concentration grad ient and across a semipermeable membrane. Convection occurs down a hydrostatic pressure gra dient with solutes moving with bulk water movement. 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 Fig. 10.2.2 Convective and diffusive blood puri \201 cation. A. DAVENPORT 330 convection, high flux membranes are required. Inappropriate use of a dialyzer designed for dialysis as a hemo \201 lter, will result in excessive clotting problems. Pure unadulterat ed cellulosic membranes have been shown to reduce renal recovery in patients with AKI. Howe ver, these membranes have generally been replaced by modi \201 ed cellulose, and such memb ranes compare favo- rably with the synthetic membranes. Septic patients and those with live r failure may have increased nitric oxide levels, and can be more prone to hypotension when \201 rst connected to the dialysis circuit, due to the generation of bradykinin. This ca n be minimized by priming the dialyzer with isotonic sodium bicarbonate, rather than 0.9% s aline (pH 5.4). Intermittent HD vs intermittent HF Initially it was thought that IHF provided greater cardi ovas- cular stability than IHD. However, it is now established that postdilutional IHF caus es greater cooling than IHD, and the predilutional mode even more cooling. In addition ther e are differences in sodium exchange between IHD and IHF. There is an obligatory sodium los s with any ultra \201 ltration. During IHF, plasma water passes across the hemo \201 lter membrane due to a hydrostatic pressure gradient (convection). However, not all sodium in p lasma water is freely available to move, as it may be asso- ciated with negatively charged proteins and other com- pounds. Thus for the same dialyzate/replacement \202 uid sodium c oncentration, patients treated by IHF will have a greater sodium gain than those by IHD, an d this is greatest in the postdilution mode. This is compounded by the fact that compared t o healthy dialysis patients, patients with AKI have a low dietary sodium intake. Continuous renal replacement therapies Continuous renal replacement therapies (CRRT) includ e: \200 continuous arteriovenous hemo \201 ltration (CAVH); \200 continuous venovenous hemo \201 ltration (CVVH); \200 continuous venovenous hemodialysis (CVVHD); \200 cont inuous venovenous hemodia \202 tration (CVVHDF). CAVH was the first CRRT, but often did no t provide adequate clearances, so IHD was still required. CAVH has now been superseded by p umped venovenous systems which provide adequate clearances (Fig. 10.2.3). Typically CRRT pr ovides greater cardiovascular stability than conventional IHD. This is most likely due to t he increased patient cooling associated with CRRT, despite warming of replacement \202 ui ds and dialyzates. While no study to date has shown an improved patient survival with CRRT compared to IHD, there are data to show that recovery of renal function is greater with CRR T when compared to standard IHD. Hemodia \201 ltration Hemodia \201 ltration (HDF) is a technique in which there is both d ialysis and \201 ltration (convection). Membranes Hemodialysis Diffusion is increased by having a large surface area, with a short distance for solutes to move, and thus dialyzer mem- branes designed for diffusion typicall y have long fiber lengths of narrow diameter. Typically dialyzer membranes restricted the p assage of small solutes, and were therefore termed low flux, but over time the membranes ha ve changed, so that many IHD treatments in AKI use high \202 ux membranes. Hemo \201 ltration For convective therapies, hydrostatic pressure is better maintained by shorter, wider diameter \201 bers. To allow Postdilutional replacement Venous line Filter Ultrafiltrate Peristaltic pump Arterial line Fig. 10.2.3 Continuous venovenous hemo \201 ltration. CHAPTER 10.2 Renal replacement therapies in acute kidney injury 331 Although there are differences between CVVH and CVVHD in terms of solute removal, it does n ot appear that one modality is superior to the other in clinical practice. Whereas there ar e guidelines as to the dose of RRT required for patients with CKD, it was unknown until rel a- tively recently whether the dose of CRRT impacted on patient survival. However, it has n ow been shown that the dose of treatment delivered has an impact on outcome, with greater p atient survival during postdilutional CVVH with a delivered dose of >20 mL/kg/h or an equiv alent dose of CVVHDF. Although CRRT generally provides an effective RRT, with cardiovascula r stability, it must be recognized that drugs, particularly antibiotics, may have a substan tial clearance, and therefore dosages need adjusting, and that water- soluble vitamins and trace elements such as selenium are lost and may need replacing. will produce a hyperchloremic acidosis. These changes will occur more rapidly if high volum es are exchanged, and if predilutional \202 uid replacement is used during CRRT, as chlor ide mass balance is more positive when compared to postdilutional replacement. Latterly bic arbonate-based, of buffer-free solutions have been developed, and although more costly have been shown to improve acid \200\223base status and cardiovascular stability in critically ill patients with AKI, compared to standard lactate-based \202 uids. The advent of citrat e as an anticoagulant for CRTT has again required further \202 uid development, as trisod ium citrate leads both to sodium gain and to metabolic alkalosis, as each citrate molecule is indirectly metabolized to three bicarbonates. Thus \202 uids for citrate-based CRRT no t only need to be calcium free, but also lower in both sodium and bicarbonate. Anticoagulation for CRRT Although unfractionated heparin (UFH) remains the most common anti coagulant used worldwide, CRRT systems can be run anticoagulant free. In AKI the platelet c ount may be reduced, and baseline clotting studies abnormal. Replacement \202 uids and/or dialyzates Whereas dialyzates for IHD have been bicarbonate- based for some time, the original \202 uids used for CRRT, as both replacement \202 uid s and/or dialyzates, were derived from peritoneal dialyzates, containing high concentration s of glucose, and were lactate-based. Over time, specialized \202 u- ids have been develo ped, nevertheless there is a marked range in electrolyte composition, particularly lactate and chloride concentrations. For the same blood \202 ow, hematocrit and ultra \201 ltrat ion volume, the \201 ltration fraction is greater for postdilutional hemo \201 ltration. (Fig. 10.2.4) A hemo \201 ltration replacement \202 uid containing a relatively high la ctate and low chloride concentration will, after several days of CRRT, result in a hypochlo remic alkalosis, and conversely a relatively low lactate \200\223high chloride solution Simple measures to reduce clotting in the circuit Adequate vascular access is required, usi ng large French gauge catheters, preferably with no side port-holes. Femoral access is more reliable than internal jugular or subclavian, but the femoral catheters need to be long en ough for the tips to lie in the inferior vena cava. A hemo \201 lter rather than a dialyse r membrane is required, and the \201 ltration fraction should be <30% (Fig. 10.2.4). Pred ilutional \202 uid replacement prolongs circuit survival compared to postdilutional CVVH, by preventing hemoconcentration and limiting protein deposition on the hemo \201 lter mem brane, and increasing cooling. Filtration fraction in CVVH Protein deposition on membrane Plasma flow QP FF = QUF/QP Ultrafiltrate QUF Predilutional Blood flow rate = 100 mL/min HCT 24% Ultrafiltration rate = 1500 mL/h FF = 15 00/[7500 x (1 \200\223 0.24)] = 0.26% Postdilutional Blood flow rate = 100 mL/min HCT 30% Ultrafiltration rate = 1500 mL/h FF = 1 500/[6000 x (1 \200\223 0.30)] = 0.36% Fig. 10.2.4 Filtration fraction in continuous venovenous hemo \201 ltration (CVVH). A. DAVENPORT 332