e4 154 Blum RH, McGowan FX Chronic upper airway obstruction and cardiac dysfunction anatomy, pathophysiology and anesthetic im plications Paediatr Anaesth 2004;14(1) 75 83 155 Chen ML, Keens TG Congen[.]
e4 154 Blum RH, McGowan FX Chronic upper airway obstruction and cardiac dysfunction: anatomy, pathophysiology and anesthetic implications Paediatr Anaesth 2004;14(1):75-83 155 Chen ML, Keens TG Congenital central hypoventilation syndrome: not just another rare disorder Paediatr Respir Rev 2004;5(3):182-189 156 Rodrigo GJ, Rodriquez Verde M, Peregalli V, Rodrigo C Effects of short-term 28% and 100% oxygen on PaCO2 and peak expiratory flow rate in acute asthma: a randomized trial Chest 2003;124(4):1312-1317 157 Priestley MA, Helfaer MA Approaches in the management of acute respiratory failure in children Curr Opin Pediatr 2004;16(3):293-298 158 Yañez LJ, Yunge M, Emilfork M, et al A prospective, randomized, controlled trial of noninvasive ventilation in pediatric acute respiratory failure Pediatr Crit Care Medicine 2008;9(5):484-489 159 Organized jointly by the American Thoracic Society, the European Respiratory Society, the European Society of Intensive Care Medicine, and the Société de Réanimation de Langue Francaise, and approved by ATS Board of Directors International Consensus Conferences in Intensive Care Medicine: noninvasive positive pressure ventilation in acute Respiratory failure Am J Respir Crit Care Med 2001;163(1):283-291 160 Marraro GA Innovative practices of ventilatory support with pediatric patients Pediatr Crit Care Med 2003;4(1):8-20 161 O’Croinin D, Ni Chonghaile M, Higgins B, Laffey JG Benchto-bedside review: Permissive hypercapnia Crit Care 2005; 9(1):51-59 162 Thome UH, Ambalavanan N Permissive hypercapnia to decrease lung injury in ventilated preterm neonates Semin Fetal Neonatal Med 2009;14(1):21-27 163 Hagen EW, Sadek-Badawi M, Carlton DP, Palta M Permissive hypercapnia and risk for brain injury and developmental impairment Pediatrics 2008;122(3):e583-e589 164 Laffey JG, Kavanagh BP Hypocapnia N Engl J Med 2002;347(1):43-53 165 Foster GT, Vaziri ND, Sassoon CS Respiratory alkalosis Respir Care 2001;46(4):384-391 e5 Abstract: Abnormalities in acid-base balance should be anticipated in all critically ill children due to their underlying disease or intensive care unit therapy and should be monitored closely Interpretation of these disorders requires an understanding of not only acids and bases but also knowledge of gas exchange and ventilation, dynamics of water and electrolyte movement at the cellular level, and renal-related mechanisms of hydrogen ions, electrolytes, and water excretion This chapter provides a thorough and practical understanding of the physiology and pathophysiology behind these disorders Key Words: Acid-base, acidosis, alkalosis, metabolic acidosis, lactic acidosis, acid-base derangements 73 Tests of Kidney Function in Children RAJIT K BASU Kidney dysfunction and injury are not unusual in the critically ill child and may develop as a consequence of the underlying disease process (e.g., sepsis, progressive glomerulonephritis) or its therapy (e.g., aminoglycoside toxicity) The ability to accurately, precisely, and rapidly assess kidney function is essential for the early detection of acute kidney injury (AKI), for dose adjustments of medications excreted by or toxic to the kidney, in risk assessment for imaging studies involving intravenous (IV) contrast agents or gadolinium, and for monitoring for medication-related nephrotoxicity AKI is now recognized to encompass a spectrum of disease ranging from mild, reversible kidney dysfunction to severe, potentially irreversible organ failure with need for dialysis support AKI occurs in a large population of critically ill children— in requiring intensive care unit (ICU) treatment develop AKI in the first days of the hospital course.1–4 In the past 10 to 15 years, standardized classification schemes for AKI based on an acute increase in serum creatinine or decrease in urine output (RIFLE [Risk, Injury, Failure, Loss, End-Stage Renal Disease]; AKIN [Acute Kidney Injury Network]; and KDIGO [Kidney Disease: Improving Global Outcomes]) have been proposed and validated in adults1,5,6 with modified versions proposed for children7,8 (Table 73.1) An increase in serum creatinine as small as 0.3 mg/dL is now well recognized to be associated with increased morbidity and mortality, underscoring the need for precise, sensitive, and timely measures of kidney function.8,9 Notably, however, none of these definitions addresses AKI in the neonate Jetton and Askenazi10 recently proposed a modification of the KDIGO classification for 896 • • • Serum creatinine is a crude assessment of filtration, influenced by several factors other than glomerular function, including gender, age, muscle mass, dilution, concentration relative to steady state, lack of baseline in many children, and testing modality Changes in serum creatinine lag behind injury in many pediatric patients Glomerular filtration estimation must be understood with precautions but may be more accurate using prediction formulas inclusive of muscle mass, kinetic changes, and consideration of other markers, such as cystatin C Filtration and tubular function are distinct entities; urine output may be a more sensitive indicator of both epithelial tubular function and renal reserve Use of glomerular filtration rate for assessment of kidney function must be adjudicated by physiology of the marker used and characteristics of the population in whom the equation was developed Use of estimating equations in neonates must be taken in context of fetal age and maternal considerations Next-generation methods of estimating kidney function will be multimodal, incorporating risk stratification, a combination of functional and damage biomarkers, integration of fluid accumulation, and assessment of renal reserve Use of these methods will facilitate identification of acute kidney injury phenotypes use in neonates (eTable 73.2) Preterm infants frequently expe rience a serum creatinine elevation of 0.3 mg/dL; such increases can be associated with increased morbidity and mortality.11 The true incidence of AKI in the pediatric intensive care unit (PICU) is not well established, but recent studies suggest that it is increasing as advances in critical care medicine have led to improved patient survival and salvage of more critically ill individuals.7,12 However, morbidity and mortality rates associated with AKI remain high.7 Therapeutic intervention trials for AKI have produced disappointing results, in part related to delays in diagnosis as well as the heterogeneity of patients enrolled.13,14 Therefore, the focus is on earlier recognition and intervention for AKI, which should provide greater potential for recovery and/or stabilization of kidney function However, the early detection of incipient AKI is severely limited by the lack of sensitive and specific tools currently available to assess kidney function • • • PEARLS Assessment of Glomerular Function and Injury Glomerular filtration rate (GFR) is considered the best overall indicator of kidney function but remains challenging to accurately and efficiently measure in clinical practice Functionally, the total kidney GFR is determined by the cumulative number of nephrons and the GFR within each nephron (single-nephron glomerular filtration rate [SNGFR]) Conceptually, it represents the volume of plasma that could be completely cleared of a substance per unit of time Kidney function may decline due to CHAPTER 73 Tests of Kidney Function in Children TABLE KDIGO Acute Kidney Injury Criteria 73.1 Stage Change in Serum Creatinine (SCr) Urine Output h 0.3 mg/dL over 48 h or h 150%–200% over days ,0.5 mL/kg/h for h h 200%–300% ,0.5 mL/kg/h for 16 h h 300%, SCr 4 mg/dL, or dialysis or eGFR #35 mL/min/1.73 m2 for patients ,18 y ,0.5 mL/kg/h for 24 h or anuria for 12 h eGFR, Estimated glomerular filtration rate From Acute Kidney Injury Work Group Kidney Disease: Improving Global Outcomes (KDIGO) KDIGO clinical practice guidelines for acute kidney injury Kidney Int Suppl 2012;2:19 hypoperfusion, resulting in a decrease in SNGFR, or due to nephron injury, resulting in fewer functioning nephrons; often both factors are present The kidney has a certain degree of reserve and attempts to adapt to nephron loss by increasing the SNGFR of the remaining nephrons, thus maintaining total kidney GFR initially and masking early kidney injury Indeed, by the time the GFR actually falls, significant injury has already occurred Loss of this renal reserve is one of the earliest manifestations of kidney injury but is even more challenging to measure than the GFR.15,16 Glomerular filtration is a dynamic variable that can fluctuate in a given individual by as much as 7% to 8% from day to day on the basis of differences in hydration status, activity, and protein consumption.17 The GFR is also influenced by age, gender, and body size; therefore, it varies between individuals as well Thus, to facilitate comparison of the GFR among children and adults of considerably different sizes, the absolute GFR is normalized to body surface area (BSA), which correlates well with kidney weight, the most direct standard of reference.17 Appreciation of the maturational increase in GFR that occurs during infancy is also necessary for proper assessment of kidney function in children At birth, the mean GFR is quite low (20 mL/min per 1.73 m2 in term infants) due to renal immaturity not yet sufficient to meet the metabolic demands of a healthy infant The GFR doubles within the first weeks of life and then continues to gradually increase to reach a mean of 77 mL/min per 1.73 m2 between and months of age and adult levels of 120 to 130 mL/min per 1.73 m2 by approximately years of age (eTable 73.3).18 The GFR itself cannot be directly measured but can be assessed by measuring the clearance of an ideal filtration marker or estimated using predictive formulas Urinary or plasma clearance studies provide the greatest accuracy but are expensive, timeconsuming, and labor-intensive Consequently, they are used mainly for research and in select clinical situations in which an accurate assessment of kidney function is necessary (e.g., chemotherapy dosing) For the daily clinical management of patients, serum creatinine and GFR estimating equations are used most commonly They offer the advantage of being convenient, noninvasive, and inexpensive, with timely accessibility of results However, accuracy and sensitivity to small changes in kidney function are sacrificed, making the detection of acute, early kidney dysfunction difficult The search for novel biomarkers of kidney function (such as cystatin C) and early kidney injury (e.g., neutrophil gelatinase-associated lipocalin [NGAL]) has been a major focus in the field of AKI for this reason (see Biomarkers of Acute Kidney Injury and the Next Generation) 897 Significant barriers exist to practical and meaningful implementation of GFR estimation in critical care environments Foremost, the majority of critically ill children not have a baseline creatinine to use for comparison, either for absolute creatinine value change or change in GFR based on the formulas described earlier Imputational methods have been derived and validated in numerous populations for the purpose of creating baseline creatinine values normative to age-, size-, or population-based GFR averages.19 Additionally, steady-state estimation for creatinine values are contextually skewed, as a high proportion of critically ill children are simply not at steady state on presentation and have total body water perturbations before, during, and after resuscitation Pragmatic and innovative solutions are required, and are being developed, to modernize the approach to estimation of renal function in the critically ill child (see Biomarkers of Acute Kidney Injury and the Next Generation) Renal Clearance Techniques Classic, gold standard techniques for measuring the GFR using inulin, iothalamate, and creatinine clearance, and plasma disappearance techniques using radioisotopes are discussed at ExpertConsult.com Iohexol Iohexol is now widely accepted as an excellent alternative to inulin and radioisotopes for clearance studies Iohexol (Omnipaque) is a low-molecular-weight (821 Da), nonionic, relatively low-osmolar IV contrast agent used routinely in the United States for radiologic studies at doses appreciably higher than that required for GFR studies.37,38 It is almost entirely eliminated through glomerular filtration and is not reabsorbed, secreted, or metabolized by the kidney, thus fulfilling many of the desired traits of an ideal filtration marker Further, it has minimal protein binding and negligible extrarenal elimination even in advanced chronic kidney failure.37,39 It can easily be measured by HPLC or mass spectroscopy.38,40,41 Iohexol has been safely used for clearance studies for many years in Scandinavia37,42 and the United States.31,43 Iohexol plasma clearance results appear to be comparable with renal inulin clearance and plasma EDTA disappearance studies across a broad range of GFRs.38,44,45 Schwartz et al.31,43 recently demonstrated the feasibility of conducting iohexol clearance studies using the finger prick technique with filter paper technology in adults, a procedure that would alleviate the need for repeated venipunctures or placement of a second IV for serial serum sample collection, making it attractive for use in children However, additional studies are necessary before it is ready for widespread clinical use Renal Inulin Clearance Compared With Other Glomerular Filtration Rate Measurement Techniques Soveri et al.48 performed a comprehensive, systematic literature review examining the accuracy of GFR measurement techniques using renal inulin clearance as the gold standard The renal clearance of EDTA and iothalamate, as well as the plasma disappearance of EDTA and iohexol, were considered suitable alternatives with an associated bias of less than 10% (mean difference between renal inulin clearance and that obtained using other techniques), P30 greater than 80% and P10 greater than 50% (percentage of GFR 897.e1 eTABLE Proposed Neonatal Acute Kidney Injury 73.2 Classification Stage Serum Creatinine (SCr) No change in Scr or h #0.3 mg/dL Urine Output 0.5 mL/kg/h SCr h 0.3 mg/dL within 48 h or h 1.5–1.9 reference SCra within days ,0.5 mL/kg/h for 6–12 h SCr h 2.0–2.9 reference SCra ,0.5 mL/kg/h for 12 h SCr h 3 reference SCra or SCr 2.5 mg/dLb or receipt of dialysis ,0.3 mL/kg/h for 24 h or anuria for 12 h a Baseline SCr is defined as the lowest previous Scr value SCr value of 2.5 mg/dL represents ,10 mL/min/1.73 m2 From Jetton JG, Askenazi DJ Acute kidney injury in the neonate Clin Perinatol 2012;41: 487–502 b Cin is usually scaled for BSA: C in GFR [(U in V)/Pin ] [1.73m /BSA] The classic protocol for inulin clearance is cumbersome, involving an IV infusion of inulin over several hours and serial timed blood and urine specimens Iothalamate Iothalamate (614 Da) is also freely filtered by the glomerulus and has been studied extensively as an alternative exogenous marker for GFR measurements Unlike inulin, however, iothalamate has some protein binding (,8%) and proximal tubular secretion (10%), raising concern for overestimation of the GFR Reported correlations between iothalamate and inulin renal clearances in the literature have been variable, with some studies demonstrating good correlation, whereas most suggest that iothalamate overestimates inulin clearance.20–22 Creatinine Clearance eTABLE Normal Glomerular Filtration Rate (GFR) 73.3 Values for Children Age GFR (mL/min/1.73 m2) Range (mL/min/1.73 m2) Preterm (,34 wk) 2–8 days 11 11–15 4–28 days 20 15–28 30–90 days 50 40–65 Term (.34 wk) 2–8 days 39 17–60 4–28 days 47 26–68 30–90 days 58 30–86 1–6 mo 77 39–114 6–12 mo 103 49–157 12–19 mo 127 62–191 2–12 y 127 89–165 Modified from Heilbron DC, Holliday MA, al-Dahwi A, et al Expressing glomerular filtration rate in children Pediatr Nephrol 1991;5:5–11 Clearance studies that make use of endogenous markers such as serum creatinine obviate the need for a constant infusion and make the study more amenable to clinical practice However, the problems associated with timed urine collections persist and, accordingly, limit the usefulness of this technique, particularly in children Further, creatinine is a flawed filtration marker Although it is predominantly eliminated by glomerular filtration, a small but variable amount (10%) is eliminated by tubular secretion As renal function deteriorates, the proportion of secreted to filtered creatinine progressively increases, leading to an overestimation of GFR and a less reliable measure of GFR.17 Administration of oral cimetidine beginning days before the study can at least partially circumvent this issue by inhibiting the tubular secretion of creatinine.23 Although timed urine collections are still necessary, they are typically obtained over a 2-hour period, facilitating performance in a monitored clinic setting Guidelines from the National Kidney Foundation no longer recommend routine performance of creatinine clearance studies to estimate GFR, as prediction formulas are considered more accurate.24 Nonetheless, creatinine clearance–based studies can still be helpful when assessing renal function in individuals with atypical body composition (e.g., anorexia, malnutrition) or dietary intake (e.g., vegetarian diet).24,25 Plasma Disappearance Techniques Inulin The renal clearance of inulin remains the gold standard for measuring GFR Inulin is an inert, uncharged 5.2-kDa polymer of fructose that possesses many characteristics of an ideal filtration marker It is not protein bound and is freely filtered at the glomerulus without being reabsorbed, secreted, or metabolized by the kidney Further, it is eliminated exclusively by the kidney.17 Therefore, in the steady state, the filtered load of inulin (GFR Pin) is equal to its urinary excretion (Uin V), where Pin and Uin are the plasma and urine concentrations of inulin (mg/dL), respectively, and V is the urine flow rate (mL/min) The renal clearance of inulin (Cin) can be calculated as follows: C in GFR (U in V)/Pin Plasma disappearance techniques further simplify the measurement of GFR and avoid the need for urine collections They are most commonly performed using a single IV injection technique, although constant infusion and subcutaneous protocols are also available.20,26,27 Serial blood samples collected at specified times over a several-hour period following injection of the filtration marker are used to generate a plasma disappearance curve This curve can be well approximated by a double exponential curve that is characterized by an initial “fast” curve and a later “slow” curve, as illustrated in eFig 73.1 The initial “fast” curve represents the distribution phase and reflects renal elimination as well as diffusion of the marker into the extravascular space, whereas the late “slow” curve reflects only the renal elimination phase Renal clearance can be calculated by dividing the delivered dose by the entire area under the plasma disappearance curve.28 ... change in Scr or h #0.3 mg/dL Urine Output 0.5 mL/kg/h SCr h 0.3 mg/dL within 48 h or h 1.5–1.9 reference SCra within days ,0.5 mL/kg/h for 6–12 h SCr h 2.0–2.9 reference SCra ,0.5 mL/kg/h... Functionally, the total kidney GFR is determined by the cumulative number of nephrons and the GFR within each nephron (single-nephron glomerular filtration rate [SNGFR]) Conceptually, it represents... injury Indeed, by the time the GFR actually falls, significant injury has already occurred Loss of this renal reserve is one of the earliest manifestations of kidney injury but is even more challenging