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RENAL PROTECTION IN PEDIATRIC CARDIAC SURGERY

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RENAL PROTECTION IN PEDIATRIC CARDIAC SURGERY Powered By Docstoc
					             BY
      DR/ WASEEM Z. AZIZ
LECTURER OF ANAESTHESIA AND
       INTENSIVE CARE
    AIN SHAMS UNIVERSITY
          MARCH 2009
                 QUESTIONS
1. The risk of development of acute renal
  failure after cardiac surgery is highest in:
• a. Neonates.
• b. Infants.
• c. Children.
• d. Adults.
              QUESTIONS
2. Which of the following causes
vasodilation of the cortical vasculature?
a. Mannitol.             c. Both.
b. Furosemide.           d. Neither.
                  QUESTIONS
3. Clinical settings in which mannitol has definitely been
shown to be effective in preventing the deterioration of
renal function is:

a. During and after cardiopulmonary bypass.
b. During and after aortic cross-clamping.
c. During and after hypovolemic shock.
d. Before the administration of cisplatin.
e. None of the above.
                     QUESTIONS
4. Which of the following statements is least accurate regarding
acute renal failure?

a. Adults with no underlying renal disease who develop acute renal
failure have a worse prognosis compared with children.
b. Following cardiac surgery, the incidence of acute renal failure is
higher in children than in adults.
c. Children over the age of 2 years with acute renal failure have a much
better outlook with meticulous medical care.
d. Spontaneous recovery from acute renal failure is likely to begin 1–3
weeks after onset.
e. The mortality rate for children with acute renal failure is much higher
than in adults
                     QUESTIONS
5. Which of the following statements is true regarding
management of suspected acute renal failure?

a. In euvolemic patients, the rapid intravenous administration of
mannitol should result in a urine output greater than 0.5 mL/kg within
1 hour if a prerenal etiology dominates.
b. The vasodilatory and natriuretic properties of furosemide are
beneficial when administered early in the course of acute renal
failure.
c. In euvolemic patients, furosemide in an incremental dose of up to 10
mg/kg may be used.
d. If there is no response to a fluid challenge, low dose dopamine could
be added.
e. All of the above
                     QUESTIONS
6. In a patient who has just been admitted to the pediatric
intensive care unit with new onset of acute renal failure, which
of the following pathophysiological changes is least likely to
occur?

a. Blood urea nitrogen (BUN) and creatinine will rise at 10 and 0.5
mg/dL/day, respectively.
b. Serum HCO3 decreases by 2 mEq/L/day because of release of
tissue phosphate.
c. Serum K+ increases by 0.3–0.5 mEq/L/day.
d. Hypernatremia is commonly observed.
e. Hypophosphatemia and associated hypocalcemia may develop
rapidly after the onset of acute renal failure
       Incidence of postoperative renal
                 dysfunction

•  Postop. renal failure (more in pediatrics) is associated with mortality
  rates of 60–90% (more in adults than pediatrics).
• The incidence of renal impairment varies between 4 and 24%
  because there is no rigid definition of renal dysfunction.
• In cardiac surgery            Postoperative ARF

                                                                   sepsis
    ↑ ICU stay
                        ↑ length of     ↑ GI        ↑ requiring
                        hospital stay   bleeding       infection
RENAL UNIT ANATOMY
        RENAL PHYSIOLOGY
• RBF = 20% of resting CO                 ↓ by

    atherosclerosis   ↓ CO         α- adrenergic ++
                                  (↓ RBF inspite of
                                   maintain BP)
• Intraglomerular blood pressure =the difference between
  the pressures in the efferent and afferent arterioles)
• GFR=100-200ml/min
        RENAL PHYSIOLOGY
• GFR autoregulated across wide range of ABP but urine
   output is not. ( UOP Linear ↑ with arterial BP.
    e.g 100mmHg         200       7 times ↑ in UOP
         ˂50mmHg         stop of UOP
 due to slight rise in GFR but ↑ peritubular vascular pr.
         ↓ reabsorption of
            filterate.
         RENAL PHYSIOLOGY
• RBF=20% of CO ≈50 ml/min→
                O2 delivery≈50ml/min/100gm tissue
• Distribution is not uniform→≈90% to cortex
• O2 utilization only 10%     low A-V O2 content
  of total body utilization    difference in kidney

                 adequate oxygen reserve

     ?? Why kidney is highly sensitive to hypoperfusion??
     ?? Why ARF is frequent complication of hypotension?
                             PARADOX???
       Due to physiological gradient of intra-renal
oxygenation with the renal medulla able to function at
ambient oxygen tensions of 2–3 Kpa

   This low oxygen tension results from the high oxygen
requirement for tubular reabsorptive activity of sodium
and chloride.
                          Although
 a high percentage of           the medullary region has a
blood goes to cortex                far smaller blood flow
                         NEED
only about 18% of total           about 79% of the
delivered oxygen                 oxygen delivered to it
     (heterogeneity of flow and oxygen requirement)
                         MEDULLA

              Needs strict
                control

                                           Loop diuretics protects
  More susiptable to
                         ATN occurs by ↓       (if any) by ↓o2
 hypoxic injury→ ATN
                                                 dependent
esp in thick ascending   40-50% of RBF      reabsorption of mTAL
     limb (mTAL)
                                             → ↓o2 requirement
       MEDIATORS AFFECT MEDULLARY
              BLOOD FLOW

                                         Tubulo-glomerular
    Vasodilators      VASOCONSTRICTORS
                                             feedback

•   NO                • ET               • insulin-like growth
•   PGE2              • Angiotensin II     factor I
•   Adenosine         • ADH              • epidermal growth
•   Dopamine                               factor
•   Urodilatin (ANP                      • tumour necrosis
    analogue)                              factor
PHARMACOLOGICAL CONTROL OF RBF
     kidney is largely devoid of β2 receptors
                  ++ α1
    so CA
                  ++ renin angiotensin system
So, ischemia→ ++ CA→ renal cortical VC

  try to redistribute blood flow to the renal
  medulla
       THE IMMATURE KIDNEY
Children undergoing heart surgery are more vulnerable to
     postoperative renal dysfunction relative to adults
                                            1-3 y

• Normal full term                            ↓
                                      Full renal fun of
                                            adults
                                     Few weeks→
                                    gain most fun =
                                    Acidification of
                                         urine
                                 At birth: anatomic
                                 growth of 1 million
                                     nephrons

                             3rd trimester→ urine =
                             amniotic fluid = 1cup/hr

                        Depends on conceptional age
• Preterm
                        Delay to retain normal kidney function
 The Problematic Definition of
   Acute Kidney injury(AKI)
The Conceptual Definition of Acute Kidney injury
 (instead of ARF):

  “Sudden loss of renal function resulting in the loss of
   the kidneys’ ability to regulate electrolyte and fluid
   homeostasis”
  The Problematic Definition of
    Acute Kidney injury(AKI)
 Pediatric AKI definition: a moving target
 Infants
   Cr in the first few weeks of life may reflect maternal
    values
 Children
   Low  baseline Cr makes 0.2-0.3 changes in Cr
    significant
   Varying muscle mass

 Adolescents
   Similar   to adults
  The Problematic Definition of
    Acute Kidney injury(AKI)
 Over    30 published ARF definitions
   Allbased on increased serum creatinine levels
   Despite extensive adult hospitalized patient study over
    the past 50 years


 Widelyvarying spectrum dependent upon study
 aims and hypothesis
   Severe (ARF requiring dialysis)
   Modest (serum creatinine increase of 0.3 mg/dl)
  The Problematic Definition of
    Acute Kidney injury(AKI)
• Diagnostic criteria for acute kidney injury
    http://ccforum.com/content/11/2/R31
 An abrupt (within 48 hours) reduction in kidney function currently defined
  as an absolute increase in serum creatinine of more than or equal to 0.3
  mg/dl (≥ 26.4 μmol/l), a percentage increase in serum creatinine of more
  than or equal to 50% (1.5-fold from baseline), or a reduction in urine output
  (documented oliguria of less than 0.5 ml/kg per hour for more than six
  hours).
    NB: - 2 cr levels within 48hrs.
        - adequate hydration
         - variation of serum creatinine with modern analyzers is relatively small and therefore
          increments of 0.3 mg/dl (25 μmol/l) are unlikely to be due to assay variation
Classification/staging system
   for acute kidney injury



     RIFLE         MODIFIED
RIFLE classification of AKI




            http://ccforum.com/content/11/2/R31
            Modified from RIFLE
Stage   Serum creatinine criteria                 Urine output criteria
1       Increase in serum creatinine of more than Less than 0.5 ml/kg per
        or equal to 0.3 mg/dl (≥ 26.4 μmol/l) or  hour for more than 6
        increase to more than or equal to 150%    hours
        to 200% (1.5- to 2-fold) from baseline


2       Increase in serum creatinine to more than Less than 0.5 ml/kg per
        200% to 300% (> 2- to 3-fold) from        hour for more than 12
        baseline                                  hours
3       Increase in serum creatinine to more than Less than 0.3 ml/kg per
        300% (> 3-fold) from baseline (or serum     hour for 24 hours or
        creatinine of more than or equal to 4.0     anuria for 12 hours
        mg/dl [≥ 354 μmol/l] with an acute
        increase of at least 0.5 mg/dl [44 μmol/l])



                                      http://ccforum.com/content/11/2/R31
Difference between two classifications

                                                         Modified
    RIFLE                 Difference
                                                          AKI
            Up to 1 wk                 Within 48hs
                         Cr changes

                            Renal
              Stages     replacement     Stage 3
               3,4,5       therapy        only

                                       1→Risk in RIFLE
                                       2,3→Injury and
              5 stages    staging      Failure
                                       No 4,5 as being
                                       chronic
    Aetiology of postoperative renal dysfunction

                            Risk Factors (In General)

          PREOPERATIVE                          INTRAOPERATIVE

          ARTERIOPATHY                   1.   Hypovolemia→
   Pre-existing renal disease.               neurohormonal effects
   IDDM
   Age ˃65ys or ˂2ys
                                         Sympatho-      aldosterone
   Major vascular disease.
                                         adrenal        ADH
                                                        Angiotensin
                                                         glucocortcoids



                                                    VC
                                         2. nephrotoxins:→intrarenal VC
                                                         →↑ osmotic load
3. Renal ischemia: by concurrent
   use of ACEI
4.Inflammation: gut ischemia→
   endotoxemia→ cytokines
5.Genetic predisposition:
      certain gene deletion
    →↑% of inflamm. response.
    →↑ IL6, IL10→↑% of renal
                    dysfunction

         this deletion is more
  with same congenital heart
  disease
The etiology of renal dysfunction in
          cardiac surgery
    Preoperative           Intraoperative             Postoperative

    Lack of renal          Decreased renal            Systemic
    reserve                perfusion                  inflammation
    Renovascular           hypotension                Reduced LV
    disease                                           function
    Prerenal azotemia      lack of pulsatile flow     Vasoactive agents

    recent diuresis        Vasoactive agents          Hemodynamic instability

    NPO status             anesthetic effects         Nephrotoxins

    impaired LV function   Embolic events             Volume depletion

    ACEI/ARB               CPB-induced inflammation   Sepsis

    Nephrotoxins           Nephrotoxins
    intravenous contrast   free hemoglobin

    other medications

    Endotoxemia
    Inflammation
      More Risk in children
• Immature kidney
• More dependent of renin angiotensin
  system for perfusion.
• Risk factors are
 as adults +
     Neonatal age group
    Cyanotic heart disease
    CPB duration
    Low CO
    Perioperative hypotension
            In cyanotic heart disease
1. Still most imp risk factor is low CO.
2. Associated pre existing renal anomalies: eg.
            Trisomy 21 (down syn)
            Trisomy 18 (Edward syn)
            Trisomy 13 (Patau syn)
            VATER association
            22q11 microdeletion

3. chronically→ cyanotic ht dis → chronic hypoxia
          3 stages
     ectasia of glomerullar capillaries→benign proteinurea (early sign
                        5 ys age                 of renal dysfunction)

    mesangial proliferation with destruction changes of capillary wall
                   2nd decade
                         glomerular sclerosis
        WHAT TO DO?




EARLY IDENTIFICATION    EARLY
RENAL INJURY           PREVENTIVE
  (MARKERS)            MEASUERS
IDENTIFICATION OF RENAL INJURY
                          Urine volume


                       Urine specific gravity


                         Urine osmolality


Renal function tests   Serum creatinine and
                        blood urea nitrogen

    available for          Urine/plasma
                          creatinine ratio

     clinical use       Urine/plasma urea
                               ratio

                         Urinary sodium
                            excretion

                       Fractional excretion
                            of sodium

                       Free water clearance

                            Creatinine
                            clearance

                         Renal blood flow
IDENTIFICATION OF RENAL INJURY
         Classic methods
                  Serum creatinine
• Easy measurement
• Proportional to GFR in steady state (not in acute injury)
• Affected by GFR in addition to tubular secretion,
  generation and elimination of creatinine.
• Varies with intravascular volume muscle mass, age, and
  sex, and it is affected by muscle trauma, fever, liver
  disease, and immobilization.
• 50% of the function of the kidney can be lost without an
  increase in sCr.
• Change with age. eg. sCr of 1.5 mg/dL corresponded to
  a GFR of approximately 77 mL/min in a 20 year-old
  black male, it corresponded to merely 36 mL/min in a 80
  year-old white female.
                          CASE
A 10-day-old male infant weighing 950 g was scheduled for
   ligation of patent ductus arteriosus (PDA).
•     He was born at 29 weeks gestation and was intubated
   immediately after delivery because of respiratory distress. His
   condition improved over the following 4 days. However, on the
   fifth day of his life the respiratory distress worsened and a
   murmur was heard over his chest. Medical treatment for PDA
   was attempted unsuccessfully. His blood pressure was 60/40
   mm Hg, heart rate 150 beats/minute. The laboratory data
   were as follows: white blood cells (WBCs), 17,000/L;
   hemoglobin, 11 g/dL; hematocrit, 34%; urine specific gravity,
   1.005; protein 1+; sugar 1+; serum calcium 6.0 mg/dL; blood
   glucose 60mg/dl, S creatinine 1.6mg/dl ; and arterial blood
   gases: pH, 7.30; PaCO2, 45 mm Hg, PaO2, 60 mm Hg on
   FIO2 50%; inspiratory pressure, 30/4 cm H2O; and ventilation
   rate, 25 breaths/minute.
• The creatinine levels of term infants at birth are 0.6 to 1.2
  mg/dL, but within 1 month fall to levels of 0.1 to 0.2 mg/dL.
  Preterm infants have relatively high serum creatinine levels
  compared with term infants. They are 0.8 to 1.8 mg/dL at birth
  and fall to 0.2 to 0.8 mg/dL in 1 month.
• The normal BUN level is 10 to 20 mg/dL in term infants,
  whereas it is 16 to 28 mg/dL in preterm infants.
• In infants weighing 1,000 to 3,300 g, the normal urine-specific
  gravity is 1.005 to 1.010. A urine specific gravity of more than
  1.020 suggests dehydration.
• Glucosuria 1+ normally presents in 13% of preterm infants
  who are less than 34 weeks gestational age because the
  preterm infant has a decreased renal tubular reabsorption for
  glucose. After 34 weeks of gestational age, glucosuria is
  usually associated with hyperglycemia.
• Albumin is normally filtered by the glomerulus and is
  completely reabsorbed. However, because of tubular
  immaturity, 16% to 21% of preterm infants have proteinuria.
IDENTIFICATION OF RENAL INJURY
         Classic methods
 Creatinine clearance (ClCr) = (urine Cr × urine volume)/ serum creatinine ≈ GFR


 Cockcroft-Gault formula:
                 CrCl = ([140 - age] X weight)/(72 X Scr)
                                   (multiplied by 0.85 if female sex)
  overestimates GFR because tubular secretion of creatinine is ignored

FENa is another measure to assess kidney function
                FEs =(Us × V) / Ps   FE =the fractional excretion, s =any substance
                          GFR        Us =the urinary concentration of the substance
                                     Ps = the plasma concentration, and V =the urine flow rate.
renal failure index (RFI) =  UNa
                           Ucr/PCr
Both RFI and FENa diff. bet renal and prerenal impairment
Also modified by diuretics
IDENTIFICATION OF RENAL INJURY
         BIOMARKERS
• Are urinary kidney-specific proteins.

 Ideally
       AKI would have a biomarkers like
 myocardial infarction (i.e. troponin-1)

 Currently no Troponin-I like marker to identify the
 site or severity of injury, although various
 markers are being evaluated
IDENTIFICATION OF RENAL INJURY
         BIOMARKERS
IDENTIFICATION OF RENAL INJURY
         BIOMARKERS
                                NAG
                                 AP
             URINARY            Ϫ GT
             ENZYMES           α GST
                               π GST



BIOMARKERS
                           Α1 microglobulin
                           β2 microglobulin
             URINARY LOW      Cystatin C
              MOLECULAR
               PROTEINS        NHE 3
                               NGAL
                                KIM 1
IDENTIFICATION OF RENAL INJURY
         BIOMARKERS
 Current status of promising acute kidney injury (AKI) biomarkers in various
clinical situations
IDENTIFICATION OF RENAL INJURY
         BIOMARKERS
Example :
                     Cystatin C

     Cysteine proteinase inhibitor.
     Not depend on muscle mass, sex, and age
     Not affected by inflammation, fever, and extrinsic
      substances
      Allow earlier detection of renal impairment than
      sCr.
 KIDNEY-SPECIFIC PROTEINS AND
      CARDIAC SURGERY
all original studies from 1990 to 2005 in which kidney-specific
    proteins were measured in patients undergoing cardiac surgery
    were reviewed…………..but:
    Mostly are observational studies.
    Small no. of patients.
    Pt population are wide (off- and on-pump surgery, CABG
     surgery, valve surgery, and even children with correction of
     congenital heart disease).
    The period of studying varied from 1 hour to 40 days after
     surgery.
    The conventional measures for detecting kidney injury varied
     widely; some used CrCl, others used sCr or UOP.
    No common definition for AKI.
    No long term kidney function followup.
   So we need more specific studies
Prevention of renal dysfunction and
 renal protection in cardiac surgery

 The superior doctor prevents sickness;
    The mediocre doctor attends to
         impending sickness;
    The inferior doctor treats actual
               sickness;
                     Chinese proverb
  Strategies of Renal Protection
1. Maintain adequate oxygen delivery—by ensuring adequate cardiac
   output, adequate oxygen carrying capacity, and proper haemoglobin
   saturation.
2. Suppression of renovascular constriction—by ensuring adequate
   volume preload, use of infusions of mannitol, calcium entry block,
   and angiotensin converting enzyme inhibitors.
3. Renal vasodilation—by dopaminergic agents, prostaglandins, and
   atrial natriuretic peptide.
4. Maintain renal tubular flow—by loop diuretics and mannitol (which
   may act to prevent tubular obstruction which can cause cellular
   swelling, ischaemia and death).
5. Decrease oxygen demand—by use of loop diuretics and mild
   cooling.
6. Attenuate ischaemic reperfusion injury—as a result of the release of
   oxygen free radicals and calcium ions.
Prevention of renal dysfunction and
 renal protection in cardiac surgery
                                  Prevention of
                                      AKI


    Strategies
                     Adequate        Pharmacological
                                                                           CPB
     for renal
                     hydration         intervention
    protection

                                                                      hemodilution
 • Enhancement of                                   • Theophylline
                               • Dopamine               • Cardiac
           DO2
                            • Dopexamine                              hypothermia
  • Suppression of                                     glycosides
                             • Fenaldopam           • Ca+2 Channel
       reflex V.C.
                           • ACEIs & ARBs                             Pulsatile perfusion
 • Pharmacological                                      blockers
                                • diuretics       • Corticosteroids
       renal V.D.
                                   •ANP                  • Insulin
    • Maintance of
                         • N- Acetylcysteine          • Endothelin
      tubular flow                                                    Oxygenators
   • Decrease VO2                                      antagonist      And filters
                                                           •PGs
                                                            •NO
                HYDRATION
• Studies for crystalloids vs colloids (no difference)
• Type: ?? NS, LR,…….Hetastarch,albumin…
• Amount:??controversy
   Target CVP of at least 14-16mmHg
   Fill till signs of overfill just manifest
      o CVP>16mmHg
      o Drop in PO2/FO2 ratio
      o Bilateral crackles
      o S3
      o Loss of stroke volume variation
                                PREVENTION
                                   CPB
                                  Why CPB is risky?
             Inflammatory                                              postbypass            Associated
           response during                                     Ischemic reperfusion injury   hypoxia and
                                                                                             hypotension
                                                                + low CO & hypovolemia
                bypass


Increased vasoconstriction        Evidence of vascular
       (due to ↑ ET)           obstruction and congestion



                              up-regulation
                               of adhesion
                                              A reduction in
                               molecules,
  Reduced                                      nitric oxide
                                    with
blood flow in   Endothelial                    production
                                increased
 capillaries    dysfunction                       (which
                                 levels of
                                                 inhibits
                               ET1, which
                                                adhesion)
                                promotes
                                 adhesion
                     Inflammation in CPB
STIMULI ( surgical trauma, blood contact with CPB surface, Endotoxemia, Ischemia, Hb)




       MEDIATORS                                                Adhesion Molecules
Complement:C3a,C5a               Transcription Factor               E,P,L selectin
Cytokines:IL1,2,6,8,10,     (NF-κB (nuclear factor kappa-        Integrin CD8/CD11
           TNFα                light-chain-enhancer of      Ig superfamily: ICAM,VCAM
                                  activated B cells)
O2 free radicals



                                       Effects
                                Leucocyte extravasation
                                  Lipid perioxidation
                                        Edema
                                      Cell death




                            ACUTE KIDNEY INJURY
Glomerulus from group A anesthetized and heparinized
only.
Well-filled capillaries with clear definition of glomerular
anatomy.
AA afferent arteriole; EA efferent arteriole;
GC glomerular capillaries; PD polar diameter
              PATHI ET AL
              RENAL MICROCIRCULATION AND CARDIOPULMONARY BYPASS
              Ann Thorac Surg1998;65:993–8
Glomerulus from group B (cardiopulmonary
bypass at 28°C, for 30 minutes)
Smaller glomerulus with narrowed
capillaries suggesting diversion of flow
through alternative channels
              PATHI ET AL
              RENAL MICROCIRCULATION AND CARDIOPULMONARY BYPASS
              Ann Thorac Surg1998;65:993–8
Glomerulus from group C (cardiopulmonary
bypass at 28°C, for 120 minutes)
Severe reduction in size of glomerulus with
complete loss of functional unit. These act as
shunts between afferent and efferent arteriolar
systems
                 PATHI ET AL
                 RENAL MICROCIRCULATION AND CARDIOPULMONARY BYPASS
                 Ann Thorac Surg1998;65:993–8
Glomerulus from group D (cardiopulmonary bypass at 28°C,
120 minutes; an 30 minutes of normothermic perfusion at the
end)
Some recovery of anatomy of the functional unit, although
shunting of blood past the nephrons is still evident. Narrowing
of the capillaries and increase in intercapillary spaces suggest
interstitial edema
                      PATHI ET AL
                      RENAL MICROCIRCULATION AND CARDIOPULMONARY BYPASS
                      Ann Thorac Surg1998;65:993–8
     CARDIOPULMONARY BYPASS
       PROCEDURAL FACTORS
clinically, although there are multiple experimental and clinical studies
suggesting that various procedural aspects of CPB may be detrimental to
   the kidney, there is no clear consensus that CPB per se causes renal
                                   failure.

                         ??                 +
                     PROTECTIVE         PROTECTIVE
                 HEMODILUTION
                      2 opposing effects
As O2 carrying capacity α HCT           Hemodilution

                            ↓ afterload                ↓ viscosity
     Hemodilution

                                 ↑ CO      ↑ bl. flow in   ↓RBCs oxygenation
                                          microcirculation at postcapillary
     ↓ O2 transport                                             venules

                                                 ↑ O2 Delivery



     the net effect is          ↑ O2 delivery
     HEMODILUTION
From the figure:
    the most suitable Hct
is 28-30%

                   blood
    priming for pediatric
         population

Hint H. The pharmacology of
dextran and the physiological
background for the clinical use of
Rheomacrodex and Macrodex. Acta
Anaesth Belg 1968;19:119–138
          HYPOTHERMIA
• ↓ metabolic rate
• ↑ intracellular PH
• ?? Controversy about:
      Warm cardioplegia
     Warm Ht surgery ( normothermic bypass)
• But studies→ less evidence of protective
  effects of hypothermia on kidneys.
  PULSATILE PERFUSION
More physiologic

Improve microcirculation

But no evidence that is superior to non
 pulsatile perfusion in renal protection.
  OXYGENATORS AND FILTERS
o When bubble oxygenators was used → multiple
  emboli was found in brain, heart and kidneys →
  less with membrane oxygenators and arterial
  filters.
o But in pediatric units → only 30% of centers use
  filters because large amount of volume required
  to prime the filters.
                         PREVENTION
                        DRUG THERAPY
                              basic   Others
                                                                                ET
                                                                            antagonists



                                                   PGE1
Dopamine                       ANP

                                                                          fenoldopam


dopexamine
                              ACEI
                                                                               clonidine
   Loop
 diuretics   mannitol
                        CCB                             pentoxyifylline




                                                                                dexamethasone



                                               N-acetylcysteine




                                                                      A single-chain antibody specific for human
                                                                                   C5 (pexelizumab(
             DOPAMINE
 ↓ Activity of Na+/K+ ATPase.
 Renal V.D.(D1 receptors in low dose
   0.5-2.5 µg/Kg/min).
 ↑ CO (β1 receptors ˃ 5-10 µg/Kg/min).
 Studies → controversy → ?? Diuretic
                          → ++ ↑ CO
            DOPEXAMINE
• Sympathomimetic agent.
• Mainly on β2 agonist→
    +ve inotropic
    +ve chronotopic
    ??↓ vascular resistance
• In animals (not in human)→DA1 agonist
  →↑ renal bl. flow→ diuresis
• But human→ diuresis only by ↑ CO.
         LOOP DIURETICS
          FUROSEMIDE
• Renal V.D.
• ?? Dose: 0.5mg/kg/min. for 48hrs
• ?? Effective prophylaxis (only pigment
  nephropathy)
• High-dose furosemide has been shown to
  decrease the duration of oliguria and need
  for dialysis in patients with ARF, but has
  no effect on mortality.
              MANNITOL
• Mech:
  Osmotic diuretic.
  Renal V.D. by ↑ PG production.
  Free radical scavenger→↓ ischemic
   reperfusion injury.
• AGAIN?????? Clinical trials failed to prove
  evidence
    Calcium Channel Blockers

• eg: verapamil, diltiazim
• Mech:↑cytoplasmic Ca+ blocked arteriolar vc
                          by CCB
                ACE I
• Pretreatment with ACEI→↓ the increase of
  renal vascular resistance associated with
  cross clamping.

• But →?? May ↑ postop. Renal dysfunction
 Atrial Natriuretic peptide (ANP)
            (Urodilatin)
   • ANP produced due to stretch by volume overload
                • VD of afferent arterioles.
                                                ↑GFR
                   VC of efferent arterioles.
• Anaritide, a synthetic analogue of ANP, there was
  improved mortality in treated patients with oliguria.
• administration of urodilatin (a natriuretic peptide found
  in human urine) is beneficial in oliguric patients after
  cardiac surgery and significantly reduces mortality and
  the need for dialysis.
• In comparison with circulating ANP, urodilatin exerts
  greater diuretic properties. Its method of action is
  thought to involve both improving renal blood flow and
  acting upon the distal collecting system
       OTHER POSSIBLE
         THEREAPIES
            1-ET Antagonist
• ET1→ V.C
• We need either→ ET receptor antagonist
             OR→ ET antibodies
           2- Prostaglandins E1
Endogenous renal V.D
  3-DOPAMINERGIC DRUGS
       FENOLDOPAM
• Selective DA1 agonist.
• Introduced mainly as an antihypertensive
  agent.
• It ↓ blood pressure in a dose-dependent
  manner while preserving RBF and GFR.
• Dose: 0.03-0.05 ng/kg/min
          3-FENOLDOPAM
• Mech1: DA1 agonist→VD→↑ RBF.
• No effect on myocardial contractility as
  dopamine(no β effect)→ less
  arrhythmogenic and no tachycardia.
• Mech2: -- of Na+ transport in the mTAL
         region →↓ O2 utilization.
              3-FENOLDOPAM
• "When  we looked at the results, there was no
 difference between the fenoldopam group and
 those treated with standard therapy," says
 Landoni (Continuous Improvement in Cardiac
 Surgery Program )(CICPS).
     End point        Fenoldopam, n     Dopamine, n (%)   p
                      (%)
     Acute renal      17 (42.5)         16 (40)           0.9
     failure (25%
     increase in
     serum creatinine
     from baseline)



     Renal            4 (10)            4 (10)            0.9
     replacement
     therapy
     Death            4 (10)            3 (7.5)           0.5

                                  Bove T et al Circulation 2005; 111:3230-3235
  Continuous Improvement in Cardiac Surgery
              Program (CICPS)

                 concluded that

         at high risk patients (eg. CABG)

   ARF depends on factors linked to poor cardiac
performance and advanced atherosclerotic vascular
                    disease

            not to vasodilatory effects

            so, in pediatric population

               need more studies
             4-CLONIDINE
• α-adrenergic ( α1 and α2) agoniost.
• Mech:
  inhibits ADH production (central α1 effect).
  Inhibits reabsorption of Na and H2O
   ( peripheral α2 effect).
  block adrenergic VC stimuli to surgical stress
    →↓ renal hypoperfusion.
• Dose: 4µg/kg
              5-PENTOXIFYLLINE
o PDE Inhibitor→-- activation of neutrophil by
  TNFα and IL-1, and TNF-α release by
  inflammatory cells.
o No direct effect on kidneys.
                    6-STEROIDS
                (DEXAMETHASONE)
o failed to protect against renal dysfunction after
  cardiac surgery.
o A recent study examined the effect of blocking
  complement activation in patients who
  underwent CPB
  7- A single-chain antibody specific for
          human C5 (pexelizumab)
C5 → block complement activation→
   ??renal function after CPB


             8- N-acetylcysteine (N-AC)
o block inflammation and oxidant stress in cardiac
  surgery patients.
o studied most extensively in the prevention of
  radiocontrast induced nephropathy.
                  SUMMARY
• Renal failure is relative rare complication but
  associated with a 10-fold increase in surgical
  mortality.
• Although CPB is a nonphysiologic state that alters
  renal blood flow and many neuroendocrine
  responses affecting the kidney, there is little clear-
  cut evidence that CPB per se is responsible for
  renal dysfunction.
• Risk factors mainly:→perop→renal dysfunc
                    →intraop→infammatory response
                      →postop→↓ COP
• Protection mainly to maximize postop. COP to
  avoid renal hypoperfusion.
                                      Assess hydration and circulation volume.

               Principles of management of
Clinical examination
                                      Urinary bladder palpable?

Measure UOP accurately                Place a urinary cath.

Biochemistry  oliguria and acute renal failure
                                      Urinary and plasma electrolytes, urea, creatinine and osmolarity.

                                      Calculate FENa

                                      Calculate U: P ratios for Na+, urea and osmolarity.
Nephrotoxins                          Withholding potentially toxic drugs (eg vancomycin, aminoglycosides,...)

                                      Myoglobin(hyperpyrexia)

                                      Hemoglobin(hemolysis)

                                      Initiate specific therapy if appropriate
Circulation                           Normalize circulating volume and cardiac output

                                      Optimize treatment of heart failure.
Renal ultrasound                      Pattern of renal arterial and venous blood flow (renal artery or vein thrombosis)

                                      Appearance of kidneys.

                                      Rule out potential obstruction.
Fluid management                      Initially restrict fluid intake to 30% of normal requirement + UOP

                                      Renal replacement therapy may be necessary if therapeutic or metabolic demand can not be met within
                                      these fluids limits.
Metabolic management                  Frequent measurements of plasma biochemistry

                                      Danger of hyperkalemia

                                      Rapid rise of urea/creatinine may determine early use of renal replacement therapy
Drug therapies to decrease injuries   Furosemide

and promote recovery                  Mannitol

                                      Hyperkalemic management
Renal replacement therapy             Peritoneal dialysis

                                      Hemofilteration

                                      Hemodialysis
                     SPECIAL SITUATION
                      AORTIC SURGERY
•   Paraplegia and renal failure are the main determinants in postoperative mortalities.
•   In pediatrics eg. Coarctation, aneurysm (Marfan,..)......
•   Problem: Aortic cross clamp (suprarenal vs infrarenal)
•   renal protection including:
      Hypothermic CPB with circulatory arrest.
      Selective volume and pressure controlled perfusion by: Retrograde aortic
         perfusion,followed by
           o   warm blood visceral perfusion,
           o   Cold crystalloids renal arteries perfusion
           o   antegrade cold blood visceral perfusion,
           o    retrograde cold blood perfusion, and
           o   the perioperative use of a renal protective pharmacologic agent, fenoldopam.
       Perform selective perfusion by 4 branched tubing system connected to extracorporeal
       circulation with the 4 braches connected to celiac, superior mesenteric and 2 renal arteries.
      Shunts
           o both temporary and permanent .
           o These included
                 permanent axillo-bifemoral graft ,
                 aorto iliac Gott shunt , axillo-femoral Gott shunt ,
                 temporary axillofemoral graft ,
                 combination of double clamping then temporary perfusion using a Javid
                   shunt.
           o These techniques have the disadvantages of complexity or of incurring
             significant period of renal ischaemia.
                 ASWERS
1. The risk of development of acute renal
  failure after cardiac surgery is highest in:
• a. Neonates.
• b. Infants.
• c. Children.
• d. Adults.
1. A
  Kidneys are able to maintain renal blood flow over a wide
    range of systemic blood pressures by autoregulation of
    intrarenal vascular resistance. Therefore, hypotension with
    renal hypoperfusion may or may not produce ischemic renal
    injury. However, these autoregulatory mechanisms are not
    well developed in neonates. Neonates have high renin
    levels, which in turn, are associated with decreased
    glomerular filtration rate (GFR) and reduced outer cortical
    blood flow. The cortical glomeruli are immature and so are
    their corresponding tubules. This pattern of high renin and
    reduced outer cortical blood flow makes neonates more
    vulnerable to renal dysfunction as a result of hypotension of
    systemic pressures only slightly below the normal range. In
    animal studies, newborn animals have decreased production
    of atrial natriuretic peptide in response to saline challenge.
    All these factors combined make the incidence of acute
    renal failure in neonates, after cardiac surgery, higher than
    in older infants and children. (Nichols DG, et al. Critical
    Heart Disease in Infants and Children, Mosby 1995; pp. 125,
    562.)
2. Which of the following causes
vasodilation of the cortical vasculature?
a. Mannitol.             c. Both.
b. Furosemide.           d. Neither.
2. C
Furosemide causes vasodilation of the cortical vasculature by
   direct action and through release of prostaglandins.
   Furosemide maintains renal blood flow and tubular blood flow
   when cardiac output is compromised. Mannitol is also a
   vasodilator of the cortical vasculature that increases renal
   blood flow either directly by drawing fluid from extravascular
   to intravascular space, thus increasing total plasma volume,
   or by increasing prostaglandin production. Increased plasma
   volume alone does not fully explain the effects of mannitol,
   because volume expansion with saline improves renal blood
   flow without improving GFR. The improvement in GFR seen
   with mannitol is associated with a decrease in afferent and
   efferent arteriolar resistance, which is probably mediated by
   prostaglandins. (Rogers MC, et al. Textbook of Pediatric
   Intensive Care, 2nd Edition; pp. 1192–1194, 1202.)
3. Clinical settings in which mannitol has
definitely been shown to be effective in
preventing the deterioration of renal function
is:

a. During and after cardiopulmonary bypass.
b. During and after aortic cross-clamping.
c. During and after hypovolemic shock.
d. Before the administration of cisplatin.
e. None of the above.
3. D
Clinical studies comparing prophylactic
   administration of mannitol (or furosemide) with
   maintenance of adequate intravascular volume
   during cardiopulmonary bypass failed to reduce
   the incidence of postoperative renal dysfunction.
   However, there are experimental studies that have
   shown some beneficial effects of mannitol.
   Mannitol has been shown to be effective in
   preventing deterioration of renal function before
   administration of Amphotericin B and Cis-
   Platinum. (Rogers MC, et al. Textbook of Pediatric
   Intensive Care, 2nd Edition; pp. 1194,1195;
   Nichols DG. Critical Heart Disease in Infants and
   Children, Mosby 1995; pp. 129,130; Olivero JJ, et
   al. Br Med J, 1975; 1:550; Hayes D, et al. Cancer,
   1977; 39:1372.)
4. Which of the following statements is least accurate
regarding acute renal failure?

a. Adults with no underlying renal disease who develop acute
renal failure have a worse prognosis compared with children.
b. Following cardiac surgery, the incidence of acute renal failure
is higher in children than in adults.
c. Children over the age of 2 years with acute renal failure have
a much better outlook with meticulous medical care.
d. Spontaneous recovery from acute renal failure is likely to
begin 1–3 weeks after onset.
e. The mortality rate for children with acute renal failure is much
higher than in adults
4. E
Children have a lower mortality compared
  with adults. (Rogers MC, et al. Textbook of
  Pediatric Intensive Care, 2nd Edition; pp.
  1198–1201.)
5. Which of the following statements is true
regarding management of suspected acute renal
failure?

a. In euvolemic patients, the rapid intravenous
administration of mannitol should result in a urine
output greater than 0.5 mL/kg within 1 hour if a
prerenal etiology dominates.
b. The vasodilatory and natriuretic properties of
furosemide are beneficial when administered early in
the course of acute renal failure.
c. In euvolemic patients, furosemide in an incremental
dose of up to 10 mg/kg may be used.
d. If there is no response to a fluid challenge, low dose
dopamine could be added.
e. All of the above
6. In a patient who has just been admitted to the
pediatric intensive care unit with new onset of
acute renal failure, which of the following
pathophysiological changes is least likely to
occur?

a. Blood urea nitrogen (BUN) and creatinine will rise
at 10 and 0.5 mg/dL/day, respectively.
b. Serum HCO3 decreases by 2 mEq/L/day because
of release of tissue phosphate.
c. Serum K+ increases by 0.3–0.5 mEq/L/day.
d. Hypernatremia is commonly observed.
e. Hypophosphatemia and associated hypocalcemia
may develop rapidly after the onset of acute renal
failure
5-6. E, D
All of the strategies mentioned are appropriate
  for oliguria in a setting of suspected renal
  insufficiency. With the onset of acute renal
  failure, hyponatremia is more commonly seen
  owing to the dilutional effect of intake of fluid
  orally, which is mostly hypotonic. (Rogers
  MC, et al. Textbook of Pediatric Intensive
  Care, 2nd Edition; p. 1202. Nichols DG.
  Critical Heart Disease in Infants and Children,
  Mosby 1995; pp. 128–138.)

				
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