Pediatric Sepsis for SF Conference

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     Aspects of the Pathophysiology of Sepsis
                                                                                                                                                                                                                          Children and Women’s
                   Syndromes in                                                                                                                                                                                             Due to open 2011
                      Children                                                                                                                                                                                        At UMHS…230-something days
      Survival Flight Conference, March 2011

Marie M. Lozon, M.D., FAAP
Associate Professor of Emergency Medicine
and Pediatrics
                                                                                                                                                   Many cases of septic shock,
Director, Children’s Emergency Services                                                                                                         due to complexity of our population

University of Michigan Medical School

                                                                                                                                                       Pediatric Septic Shock- Associated
Pediatric Shock                                                                             Pediatric Septic Shock                                     Infections

5 major types of shock (hypovolemic, septic,                                                     Sepsis is “a systemic inflammatory response              Infections associated with septic shock:
                                                                                                                                                            Staph mentioned in some sources as the most common cause
   cardiogenic, “distributive” and obstructive)                                                   syndrome” (SIRS) associated with infection                of – this includes all types of staphylococcus, but aureus most
  Concentration on septic shock, with                                                           Sepsis is the most common cause of                        common type
                                                                                                                                                            Strep concerning still in USA despite widespread vaccination
   highlights on differences in the                                                               mortality in children worldwide                       
                                                                                                                                                            with pneumococcal vaccine
   pathophysiology between adults and                                                            In many countries (USA included), neonates               Pseudomonas
   children/neonates                                                                              and small infants at highest risk                        Gram negative rods (E. Coli)
  Discussion of SIRS and MODS                                                                                                                             Neonates can have sepsis-like symptoms from HSV

                                                                                       Pediatric Septic Shock-Risk
Pediatric SIRS and Septic Shock                                                        Factors

    Mediators of tissue damage assist progression from                                    Seriously injured
     compensated to uncompensated shock
     –    Vascular endothelium both a target of tissue injury and                          Neonates
          source of mediators that lead to further injury
     –    Other systemic factors                                                           Chronic illness
               Complement pathway
               Coagulation system                                                         Host immunosuppression (HIV, asplenia,
               Activation of white cells, platelet-activating factor, nitric oxide,
                oxygen free radical production
                                                                                            congenital immunodeficiencies, chemo,
     –    Bacterial sources of tissue injury                                                chronic antibiotics, malnutrition)
               Endo- and exotoxin, which induce production of inflammatory
                molecules such as interleukins and other proinflammatory                   Invasive devices                                                                   Host response to injury or infection:
                mediators                                                                                                                       Shock states vasoplegia +Myocardial depressionAcute renal FailureAggravate capillary leakWorsen Lung injury
                                                                                           Burn wounds/trauma wounds


Pediatric SIRS Definition                                  Pediatric SIRS…other symptoms                                          Definitions of Shock

    Presence of 2 of 4 criteria:                              Rigors, grunting, mental confusion (irritable                         The most basic definition: inadequate
     –    Core temperature > 38.5C° or < 36° C                  or lethargic in infant)                                                perfusion to tissues, impairing the delivery of
     –    Tachycardia (HR > 2 SD normal for age with                                                                                   oxygen and substrate for metabolic needs
          absence of other stimulus OR, for children < 1
                                                               Skin mottled or with petechiae or purpura
          year, bradycardia (HR<10th percentile for age)        (UNDRESS)
     –    Mean respiratory rate > 2 SD above normal            History of poor feeding in infant, decreased
     –    Leukocyte count elevated or depressed for age         tone, hypoglycemia
          (not because of chemotherapy) or >10%
          immature neutrophils

Definitions of Shock                                       Pediatric Septic Shock                                                 Overview of Shock Progression

                                                                                                                                  Initial insult triggers shock, disrupting blood flow
                                                                                                                                     to end-organs, causing inadequate tissue
                                                                                                                                     perfusion…compensatory mechanisms begin
                                                                                                 Threshold Heart Rates and Mean
                                                                                                   Arterial Pressures by Age…
                                                                                                                                     -maintain perfusion to vital organs to achieve
                                                                                                                                     COMPENSATED shock. If treatment not
                                                                                                                                     optimal, DECOMPENSATED SHOCK
                                                                                                                                     develops which leads to MULTISYSTEM
                                                                                                                                     ORGAN DYSFUNCTION and DEATH

                                                                                                                                  Pediatric Multiple Organ Dysfunction
                                                           Compensatory Responses                                                 Syndrome

                                                               Increased heart rate (HR) and stroke volume                           Pediatric MODS- can occur with congenital heart
                                                               Increased vascular smooth muscle tone                                  disease, trauma, transplantation, but we will discuss
                                                                –    Regulated through neurohormonal changes in sympathetic            sepsis
                                                                     nervous system
                                                                –    Preserve blood flow to vital organs
                                                                                                                                      Regardless of age, organ dysfunction represents a
                                                                                                                                       continuum of physiologic abnormalities rather than a
                                                               Increased respiratory rate to promote excretion CO2
                                                                                                                                       dichotomous state and may occur with or without any
                                                               Increased renal excretion of hydrogen ions and                         identifiable source of infection
                                                                retention of bicarbonate
                                                               Maintenance of vascular volume facilitated by renin-                  MODS=2 or more organ systems fail simultaneously
                                                                angiotensin-aldosterone and atrial natriuretic factor                 Increasing number of failed organ systems=
                                                                axes, cortisol and catecholamine release                               increased mortality


Adult MODS vs. Pediatric MODS                                                 Pediatric Septic Shock                                                Pediatric Septic Shock

    Adult MODS risk factors                                                      Sepsis and Cardiovascular Organ Dysfunction                          Respiratory Changes (PaO2/FIO2 < 300,
     –    Delayed or inadequate resuscitation
     –    Persistent focus of infection or inflammation                            –    Cardiovascular dysfunction despite 2 boluses in one hour         hypercarbia, high O2 needs, need for mechanical
     –    Advanced age                                                             –    Decreased BP for age                                             ventilation)
     –    Chronic conditions (cancer, malnutrition)                                     Need for vasoactive drugs to keep BP in normal range OR
    Pediatric MODS
                                                                                   –                                                                    Mental status changes (Glasgow Coma Score < 11,
                                                                                        two of the following                                             or acute change from baseline)
     –    Risk factors LESS clear
     –    Less than one year of age?                                                         Unexplained metabolic acidosis
     –    Pattern different for neonates?                                                    Increased arterial lactate                                Hematologic (platelets < 80,000, INR >2)
     –    Developmental changes influence maturation of renal, liver and GI                  Oliguria                                                  Renal (Creatine > 2x normal for age)
          and nervous systems                                                                 Prolonged capillary refill > 5 seconds
     –    Drug metabolism
                                                                                                                                                        Hepatic (increased bilirubin and transaminase)
     –    Variations in body’s water balance and glomerular filtration rate                  Core to peripheral temperature gap > 3° C

Cardiovascular system dysfunction                                             Capillary Leak and ARDS                                               Capillary Leak and ARDS

    Although adults with septic shock experience                                 MODS associated with abnormal systemic
     increased cardiac output with vasoplegia, children                                                                                                   Platelet activation,
                                                                                                                                                                                                       Early injuryrestrictive
     with septic shock have unpredictable hemodynamic                              vascular permeability  capillary leak                                    Neutrophils,
                                                                                                                                                                                                       decreased compliance
     profiles                                                                      syndrome                                                              Macrophage infiltration
    20% with fluid refractory shock have the “classic”
     picture of high cardiac index and low SVR, in fact,                          Younger children with increased
     data may support that most children exhibit the                               susceptibility to capillary leakage                                                                                    More aggressive
                                                                                                                                                           Fibrin exudate,
     opposite                                                                                                                                            Membrane formation                                 ventilation
    Significant misconception: that shock only occurs                             –    Increased permeability of growing capillaries?
     with low blood pressure…we know that in children                              –    Changes in microvascular density associated with
     this can be a very late finding                                                    growth?                                                                                     Inflammatory mediators,
                                                                                                                                                                                   More leak, more damage to
                                                                                                                                                                                   Alveolar-capillary interface

                                                                              Inflammation, Coagulation,                                            Inflammation, Coagulation,
                                                                              Fibrinolysis                                                          Fibrinolysis

                                                                                  Sepsis Activation of coagulation system with                        Children’s reaction to the tissue factors that
                                                                                   inhibition of fibrinolysis triggered by inflammation
                                                                                                                                                         caused dysfunction of thrombosis and
                                                                                  LPS, TNF-α, IL-1 Activation of Coagulation
                                                                                   Factors VII, X and V                                                 fibrinolysis likely explain the results of trials,
                                                                                  Increasing thrombin generation and fibrin deposition                  when compared to adults, of Recombinant
                                                                                  Thrombocytopenia-associated MOD                                       Human Activated Protein C, leading
                                                                                   –    Many children with sepsis have reduced amount of cleaving        investigators to stop trial early and NOT
                                                                                        enzyme of ultralarge form of vonWillebrand factor into
                                                                                        smaller, less sticky fragments, meaning more                     recommend its use in young patients (they
                                                                                        microthromboses                                                  got head bleeds).


Neuroendocrine Response                                         Hypermetabolism                                                      Adaptive Immunity

    Previously mentioned renin-aldosterone and                     “Ebb phase” describes the phenomenon of                             Develops over several days after onset of infectious
                                                                     decreased metabolic rate and sometimes                               insult
     adrenal compensations/dysfunctions
                                                                     hypothermia at onset of severe infection                            Increased risk of nosocomial infections among
    “Sick euthyroid” syndrome: No change in                                                                                              critically ill children linked to “secondary immune
                                                                    “Flow phase” describes hypermetabolism starting
     TSH, normal free T4, but decreased total T3                                                                                          paralysis”
                                                                     within one day of injury
     and T4                                                                                                                              Hyporeactivity of circulating leukocyte
                                                                     –    In adults, hypermetabolism due to increased oxidation of
                                                                          glucose and fatty acids and gluconeogenesis through            Patients with activated cytoxic T-cells and natural
    Neonates experience suppression of growth                            lactate, etc                                                    killer cells in septic shock had higher mortality rates
     and other hormones when given dopamine,                         –    The phases of this phenomenon in children less clear           Prolonged lymphopenia correlated with pediatric
     which may aggravate above syndrome                                                                                                   MODS

Intestinal Mucosal Barrier and MODS                             Other Organ Dysfunction in MODS                                      Final Cause of Death in Septic Shock

    Older theories of gut bacterial or endotoxin                   Upper GI bleeding                                                   Cause of death in adults with septic shock is
     translocation not borne out clearly                            Neuromuscular syndromes                                              vasomotor paralysis
    Newer data support that mesenteric lymph                        –    “critical illness polyneuropathy”                              Contrast with children, who have low cardiac
     translocates factors that activate neutrophils                  –    Pure motor polyneuropathy                                       output which results in impaired O2 delivery
     and injure endothelial cells                                    –    Myopathies                                                      and cardiovascular collapse
    Gut ischemia-reperfusion reduces gut                            –    Worsened by steroids and neuromuscular                         Collapse most often related to intrinsic
     lymphoid tissue and may increase risk of                             blocking agents?                                                myocardial dysfunction

Background Pediatric Sepsis                                                                                                          Background: Pediatric Sepsis
Outcomes                                                                                                                             Guideline Outcomes

    Mortality already improving by 2002                                                                                                 Original guidelines an outgrowth of pediatric
     –    Advent of NICUs and PICUs over the years                                                                                        expert review of research/consensus
          brought reduction in mortality from sepsis from                                                                                 discussions as part of “Surviving Sepsis
          97% to 9% in the US, which is better than adult
          population                                                                                                                      Campaign”
     –    ACCM Clinical Practice Parameters for                                                                                           2002 Guidelines reviewed in 2007 by similar
          Hemodynamic Support of Pediatric and Neonatal                                                                                   expert panel method, using evidenced based
          Shock published to achieve “best practice” (0-5%
          mortality in previously healthy children and 10% in                                                                             system to assess outcomes of dissemination,
          chronically ill childen)                                                                                                        acceptance and implementation

                                                                                 This is an international consensus group


Background Pediatric Sepsis Guideline
Outcomes                                                                 Results of Review                                             Results of Expert Review: UPDATES

    Various studies of outcomes:                                            No major change in emphasis of early goal-
     –    Wills et al: near 100% survival when fluid resuscitation            directed therapy                                             In 2002, recommended NOT giving
          provided to children with dengue shock
     –    Maitland et al: reduction in mortality from malaria shock          First hour fluid resuscitation and inotrope                   cardiovascular agents until central venous
          from 18% to 4% (using albumin)                                      drug therapy directed to goals of threshold                   access achieved (concern regarding
     –    Han et al: reduction in mortality when guidelines used in           heart rates (HR), normal blood pressure,                      vasoactive agent through peripheral vein)
          community hospitals in USA, from 38% to 8%
     –    Lin et al reported that implementation in US tertiary center        normal capillary refill                                      Now, knowing central access could take
          achieved best practice mortality outcomes better than              PICU hemodynamic support                                      hours and mortality increased with inotrope
          targets (overall 6%)
     –    US child health outcomes database reports hospital
                                                                              –    Goals of saturation of mixed central venous blood        delay, now guidelines suggest inotropes (not
          mortality from severe sepsis 2.3% in previously healthy                  >70% and cardiac index 3.3-6 L/min/M²                    pressors) until central access obtained
          children and 7.8% in chronically ill children, down from
          global rate of 9% in 1999

                                                                                                                                       Understanding Adult vs. Pediatic
Results of Expert Review: UPDATES                                        Results of Expert Review: UPDATES                             Response to Sepsis

    2002 Guidelines did not make                                            2002 Guidelines made no recommendations                      Predominant cause of              Pediatric patient
                                                                                                                                            death in adult patient             predominant cause of death
     recommendations regarding use of sedatives                               about fluid removal
     or analgesia in children with septic shock                              Early aggressive fluid resuscitation remains
                                                                                                                                          Myocardial dysfunction
    New data reported that etomidate was                                     the goal, but studies show the importance of              Decreased Ejection Fraction
                                                                                                                                                                           Low Cardiac Output NOT low SVT
                                                                                                                                                                            Associated with higher mortality
     associated with higher mortality in septic                               early fluid removal in overloaded shock/
     shock and its use is NOT recommended in                                  MODS patients                                                    Tachycardia                               Attainment of optimal
                                                                                                                                              Reduced SVT
     this patient population                                                  –    Diuretics, peritoneal dialysis, continuous renal                                                          Cardiac index

                                                                                   replacement therapy (CRRT)
                                                                                                                                                              Maintain Cardiac Output

Emergency Department Therapies                                           Emergency Department Therapies                                Intraosseous Access

    Ideal first step: RECOGNITION OF SIRS                                   Vascular access often more difficult in child
     BEFORE SHOCK                                                             than adult
    ED Therapies directed toward restoring:                                 ACCM/PALS guidelines with essential age-
     –    Normal mental status                                                specific difference
     –    Threshold heart rates                                               –    Umbilical line in neonates
     –    Peripheral perfusion (capillary refill < 3 seconds)                 –    Rapid Intraosseous access in children
     –    Palpable pulses                                                     –    US guidance of central venous access, if needed
     –    Normal blood pressure


                                                                                                                                 Emergency Department Therapies

                                 Intraosseous Drill
                            Needle attached with magnet                                                                                                                   ANTIBIOTICS!
                                   Drill reusable
                             Needle can be left in place
                                 and is very stable                                                                              Emergency Dept. Staff: PUSH ANY GOOD FLUID FAST!!!

Emergency Department Therapies                              Emergency Department Therapies                                       Emergency Department Therapies

    Some thoughts about antibiotics                            Many studies since 2002 Guidelines:                                 Emergency medicine investigators have
     –    Is the child a neonate…should you think of HSV?        –    Nearly 100% survival in dengue shock regardless                 shown that 2002 Guidelines regarding rapid
          (add acyclovir?) Should you NOT give                        of fluid composition                                            boluses of 20cc/kg over 5 minutes, followed
          Ceftriaxone?                                           –    Albumin vs. crystalloid?                                        by assessment for improved perfusion and
     –    Is the child immunosuppressed…should you think                 some adult and pediatric data that albumin may be
                                                                                                                                      fluid overload, and removal of fluid by
          of Pseudomonas (coverage depends on age…)?                      associated with decreased mortality                         diuretics or dialysis if needed
     –    Is there any reason to think of vancomycin                     Indian study showed no difference in outcome between       “Large volumes of fluid for acute stabilization
                                                                          crystalloid and gelatin product
          (MRSA, etc)?                                                                                                                in children have not been shown to increase
                                                                         Crystalloid is cheap and easier to store
                                                                                                                                      the incidence of ARDS or cerebral edema”

Emergency Department Therapies                              Emergency Department Therapies                                       Emergency DepartmentPICU

    Fluid choices: Crystalloid (normal saline,
     lactated Ringer’s), colloids (dextran, gelatin,
     5% albumin)
     BE PUSHED because it may produce acute
     hypotensive effects caused by citrate
     preservative and vasoactive kinins


                                                                           When To Establish Emergency Airway/                    When To Establish Emergency Airway/
                                                                           Ventilation                                            Ventilation

                                                                               Lung compliance and work of breathing may             Base decision on clinical parameters of
                                                                                change quickly                                         increased work of breathing, not laboratory
                                                                               Early sepsis= respiratory alkalosis
                                                                                                                                      Up to 40% of the cardiac output is used for
                                                                               Sepsis progresseshypoxemia plus                       work of breathing…just taking that work away
                                                                                metabolic acidosis PLUS possible respiratory           can reverse shock
                                                                                acidosis from lung disease or poor                    Some experts recommend ketamine with
                                                                                respiratory effort due to altered mental status
                                                                                                                                       atropine to intubate, almost all recommend
                                                                                                                                       avoiding etomidate in children suspected of
                                                                                                                                       having sepsis…

Beginning Inotropes in the ED                                              Other Therapies in the ED                              Some Comments on Newborn Sepsis

    If fluid refractory, begin peripheral inotropes                           Look for and correct hypoglycemia and/or              Sometimes difficult to diagnose sepsis vs. congenital
                                                                                                                                       heart disease (ductal dependent lesion) or inborn
      –    Low-dose dopamine or epinephrine into second                         hypocalcemia
           access as dilute solution or with carrier solution                                                                          error of metabolism (prostaglandins???)
                                                                               If central inotropes are being attempted and          Resuscitation essentially the same, except for the
           for high flow rate
                                                                                the patient not responding, may consider               consideration of possible above conditions
      –    TAKE CARE of peripheral vasocontriction/
                                                                                hydrocortisone (should obtain cortisol level,         Many experts advocate for 10cc/kg boluses to
                                                                                but some would start Hydrocortisone for                start…also take care to avoid hypoglycemia
      –    Start central line or transfer to PICU
                                                                                stress coverage and shock reversal)                   Consider that in neonate, dopamine has effects on
                                                                                                                                       pulmonary vascular resistance, considering
                                                                                                                                       combination of low-dose dopamine and dobutamine

                                                                                                                                  ECMO-Extracorporeal Membrane
PICU CARE                                                                                                                         Oxygenation

    Invasive monitoring can be established to carry out goal of keeping
     cardiac index in appropriate range                                                                                               Proud to say that this therapy was invented
     Newer, non-invasive methods of measuring cardiac output
     DVT prophylaxis-suggested for postpubertal children (most young
                                                                                                                                       by University of Michigan physician and
     children have DVT as a result of central venous catheter)                                                                         perfected there…
    Stress ulcer prophylaxis-same as adults, H2 blockers
    Blood Products-Keep central venous O2 saturation > 70%                                                                           Very complex, intensive technology that has
     Renal Replacement Therapy-Treat fluid overload
    Glycemic control-Take care of HYPOglycemia in neonates; avoid long
                                                                                                                                       limited availability but if available, the current
     periods of hyperglycemia? No data exist on optimal method for
                                                                                                                                       ECMO survival rate for newborn sepsis is
    Sedation-standard of care; avoid prolonged propofol infusions                                                                     80%
    Intravenous immunoglobulin-Data support administering in severe


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