Glucose Metabolism

The fetus maintains a blood glucose value 70–80% of maternal value by facilitated diffusion across the placenta. There is a build-up of glycogen stores in the liver, skeleton, and cardiac muscles during the later stages of fetal development, but little gluconeogenesis. The newborn must depend on glycolysis until exogenous glucose is supplied. Following delivery, the baby depletes its hepatic glycogen stores within two to three hours. The newborn is severely limited in his or her ability to use fat and protein as substrates to synthesize glucose. When total parenteral nutrition (TPN) is needed, the glucose infusion rate should be initiated at 4–6 mg/kg/min and advanced 1–2 mg/kg/min to a goal of 12 mg/kg/min.

Calcium

Calcium is actively transported across the placenta. Of the total amount of calcium transferred across the placenta, 75% occurs after 28 weeks’ gestation.⁴ This observation partially accounts for the high incidence of hypocalcemia in preterm infants. Neonates are predisposed to hypocalcemia due to limited calcium stores, renal immaturity, and relative hypoparathyroidism secondary to suppression by high fetal calcium levels. Some infants are at further risk for neonatal calcium disturbances due to the presence of genetic defects, pathological intrauterine conditions, or birth trauma.⁵ Hypocalcemia is defined as an ionized calcium level of less than 1.22 mmol/L (4.9 mg/dL).⁶ At greatest risk for hypocalcemia are preterm infants, newborn surgical patients, and infants of complicated pregnancies, such as those of diabetic mothers or those receiving bicarbonate infusions. Calcitonin, which inhibits calcium mobilization from the bone, is increased in premature and asphyxiated infants.

Signs of hypocalcemia are similar to those of hypoglycemia and may include jitteriness, seizures, cyanosis, vomiting, and myocardial arrhythmias. Hypocalcemic infants have increased muscle tone, which helps differentiate infants with hypocalcemia from those with hypoglycemia. Symptomatic hypocalcemia is treated with 10% calcium gluconate administered IV at a dosage of 1–2 mL/kg (100–200 mg/kg) over 30 minutes while monitoring the electrocardiogram for bradycardia.¹ Asymptomatic hypocalcemia is best treated with calcium gluconate in a dose of 50 mg of elemental calcium/kg/day added to the maintenance fluid: 1 mL of 10% calcium gluconate contains 9 mg of elemental calcium. If possible, parenteral calcium should be given through a central venous line given necrosis that may occur should the peripheral IV infiltrate.

Magnesium

Magnesium is actively transported across the placenta. Half of total body magnesium is in the plasma and soft tissues. Hypomagnesemia is observed with growth retardation, maternal diabetes, after exchange transfusions, and with hypoparathyroidism. While the mechanisms by which magnesium and calcium interact are not clearly defined, they appear to be interrelated. The same infants at risk for hypocalcemia are also at risk for hypomagnesemia. Magnesium deficiency should be suspected and confirmed in an infant who has seizures that do not respond to calcium therapy. Emergent treatment consists of magnesium sulfate 25–50 mg/kg IV every six hours until normal levels are obtained.

Blood volume

Total RBC volume is at its highest point at delivery. Estimation of blood volume for premature infants, term neonates, and infants are summarized in Table 1-2. By about 3 months of age, total blood volume per kilogram is nearly equal to adult levels as they recover from their postpartum physiologic nadir. The newborn blood volume is affected by shifts of blood between the placenta and the baby prior to clamping the cord. Infants with delayed cord clamping have higher hemoglobin levels.⁷ A hematocrit greater than 50% suggests placental transfusion has occurred.

Anemia

Anemia present at birth is due to hemolysis, blood loss, or decreased erythrocyte production.

Jaundice

In the hepatocyte, bilirubin created by hemolysis is conjugated to glucuronic acid and rendered water soluble. Conjugated (also known as direct) bilirubin is excreted in bile. Unconjugated bilirubin interferes with cellular respiration and is toxic to neural cells. Subsequent neural damage is termed kernicterus and produces athetoid cerebral palsy, seizures, sensorineural hearing loss, and, rarely, death.

The newborn’s liver has a metabolic excretory capacity for bilirubin that is not equal to its task. Even healthy full-term infants usually have an elevated unconjugated bilirubin level. This peaks about the third day of life at approximately 6.5–7.0 mg/dL and does not return to normal until the tenth day of life. A total bilirubin level greater than 7 mg/dL in the first 24 hours or greater than 13 mg/dL at any time in full-term newborns often prompts an investigation for the cause. Breast-fed infants usually have serum bilirubin levels 1–2 mg/dL greater than formula-fed babies. The common causes of prolonged indirect hyperbilirubinemia are listed in Table 1-3.

Pathologic jaundice within the first 36 hours of life is usually due to excessive production of bilirubin. Hyperbilirubinemia is managed based on the infant’s weight. While specific cutoffs defining the need for therapy have not been universally accepted, the following recommendations are consistent with most practice patterns.¹² Phototherapy is initiated for newborns: (1) less than 1500 g, when the serum bilirubin level reaches 5 mg/dL; (2) 1500–2000 g, when the serum bilirubin level reaches 8 mg/dL; or (3) 2000–2500 g, when the serum bilirubin level reaches 10 mg/dL. Formula-fed term infants without hemolytic disease are treated by phototherapy when levels reach 13 mg/dL. For hemolytic-related hyperbilirubinemia, phototherapy is recommended when the serum bilirubin level exceeds 10 mg/dL by 12 hours of life, 12 mg/dL by 18 hours, 14 mg/dL by 24 hours, or 15 mg/dL by 36 hours.¹³ An absolute bilirubin level that triggers exchange transfusion is still not established, but most exchange transfusion decisions are based on the serum bilirubin level and its rate of rise.

Retinopathy of Prematurity

Retinopathy of prematurity (ROP) develops during the active phases of retinal vascular development from the 16th week of gestation. In full-term infants the retina is fully developed and ROP cannot occur. The exact causes are unknown, but oxygen exposure (greater than 93–95%) and extreme prematurity are two risk factors that have been demonstrated.¹⁴ The risk and extent of ROP is probably related to the degree of vascular immaturity and abnormal retinal angiogenesis in response to hypoxia. ROP is found in 1.9% of premature infants in large neonatal units.¹⁵ Retrolental fibroplasia (RLF) is the pathologic change observed in the retina and overlying vitreous after the acute phases of ROP subsides. Treatment of ROP with laser photocoagulation has been shown to have the added benefit of superior visual acuity and less myopia when compared to cryotherapy in long-term follow-up studies.^16–19 The American Academy of Pediatrics’ guidelines recommends a screening examination for all infants who received oxygen therapy who weigh less than 1500 g and are fewer than 32 weeks’ gestation, and selected infants with a birth weight between 1500 and 2000 g or gestational age of more than 32 weeks with an unstable clinical course, including those requiring cardiorespiratory support.²⁰

Thermoregulation

Newborns have difficulty maintaining body temperature due to their relatively large surface area, poor thermal regulation, and small mass to act as a heat sink. Heat loss may occur owing to: (1) evaporation (wet newborn); (2) conduction (skin contact with cool surface); (3) convection (air currents blowing over newborn); and (4) radiation (non-contact loss of heat to cooler surface, which is the most difficult factor to control). Thermoneutrality is the range of ambient temperatures that the newborn can maintain a normal body temperature with a minimal metabolic rate by vasomotor control. The critical temperature is the temperature that requires adaptive metabolic responses to the cold in an effort to replace lost heat. Infants produce heat by increasing metabolic activity by shivering like an adult, nonshivering thermogenesis, and futile cycling of ions in skeletal muscle.²¹ Brown adipose tissue (BAT) may be involved in thermoregulatory feeding and sleep cycles in the infant with an increase in body temperature signaling an increase in metabolic demand.²² The uncoupling of mitochondrial respiration that occurs in BAT where energy is not conserved in ATP but rather is released as heat may be rendered inactive by vasopressors, anesthetic agents, and nutritional depletion.^23–25 Failure to maintain thermoneutrality leads to serious metabolic and physiologic consequences. Double-walled incubators offer the best thermoneutral environment, whereas radiant warmers cannot prevent convection heat loss and lead to higher insensible water loss. In the operating room, special care must be exercised to maintain the neonate’s body temperature in the normal range.

Glomerular Filtration Rate and Early Renal Function

The glomerular filtration rate (GFR) of newborns is slower than that of adults.²⁷ From 21 mL/min/1.73 m² at birth in the term infant, GFR quickly increases to 60 mL/min/1.73 m² by 2 weeks of age. GFR reaches adult levels by 18 months to 2 years of age. A preterm infant has a GFR that is only slightly slower than that of a full-term infant. In addition to this difference in GFR, the concentrating capacity of the preterm and the full-term infant is well below that of the adult. An infant responding to water deprivation increases urine osmolarity to a maximum of 600 mOsm/kg. This is in contrast to the adult, whose urine concentration can reach 1200 mOsm/kg. It appears that the difference in concentrating capacity is due to the insensitivity of the collecting tubules of the newborn to antidiuretic hormone. Although the newborn cannot concentrate urine as efficiently as the adult, the newborn can excrete very dilute urine at 30–50 mOsm/kg. Newborns are unable to excrete excess sodium, an inability thought to be due to a tubular defect. Term babies are able to conserve sodium, but premature infants are considered ‘salt wasters’ because they have an inappropriate urinary sodium excretion, even with restricted sodium intake.

Neonatal Fluid Requirements

To estimate fluid requirements in the newborn requires an understanding of: (1) any preexisting fluid deficits or excesses; (2) metabolic demands; and (3) losses. Because these factors change quickly in the critically ill newborn, frequent adjustments in fluid management are necessary (Table 1-4). Hourly monitoring of intake and output allows early recognition of fluid balance that will affect treatment decisions. This dynamic approach requires two components: (1) an initial hourly fluid intake that is safe and (2) a monitoring system to detect the patient’s response to the treatment program selected. No ‘normal’ urine output exists for a given neonate, yet one may generally target 1–2 mL/kg/h.

After administering the initial hourly volume for four to eight hours, depending on the patient’s condition, the newborn is reassessed by observing urine output and concentration. With these two factors, it is possible to determine the state of hydration of most neonates and their responses to the initial volume. In more difficult cases, changes in serial serum osmolarity, sodium (Na), creatinine, and blood urea nitrogen (BUN), along with urine osmolarity, Na, and creatinine make it possible to assess the infant’s response to the initial volume and to use fluid status to guide the next 4-8 hours’ fluid intake.

• Embryonic phase (begins approximately week 3)

• Pseudoglandular phase (5–17 weeks)

• Canalicular phase (16–25 weeks)

• Terminal saccular phase (24 weeks to full-term birth)

• Alveolar phase (late fetal phase to childhood).

Surfactant

The development of exogenous surfactant in the 1990s has significantly advanced the field of neonatology resulting in reductions in the rates of neonatal mortality. Surfactant deficiency is the major cause of HMD. Surfactant replacement therapy reduces the surface tension on the inner surface of the alveoli preventing the alveoli from collapsing during expiration, thereby improving air exchange. Three exogenous surfactants are available: (1) surfactant derived from bovine or porcine lung; (2) synthetic surfactant without protein components; and (3) synthetic surfactant containing protein components. A human derived surfactant was tested but is not currently in use.

The most efficacious administration method is currently under investigation. The standard approach is to instill aliquots into an endotracheal tube. The indications for the use of surfactant include: (1) intubated infants with RDS; (2) intubated infants with meconium aspiration syndrome (MAS) requiring more than 50% oxygen; (3) intubated infants with pneumonia and an oxygen index great than 15; and (4) intubated infants with pulmonary hemorrhage that have clinically deteriorated. Its efficacy is uncertain in neonates with pulmonary hemorrhage and pneumonia. Worse outcomes are associated with surfactant use in CDH.30,31

The acute pulmonary effects of surfactant therapy are improved lung function and alveolar expansion leading to improved oxygenation, which results in a reduction in the need for mechanical ventilation and extracorporeal oxygenation.32–34

Two meta-analyses support the use of surfactant therapy in infants with RDS to reduce air leak syndromes, pneumothorax, bronchopulmonary dysplasia (BPD), pulmonary interstitial emphysema, and mortality.35,36 The INSURE (INtubate, SURfactant, Extubate) technique consists of administration of surfactant followed by extubation within one hour to nasal continuous positive airway pressure (nCPAP). Another randomized trial demonstrated the reduced mortality and air leaks for infants assigned to early surfactant treatment versus nCPAP alone.³⁷ In large trials that reflect the current practice of treating infants at risk for the development of RDS (administration of maternal steroids and the routine stabilization on CPAP), the selective use of surfactant in infants with established RDS demonstrates a decreased risk of chronic lung disease or death when compared to infants who are more aggressively treated with prophylactic administration of surfactant.³⁸

Several adverse outcomes have been associated with the use of surfactant (Table 1-5). Intraventricular hemorrhage is one of the most worrisome potential side effects. However, meta-analyses of multiple trials have not shown a statistically significant increase in this risk.^35,36

Monitoring

Continuous monitoring of physiologic indices provides data to assess the response to therapy. In retrospect, many episodes of ‘sudden deterioration’ in critically ill patients are viewed as changes in clinical condition that had been occurring for some time.

Hypovolemic Shock

In infants and children, most shock situations are the result of reduced preload secondary to fluid loss, such as from diarrhea, vomiting, or blood loss from trauma. Preload is a function of blood volume. In most clinical situations, right atrial pressure or CVP is the index of cardiac preload. In situations in which left ventricular or right ventricular compliance is abnormal or in certain forms of congenital heart disease, right atrial pressure may not correlate well with left atrial pressure.

Hypovolemia results in decreased venous return to the heart. Preload is reduced, cardiac output falls, and the overall result is a decrease in tissue perfusion. The first step in treating all forms of shock is to correct existing fluid deficits. Inotropic drugs should not be initiated until adequate intravascular fluid volume has been established. The speed and volume of the infusate are determined by the patient’s responses, particularly changes in blood pressure, pulse rate, urine output, and CVP. Shock resulting from acute hemorrhage is treated with the administration of 20 mL/kg of Ringer’s lactate solution or normal saline as fluid boluses. If the patient does not respond, a second bolus of crystalloid is given. Type-specific or cross-matched blood is given to achieve an SvO2 of 70%. In newborns with a coagulopathy, we provide fresh frozen plasma or specific factors as the resuscitation fluid.

The rate and volume of resuscitation fluid given is adjusted based on feedback data obtained from monitoring the effects of the initial resuscitation. After the initial volume is given, the adequacy of replacement is assessed by monitoring urine output, urine concentration, plasma acidosis, oxygenation, arterial pressure, CVP, and pulmonary wedge pressure, if indicated. When cardiac failure is present, continued vigorous delivery of large volumes of fluid may cause further increases in preload to the failing myocardium and accelerates the downhill course. In this setting, inotropic agents are given while monitoring cardiac and pulmonary function, as outlined previously.

Cardiogenic Shock

Myocardial contractility is usually expressed as the ejection fraction that indicates the proportion of left ventricular volume that is pumped. Myocardial contractility is reduced with hypoxemia and acidosis. Inotropic drugs increase cardiac contractility. Inotropes are most effective when hypoxemia and acidosis are corrected. In cases of fluid-refractory shock and cardiogenic shock, inotropic drugs are necessary. Traditionally, administration of inotropes requires the adjunct of central venous access. However, initial administration of pressors through peripheral IVs may be prudent.

Adrenergic receptors are important in regulating calcium flux, which, in turn, is important in controlling myocardial contractility. The α and β receptors are proteins present in the sarcolemma of myocardial and vascular smooth muscle cells. The β₁ receptors are predominantly in the heart and, when stimulated, result in increased contractility of myocardium. The β₂ receptors are predominately in respiratory and vascular smooth muscle. When stimulated, these receptors result in bronchodilation and vasodilation. The α₁-adrenergic receptors are located on vascular smooth muscle and result in vascular constriction when stimulated. The α₂ receptors are found mainly on prejunctional sympathetic nerve terminals. The concept of dopaminergic receptors has also been used to account for the cardiovascular effects of dopamine not mediated through α or β receptors. Activation of dopaminergic receptors results in decreased renal and mesenteric vascular resistance and, usually, increased blood flow. The most commonly used inotropic and vasoactive drugs are listed in Table 1-6.

Distributive Shock

Distributive shock is caused by derangements in vascular tone from endothelial damage that lead to end-organ hypotension and is seen in the following clinical situations: (1) septic shock; (2) SIRS; (3) anaphylaxis; and (4) spinal cord trauma. Septic shock in the pediatric patient is discussed in further detail.

Septic Shock

Afterload represents the force against which the left ventricle must contract to eject blood. It is related to SVR and myocardial wall stress. SVR is defined as the systemic mean arterial blood pressure minus right arterial pressure divided by cardiac output. Cardiac contractility is affected by SVR and afterload. In general, increases in afterload reduce cardiac contractility, and decreases in afterload increase cardiac contractility.

Septic shock is a distributive form of shock that differs from other forms of shock. Cardiogenic and hypovolemic shock lead to increased SVR and decreased cardiac output. Septic shock results from a severe decrease in SVR and a generalized maldistribution of blood and leads to a hyperdynamic state.⁵⁸ The pathophysiology of septic shock begins with a nidus of infection. Organisms may invade the blood stream, or they may proliferate at the infected site and release various mediators into the blood stream. Substances produced by microorganisms, such as lipopolysaccharide, endotoxin, exotoxin, lipid moieties, and other products can induce septic shock by stimulating host cells to release numerous cytokines, chemokines, leukotrienes, and endorphins.

Endotoxin is a lipopolysaccharide found in the outer membrane of Gram-negative bacteria. Functionally, the molecule is divided into three parts: (1) the highly variable O-specific polysaccharide side chain (conveys serotypic specificity to bacteria and can activate the alternate pathway of complement); (2) the R-core region (less variable among different gram-negative bacteria; antibodies to this region could be cross protective); and (3) lipid-A (responsible for most of the toxicity of endotoxin). Endotoxin stimulates tumor necrosis factor (TNF) and can directly activate the classic complement pathway in the absence of antibody. Endotoxin has been implicated as an important factor in the pathogenesis of human septic shock and Gram-negative sepsis.⁵⁹ Therapy has focused on developing antibodies to endotoxin to treat septic shock. Antibodies to endotoxin have been used in clinical trials of sepsis with variable results.^60–62

Cytokines, especially TNF, play a dominant role in the host’s response. Endotoxin and exotoxin both induce TNF release in vivo and produce many other toxic effects via this endogenous mediator.63–65 TNF is released primarily from monocytes and macrophages. It is also released from natural killer cells, mast cells, and some activated T-lymphocytes. Antibodies against TNF protect animals from exotoxin and bacterial challenge.^66,67 Other stimuli for its release include viruses, fungi, parasites, and interleukin-1 (IL-1). In sepsis, the effects of TNF release may include cardiac dysfunction, disseminated intravascular coagulation, and cardiovascular collapse. TNF release also causes the release of granulocyte–macrophage colony-stimulating factor (GM-CSF), interferon-α, and IL-1.

IL-1 is produced primarily by macrophages and monocytes. IL-1, previously known as the endogenous pyrogen, plays a central role in stimulating a variety of host responses, including fever production, lymphocyte activation, and endothelial cell stimulation, to produce procoagulant activity and to increase adhesiveness. IL-1 also causes the induction of the inhibitor of tissue plasminogen activator and the production of GM-CSF. These effects are balanced by the release of platelet-activating factor and arachidonic metabolites.

IL-2, also known as T-cell growth factor, is produced by activated T-lymphocytes and strengthens the immune response by stimulating cell proliferation. Its clinically apparent side effects include capillary leak syndrome, tachycardia, hypotension, increased cardiac index, decreased SVR, and decreased left ventricular ejection fraction.68,69

Studies in dogs have suggested that in immature animals, septic shock is more lethal and has different mechanisms of tissue injury.⁷⁰ These include more dramatic aberrations in blood pressure (more constant decline), heart rate (progressive, persistent tachycardia), blood sugar level (severe, progressive hypoglycemia), acid–base status (severe acidosis), and oxygenation (severe hypoxemia). These changes are significantly different from those seen in the adult animals that also experience an improved survival of almost 600% (18.5 vs 3.1 hours) compared with the immature animal.

The neonate’s host defense can usually respond successfully to ordinary microbial challenge. However, defense against major challenges appears limited, which provides an explanation for the high mortality rate with major neonatal sepsis. As in adults, the immune system consists of four major components: cell-mediated immunity (T-cells), complement system, antibody-mediated immunity (B-cells), and macrophage–neutrophil phagocytic system. The two most important deficits in newborn host defenses that seem to increase the risk of bacterial sepsis are the quantitative and qualitative changes in the phagocytic system and the defects in antibody-mediated immunity.

The proliferative rate of the granulocyte–macrophage precursor has been reported to be at near-maximal capacity in the neonate. However, the neutrophil storage pool is markedly reduced in the newborn compared with the adult. After bacterial challenge, newborns fail to increase stem cell proliferation and deplete their already reduced neutrophil storage pool. Numerous in vitro abnormalities have been demonstrated in neonatal polymorphonuclear neutrophils, especially in times of stress or infection.⁷¹ These abnormalities include decreased deformability, chemotaxis, phagocytosis, C3b receptor expression, adherence, bacterial killing, and depressed oxidative metabolism. Chemotaxis is impaired in neonatal neutrophils in response to various bacterial organisms and antigen–antibody complexes.⁷² Granulocytes are activated by their interaction with endothelial cells followed by entry into secondary lymphoid issues via the endothelial venules. Initial adhesion of granulocytes is dependent on their expression of L-selectin, a cell adhesion molecule expressed on the granulocyte cell surface. Evaluation of cord blood has demonstrated a significantly lower expression of L-selectin on granulocyte surfaces when compared to older newborn (5 days old) and adult samples, indicating a depressed level of interaction with vascular endothelial cells at the initial stage of adhesion.⁷³ Although phagocytosis has additionally been demonstrated to be abnormal in neonatal phagocytes, it appears that this phenomenon is most likely secondary to decreased opsonic activity rather than an intrinsic defect of the neonatal polymorphonuclear neutrophils.^74,75 Currently, there is inconclusive evidence to support or refute the routine use of granulocyte transfusions in the prevention or treatment of sepsis in the neonate.⁷⁶

Preterm and term newborns have poor responses to various antigenic stimuli, reduced gamma globulin levels at birth, and reduced maternal immunoglobulin supply from placental transport. Almost 33% of infants with a birth weight less than 1500 g develop substantial hypogammaglobulinemia.⁷⁷ IgA and IgM levels are also low due to the inability of these two immunoglobulins to cross the placenta. Thus, neonates are usually more susceptible to pyogenic bacterial infections because most of the antibodies that opsonize pyogenic bacterial capsular antigens are IgG and IgM. In addition, neonates do not produce type-specific antibodies because of defects in the differentiation of B-lymphocytes into immunoglobulin-secreting plasma cells and in T-lymphocyte-mediated facilitation of antibody synthesis. In the term infant, total hemolytic complement activity, which measures the classic complement pathway, constitutes approximately 50% of adult activity.⁷⁸ The activity of the alternative complement pathway, secondary to lowered levels of factor B, is also decreased in the neonate.⁷⁹ Fibronectin, a plasma protein that promotes reticuloendothelial clearance of invading microorganisms, is deficient in neonatal cord plasma.⁸⁰

The use of intravenous immunoglobulins (IVIGs) for the prophylaxis and treatment of sepsis in the newborn, especially the preterm, low birth weight infant, has been studied in numerous trials with varied outcomes. In one study, a group of infants weighing 1500 g was treated with 500 mg/kg of IVIG each week for four weeks and compared with infants who were not treated with immunoglobulin.⁸¹ The death rate was 16% in the IVIG-treated group compared with 32% in the untreated control group. Another recent analysis examined the role of IVIG to prevent and treat neonatal sepsis.⁸² A significant (but only marginal) benefit was noted from prophylactic use of IVIG to prevent sepsis in low birth weight premature infants. However, using IVIG to treat neonatal sepsis produced a greater than 6% decrease in the mortality rate. A review of nineteen randomized control trials found a 3% decrease in the incidence of neonatal sepsis in preterm infants without a significant difference in all-cause and infection-related mortality when prophylactic IVIG was administered.⁸³ Based on the marginal reduction of neonatal sepsis without a reduction in mortality, routine use of prophylactic IVIG cannot be recommended.

Colony-stimulating factors (CSFs) are a family of glycoproteins that stimulate proliferation and differentiation of hematopoietic cells of various lineages. GM-CSF and granulocyte CSF (G-CSF) have similar physiologic actions. Both stimulate the proliferation of bone marrow myeloid progenitor cells, induce the release of bone marrow neutrophil storage pools, and enhance mature neutrophil effect or function.82–84 Preliminary studies of GM-CSF in neonatal animals demonstrate enhancement of neutrophil oxidative metabolism as well as priming of neonatal neutrophils for enhanced chemotaxis and bacterial killing. Both GM-CSF and G-CSF induce peripheral neutrophilia within two to six hours of intraperitoneal administration. This enhanced affinity for neutrophils returns to normal baseline level by 24 hours.⁸⁵ Studies have confirm the efficacy and safety of G-CSF therapy for neonatal sepsis and neutropenia.⁸⁶ Other investigations have demonstrated no long-term adverse hematologic, immunologic, or developmental effects from G-CSF therapy in the septic neonate. Prolonged prophylactic treatment in the very low birth weight neonate with recombinant GM-CSF has been shown to be well tolerated and have a significant decrease in the rate of nosocomial infections.^87,88

Unique to the newborn in septic shock is the persistence of fetal circulation and resultant pulmonary hypertension.⁸⁹ In fact, the rapid administration of fluid can further exacerbate this problem by causing left to right shunting through a patent ductus arteriosus (PDA) and subsequent congestive heart failure from ventricular overload. Infants in septic shock with a new heart murmur should undergo a cardiac echocardiogram. If present, a PDA may warrant treatment with indomethacin (prostaglandin inhibitor) or surgical ligation to achieve closure, depending on the clinical picture.

The critical care of a neonate/infant in septic shock can be extremely challenging. Septic shock has a distinctive clinical presentation and is characterized by an early compensated stage where one can see a decreased SVR, an increase in cardiac output, tachycardia, warm extremities, and an adequate urine output. Later in the clinical presentation, septic shock is characterized by an uncompensated phase where one will see a decrease in intravascular volume, myocardial depression, high vascular resistance, and a decreasing cardiac output.⁹⁰ Management of these patients is based on the principles of source control, antibiotics (broad-spectrum, institutionally based when possible and including antifungal agents as warranted), and supportive care.

Patients with severe septic shock often do not respond to conventional forms of volume loading and cardiovascular supportive medications. The administration of arginine vasopressin has been shown to decrease mortality in adult patients with recalcitrant septic shock.91,92 Vasopressin (see Table 1-6), also known as antidiuretic hormone (ADH), is made in the posterior pituitary and plays a primary role in water regulation by the kidneys. In septic shock, vasopressin has profound effects on increasing blood pressure in intravascular depleted states. Sparked initially by a randomized, double-blinded, placebo-controlled study in adults that demonstrated a beneficial effect of vasopressin in recalcitrant septic shock, its utilization in the pediatric population has become common.^93,94 While a detailed discussion is beyond the scope of this chapter, current trends suggest that ECMO may serve as rescue therapy in select patients with profound sepsis and cardiopulmonary failure refractory to other measures (reported ELSO database newborn survival 80%, older children 50%).^94,95

Given the difficult nature of caring for septic patients, extensive investigation has been launched in attempt to identify patients at risk.96–98 Early serum markers such as C-reactive protein, IL-6, and procalcitonin carry promise but warrant further validation.

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