Understanding and Optimizing Outcome in Neonates with Sepsis and Septic Shock

with Sepsis and Septic Shock

K.N. Haque

Introduction

It is estimated that four million newborn infants die every year, of these 35 % (1.6 million) die from sepsis [1]. Preterm infants are at greater risk of developing infec- tion (often multiple) between birth and the first month of life compared to term infants. It is estimated that intra-uterine infection, a risk factor for developing severe infection, is present in up to 35 % of preterm deliveries [2].

While most of the mortality from sepsis is mainly in the developing world, in UK, USA, and Australia it is around 20 % among low birth weight infants. This figure has not declined over the last three decades [3], despite modern perinatal and neonatal intensive care.

The prevalence of sepsis, meningitis, and other confirmed bacterial infections has been estimated to range between 1 to 5/1000 live births. However, for preterm infants this prevalence is much higher at 1/230 preterm births. Thus, it is not sur- prising that the number of very low birth weight infants evaluated and treated for infections is around 50 % of all admissions to neonatal nurseries [4]. In the USA, as many as 600,000 infants are screened to ‘rule out’ sepsis and an estimated 130,000 to 400,000 are treated with antibiotics every year [5] with less than 20,000 actually hav- ing proven infection!

Worryingly, term, and preterm infants in particular, who develop infection have between 30 – 80 % increased risk of neuro-developmental impairment and have a 30 – 100 % increase in odds for poor head growth, a good predictor of long term morbidity [6, 7].

Preterm infants are 20 times more likely to get infection than term infants. This risk is greatest after the first week of life except for Group B streptococcus (GBS) infection, which is more frequent during the first week of life. With near universal use of intra-partum prophylaxis for maternal GBS carriage, the incidence of neona- tal infection with GBS is falling. However, there are reports [8] suggesting a gradual increase in the incidence of early onset Gram-negative infection.

Whil the incidence of sepsis (1 – 5/1000 live births) is nearly universal in the

developed world, the incidence of septic shock in neonates has not been well docu-

mented though it is not uncommon with Gram-negative, GBS, and herpes simplex

infections. With current modalities of management, the progress of sepsis to septic

shock can be limited, but if organ systems become dysfunctional then sepsis can

rapidly progress to ‘severe sepsis’ and ‘septic shock’, which is viewed as a continuum

of the same condition [9]. Though the exact figures for septic shock in the neonatal

period are difficult to obtain, it is thought to be around 1 – 5 % of all infants with

proven severe sepsis [10].

Defining Neonatal Sepsis

The beginning of wisdom is calling things by their right names Chinese Proverb Sepsis means ‘putrefaction’, i.e., the decomposition of organic matter (by bacteria or fungi) resulting from an interaction between germs and host [11]. Until the land- mark consensus conference of experts organized by Roger Bone in 1991 [12], clini- cians defined infection and/or sepsis as they pleased. The definitions of infection and sepsis suggested by Bone and his colleagues in 1991 were for adults. They were adapted according to age-adjusted values of clinical variables for children by Hayden in 1994 [13], but for a number of reasons clinicians did not find these definitions immediately useful in clinical practice; thus, most pediatricians did not use them. In 2002, an international pediatric consensus conference was specifically organized with the aim of defining sepsis and organ dysfunction in children. Their recommen- dations were published in 2005 [14]. These definitions related mainly to children and not neonates, hence, a follow-up conference under the sponsorship of the Inter- national Sepsis Forum was held in 2004 to resolve this and other issues from the 2002 conference. The definitions that follow have been adapted from the recommen- dations of the last (2004) conference [9].

Sepsis is a common and complex entity, with marked heterogeneity in the patients affected and with wide variations in outcome [15]. While the ability of a senior clinician to diagnose sepsis in a neonate is high [16] there is still a lack of diagnostic certainty at the cot side. This lack of certainty may be due to a lack of specific and sensitive clinical and laboratory parameters, and differing patho-physi- ology, exposure, and susceptibility of the newborn to infection according to gesta- tional maturity.

The preterm infant, due to poor host defense mechanisms, responds differently from an adult or even older child to infection with the same pathogen. To add to this complexity, we now know that there is significant genetic variation in how one responds to infection, e.g., some babies have predominantly interleukin (IL-6, IL-8) based response to infection whilst others enlist a predominantly granulocyte colony- stimulating factor (G-CSF) response [17]. Another difficulty in reaching a consensus on the definition of sepsis is that the international consensus definitions that have been adapted for pediatric and neonatal use [13, 14, 18] differ from those being used by large neonatal research networks [19]. This lack of consensus highlights the fact that infection, far from being a homogeneous condition, reflects a continuum from fetal inflammatory response syndrome to sepsis, severe sepsis, septic shock, multi- organ failure, and death (Fig. 1). The difficulty for the clinician is to determine and define precisely the phase in which his/her patient is at any given moment as the patient may move from one phase to another imperceptibly.

Controversy is also rife on how to define septic shock in children and no defini- tion of septic shock exists for neonates. In general terms, shock is defined as a state of inadequate tissue perfusion with insufficient delivery of oxygen and other meta- bolic substrates necessary to meet metabolic needs. Traditionally, shock has been classified according to its pathophysiology and etiology, i.e., hypovolemic, cardio- genic, or distributive. Hypovolemic and distributive shock are most common in neonates, representing a decrease in circulating intravascular volume that signifi- cantly affects tissue perfusion.

Thus, to simplify the matter of definitions, for this chapter we will be using the

definitions suggested by ourselves [9].

Fig. 1. Neonatal sepsis is a continuum

Specific Definitions

Systemic Inflammatory Response Syndrome

The term, systemic inflammatory response syndrome (SIRS) was proposed by the consensus conference of experts in 1991 [12] to describe a non-specific inflammatory process following trauma, burns, infection, pancreatitis, and other diseases in adults.

The definition of SIRS was modified at the pediatric consensus conference in 2002 [14] such that the presence of either temperature or total leukocyte count had to be met. The age-specific values for abnormal vital signs and laboratory parameters used in these definitions were not evidence-based but were based upon expert opinion.

SIRS represents physiological derangements that are non-specific but are fre- quently present in patients with sepsis. Addition of predisposing factors and or bio- logical markers (such as C-reactive protein [CRP], procalcitonin [PCT], and cyto- kines) may help to identify sepsis as the cause of SIRS. It is recognized that progres- sion from SIRS to sepsis to severe sepsis and to septic shock is associated with an incrementally greater mortality risk.

Fetal Inflammatory Response Syndrome

A diagnosis of fetal inflammatory response syndrome (FIRS) can be made in an infant of less than 72 hours of age, who manifests two or more of the parameters shown in Table 1, usually secondary to either an ascending infection from the birth canal, or rarely, hematogenous spread from the mother.

Sepsis

Sepsis results from a complex interaction between pathogens and the human host. It

is diagnosed when the signs and symptoms of SIRS or FIRS are present and the

cause is confirmed as an infectious process.

Table 1. Two or more of the following are required to diagnose the fetal inflammatory response syndrome (FIRS) [9].

) Infant 72 hours or less in age.

) Tachypnea (respiratory rate

60 bpm) plus either grunting/retraction or desaturations.

) Temperature instability (

36 °C or

37 – 9 °C) ) Capillary refill time

3 seconds

) WBC count (

4000 × 10

/L or

34,000 × 10

/l) ) CRP

10 mg/dl

) IL-6 or IL-8

70 pg/ml ) 16S rRNA gene PCR: Positive.

WBC: white blood cell; CRP: C-reactive protein; IL: interlukin; rRNA: recombinant RNA; PCR: polymerase chain reaction.

Severe Sepsis

Severe sepsis in neonates is defined as sepsis plus respiratory distress plus at least one organ dysfunction or evidence of hypoperfusion or hypotension.

Septic Shock

As alluded to earlier, definition of septic shock is problematic. In the newborn, sep- tic shock is frequently due to significant redistribution and loss (third spacing) of intravascular fluid usually without a fall in blood pressure until late. Shock in neonates is better represented and recognized clinically by tachycardia (heart rate 8 180 bpm), signs of decreased perfusion (measured differently, e.g., increased capil- lary refill time 8 3 seconds, or hypotension & 2SD below normal range for age), decreased peripheral pulses compared to central pulses, mottled or cool extremities or decreased urine output.

Pathophysiology

It is believed that sepsis represents an uncontrolled inflammatory response initiated by a pathogen. Conventional wisdom has been that the pathogen is responsible for disease and outcome. However, it is more likely that it is the host’s own response to the presence of the pathogen that makes the disease and determines the outcome, because our arsenal for fighting off pathogens is so powerful that we are more in danger from them than from the invaders.

Previously, sepsis was viewed primarily as an inflammatory disorder. More recent studies indicate that the mechanism of sepsis include activation of hemopoietic cells, release of mediators, derangement of coagulation and cytokine homeostasis, and endothelial alterations, the latter being responsible for the leak of intravascular fluid, hypoperfusion, and hypotension.

The Sepsis Cascade

Sepsis results from a complex but sequential array of interactions between patho-

gens and the host; for example, despite similar clinical presentation, the molecular

and cellular processes depend on whether the organism is Gram-negative, Gram-

positive, fungal, or viral in origin. Gram-negative organisms release lipopolysaccha-

Fig. 2. The sepsis cascade

ride (LPS), an endotoxin from within the cell wall of the bacteria during lysis, while Gram-positive bacteria, fungi, and viruses initiate sepsis response by releasing exo- toxins and cellular antigenic components. Both responses initiate the sepsis cascade (Fig. 2) by release of primary inflammatory mediators from activated cells e.g., mac- rophages. Release of mediators also activates both coagulation/complement and cytokine systems leading to damage of the endothelium resulting in leukocyte migration outside the blood vessel into the parenchyma towards the site of infection, and micro-thrombin formation [20] over the inflamed and activated endothelium.

Normal endothelium is responsible for vascular integrity and permeability. Infec- tion damages the endothelial integrity resulting in vasodilatation and leak of cells and fluids into the tissues, which in turn leads to accumulation of fluid in the extra- vascular compartment, tissue edema and hypotension. To overcome this leak, the activated endothelium increases the number of thrombin receptors on its surface to localize coagulation factors and platelets at the site of injury.

The Inflammatory Response

The inflammatory response in the newborn is the same as in an adult albeit this

response may be deficient quantitatively rather than qualitatively. Activated macro-

phages produce a range of pro-inflammatory mediators, like tumor necrosis factor

(TNF)- [ , IL-1, IL-6, IL-8, platelet activating factor (PAF), leukotrienes, and throm-

boxane-A

, which activate many other cells leading to endothelial damage [21].

Injured endothelium allows granulocytes and other mediators to leak into the parenchyma, leading to ‘CHAOS’ and organ damage (Fig. 2).

Complement system essential for innate immunity is activated by pro-inflamma- tory cytokines and not only increases chemotaxis and phagocytosis, but also increases the release of histamine from mast cells, which further increases capillary permeability and enhances the ‘third spacing’ of fluid commonly seen in preterm infants with severe sepsis or septic shock.

In adults and the newborn, inflammation and coagulation are closely linked in sepsis; for example, TNF- [ , IL-1, and IL-6 activate monocytes that express tissue factor, which in turn stimulates the extrinsic arm of the coagulation pathway leading to formation of fibrin. Interestingly, thrombin, which maintains the balance between coagulation and fibrinolysis, also has a pro-inflammatory effect on macrophages, monocytes, and endothelial cells. In sepsis, thrombin generation becomes unregu- lated leading to an initial hypercoagulable state. Sepsis impairs the normal fibrino- lytic response leaving the body less able to remove micro-thrombins, frequently rec- ognized as disseminated intravascular coagulation (DIC) seen early in sepsis in the newborn. Following the initial phase of DIC, coagulation factors are consumed very rapidly leading to fibrinolysis and bleeding.

Inflammation and the Preterm Brain

Animal studies have shown that endotoxin dramatically sensitizes the immature brain to injury [22]. Relationship between infection, brain injury, and neuro-devel- opmental impairment is slowly being elucidated. Brain injury associated with infec- tion is most likely to be the result of multi-factorial events involving cytoxic injury and vascular compromise associated with hypoxic ischemic events. The presence of inflammatory cytokines in the central nervous system is known to inhibit prolifera- tion of neuronal precursor cells, activate astrogliosis, and stimulate oligodendrocyte death, all of which increase the risk of white matter injury [23]. Oligodendrocytes, which play a central role in the development of periventricular leukomalacia, appear to be particularly vulnerable to damage in sepsis and hypoperfusion.

In a large cohort of 1078 infants born before 32 weeks gestation, and/or weighing less than 1500 grams at birth, Leviton and colleagues [24] have shown that intrauter- ine infection and FIRS were independent predictors for development of cystic white matter injury.

Clinical Events Leading to Septic Shock

Sudden septic shock in infants with Gram-negative infection is not unusual in new- born infants, particularly in very preterm infants whose host defenses are poor and who frequently undergo invasive procedures or have intravascular devices inserted.

One of the most important factors in progression from infection to septic shock is the use of inappropriate or delayed antibiotic therapy [25]. In the neonate, the usual cause of shock secondary to infection is the redistribution and leak of intravascular fluid causing hypovolemic shock and tissue (including cardiac) hypoperfusion.

Herpes simplex virus Type I, an infection that occurs in approximately 1:5000 live

births is one infection that may present with intractable ‘shock’ without any history

of maternal infection with herpes virus. Thus, it is advisable to include anti-viral

(acyclovir) medication in the management of an infant who either does not respond

to standard therapy or has persistent signs and symptoms of infection with negative bacterial or fungal cultures or an infant who presents in septic shock.

Biological Markers

Investigators have long sought biological marker/s that would serve for early and accurate detection of sepsis. There are an increasing number of such tests, but despite initial enthusiasm most of them can be relegated to the growing heap of bio- markers that have failed to accurately differentiate between sepsis and other non- septic critical illness [26]. Of the new biomarkers, soluble triggering receptor expressed on myeloid cells –1 (sTREM-1) appears to be promising. It has a sensitiv- ity of 96 % and specificity of 89 % [27]. Using a multiplex bead system we have per- fected measurement of an array of cytokines using a drop of blood on blotting paper with a 2-hour turn around time. We find macrophage inflammatory protein (MIP)- 1 q to be most predictive, sensitive and specific for sepsis in the newborn. The most commonly available and used biomarkers are shown in Table 2.

Table 2. Sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values of commonly used biomarkers of sepsis in the newborn (adapted from [3]).

Test Sensitivity Specificity PPV NPV

Blood Culture 11 – 38 68 – 100 90 – 100 72 – 100

WBC

4000,

30,000 17 – 90 31 – 100 50 – 86 60 – 89

I/T ratio

0.02 81 45 23 92

CRP

10 mg/dl 37 95 63 87

IL-8

70 pg/ml 77 76 42 94

I/T ratio +CRP 89 41 24 94

IL-8+CRP 91 74 43 98

16 sPCR 96 99 89 99

sTREM-1

60 ng/ml 96 89 86 96

WBC: white blood cell; I/T ratio: immature to total neutrophil ratio; CRP: C-reactive protein; IL: interleukin;

PCR: polymerase chain reaction; sTREM-1: soluble trigger receptor expressed on myeloid cells-1. All values are percentages

Management

Management of neonatal sepsis and septic shock is based on the principles of initial resuscitation, killing the pathogen by early administration of appropriate antibiotics, correction of the consequences of sepsis, and correction of both coagulation and immunological homeostasis along with boosting host defenses [9].

While there are evidence-based recommendations for management of severe sep- sis and septic shock in adults and children there is either a total lack or a severe paucity of such evidence-based recommendation for management in the newborn.

Recommendations offered here are based on available evidence from literature and

clinical practice; they cannot replace the wisdom of an experienced clinician who

makes a clinical judgment based on the availability of unique sets of clinical vari-

ables for individual patients.

Initial Resuscitation

This should begin as soon as it is recognized that the patient has either severe sepsis or is in septic shock and not delayed until the patient is transferred toneonatal intensive care facility. Early goal-directed therapy has been shown to reduce mortal- ity from septic shock in adults [28] and its principles can be applied to neonates.

Most severely septic babies will be tachycardic and hypovolemic before their blood pressure falls; therefore, blood pressure should not be used as a marker of either shock or hypoperfusion. Measurement of oxygen saturation and serum lactate are more acceptable measures of tissue oxygenation and perfusion.

Antibiotics

As soon as the diagnosis of severe sepsis or septic shock is made, appropriate cul- tures and tests for biomarkers of sepsis should be taken and appropriate broad-spec- trum bactericidal antibiotic therapy initiated. Delay in starting or inappropriate therapy has been shown to increase poor outcome [25]. The choice of antibiotic depends on the susceptibility pattern, but should cover all likely pathogens. Initial antibiotic regimen should be altered on the basis of microbiological and clinical data. Once the causative organism has been identified then antibiotics can be tar- geted only against that organism. It should be remembered, however, that in sepsis and septic shock often there is accompanying renal and hepatic dysfunction leading to abnormal volumes and levels of distribution of drugs; therefore, therapeutic plasma levels should be monitored.

The duration of antibiotic therapy is debatable. A balance should be achieved between adequate duration versus the desire to minimize resistance, super-infection, and other complications from prolonged use of antibiotics. We would recommend monitoring and titrating the duration of antibiotic therapy with serial measure- ments of CRP or preferably IL-6 or IL-8. It is also important for clinicians to remem- ber that blood cultures are frequently negative in newborns with sepsis and septic shock, thus the decision to continue or stop antibiotic therapy must be made on clinical grounds plus the use of other surrogate biomarkers of sepsis and not only on negative blood culture results (Table 2).

Intravascular access devices are potentially a major source of severe sepsis or sep- tic shock; they should be promptly removed after establishing other vascular access.

Prophylactic antibiotic (vancomycin) therapy has been shown to be of some benefit [31] but it increases the development of resistant or insensitive organisms, hence it is not recommended.

Mechanical ventilation

Respiratory failure in severe sepsis and septic shock is common. Due to low func-

tional residual capacity, neonates with severe sepsis may require elective intubation

and ventilation [29]. A clear airway does not indicate effective breathing. Failure of

gas exchange may be caused by lung parenchyma infection or infiltration with acti-

vated neutrophils. Thus it may be beneficial for the newborn to be electively

sedated and ventilated. Care should be taken in premature babies to avoid hypero-

xemia to prevent retinopathy and free radical lung damage. It is equally important

to avoid over distention of alveoli, which is a potent inducer of IL-6 release. IL-6

release is associated with immune paralysis, increased severity of systemic infec-

tion, and emergence of secondary lung infection (i.e., ventilator-associated pneu-

monia).

Newborn babies with septic shock frequently have radiological changes similar to those seen in acute lung injury (ALI) in adults. This is due to consumption of surfac- tant. This secondary surfactant deficiency induces a respiratory distress syndrome- like clinical picture. It has recently been reported that the use of a surfactant called Calfactant® which has a high concentration of collectin, a protein that collects bacte- ria and contributes to their killing [30], is beneficial in this situation.

Fluid therapy

Fluid resuscitation is the hallmark of hypovolemic and septic shock reversal. It does not matter whether colloid or a crystalloid solution is used. However, volume distri- bution is much larger for crystalloids and, therefore, resuscitation with crystalloids requires more volume of fluid than colloid to achieve the same end point. To prevent reperfusion injury it is preferable to increase the total volume and rate of fluid infu- sion rather than give repeated boluses of fluids. Isolated boluses of 20 ml/kg given over 20 to 30 minutes may occasionally be required to improve heart rate, cardiac, and urine output. Reliance should not be placed on blood pressure as an end point for adequacy of fluid resuscitation. In severe sepsis and septic shock the endothe- lium is ‘leaky’, thus the end points to aim for are normalization of heart rate, capil- lary refill time, oxygen saturation, and acidosis. It is important to remember that those infants who after adequate fluid resuscitation do not self-diurese may need diuretics to prevent fluid overload.

Inotropic and Vasopressor Therapy

Adequate fluid resuscitation is the fundamental ‘key’ to the hemodynamic manage- ment of septic shock and must be achieved before instituting either vasopressor or inotropic agents. Dopamine increases heart rate, cardiac output and mean arterial blood pressure due to its vasoconstrictive effect. Dobutamine improves cardiac con- tractibility and cardiac output. In neonates, there is usually low cardiac output and low systemic resistance in severe sepsis and shock; therefore, dopamine is usually the first choice. In a systematic review [32] dopamine was found to be marginally more effective in the short term. Clinically it does not significantly alter the outcome which inotrope is used first. Experience with vasopressors in the newborn is limited, with no randomized controlled trials.

Coagulation

In severe sepsis and septic shock, endothelium all over the body becomes prothrom- botic and anti-fibrinolytic. Systemic anti-thrombotic factors like protein C are con- sumed leading initially to predominance of prothrombotic factors causing DIC.

When enough prothromotic factors are consumed then spontaneous bleeding

occurs. It is important, therefore, to determine early whether the infant is in a pro-

thrombotic or fibrinolytic phase. Appropriate coagulation studies should be under-

taken frequently. If the baby has a prolonged prothrombin time/partial thrombo-

plastin time and low fibrinogen then it is likely to be DIC. If, however, fibrinogen

levels are normal or high then it is likely to be thrombotic thrombocytopenic pur-

pura. Although routine use of fresh frozen plasma to correct laboratory clotting

abnormalities is not recommended, some professional bodies [32] have recom-

mended its use and we also find it useful. There is no consensus or firm guideline

on when to give platelet transfusion. Most authorities recommend that platelets

should be transfused when an infant’s platelets are anywhere between 5000 and 30,000 × 10

/l.

Anemia

Red blood cell transfusion in septic patients improves oxygen delivery to tissues. No optimum level of hemoglobin has been established but it is recommended that hemoglobin be maintained above 10 g/dl in neonates with sepsis.

Glucose Control

Tight glycemic control has become very popular as an approach to goal-directed therapy and has been incorporated into many sepsis ‘care bundles’. Hyperglycemia, particularly cortisol-induced hyperglycemia as seen in severe sepsis or septic shock, is immunosuppressive and prothrombotic. Hyperglycemia in severe sepsis is due to insulin resistance, which prevents glucose entering into the Krebs cycle. Muscles, and in particular cardiac muscle, depend on insulin dependent type II and type IV glucose transporters to get glucose into the Krebs cycle. Hence early institution of insulin therapy in hyperglycemic states (as seen in severe sepsis) ensures that glu- cose is delivered into the Krebs cycle. There is no consensus as to what is the ideal blood glucose level except that it should not be lower than 30 mg/dl. Similarly, there is no agreement as to what is the upper limit of blood sugar when insulin therapy should be initiated. Solutions containing 10 % dextrose as maintenance fluid are ade- quate to provide energy (glucose 4 to 8 mg/kg/minute). Care should be taken to avoid rapid fluctuation in blood glucose levels by giving boluses or high concentra- tion glucose infusion.

Bicarbonate Therapy

There is no evidence to support the use of bicarbonate therapy in the treatment of hypoperfusion induced acidemia associated with sepsis. Bicarbonate solutions are very hyperosmolar even when diluted. Bicarbonate infusion if given rapidly may increase the chances of ventricular hemorrhage in the newborn, particularly the pre- term infant.

Nutrition

During severe illness, an infant’s metabolic requirements are increased and the

infant is catabolic, breaking down his/her own tissues (especially muscle) to use as

metabolic fuel. This is worse in preterm infants who have poor muscle mass and

energy reserves. This catabolic process can and should be limited by providing

appropriate quantities of energy, minerals, and vitamins. Enteral feeding is prefera-

ble as it reduces bacterial translocation from the gut mucosa into the circulation and

also helps preserve gut mucosal function. If enteral feeding is not possible or an

additional energy source is required then it should be provided by the intravenous

route remembering that parenteral nutrition is associated with significant complica-

tions, which are exaggerated during sepsis.

Strategies to Prevent Organ Function

Organ failure results from inadequate organ oxygenation due to poor perfusion. In developing strategies to maintain or restore organ function the aim should be to improve delivery of oxygen and nutrition to all tissues.

Kidney

Ion channels in tubular epithelium are energy/oxygen dependent thus particularly sensitive to hypotension and hypoxia. Nearly two thirds of infants with severe sepsis or septic shock will develop renal function abnormalities. These should be looked for and urgently addressed with conventional methods. There is no evidence that renal replacement therapy (hemofiltration or hemodialysis) is of any benefit. Stan- dard measures should be taken to correct hyperkalemia, metabolic acidosis, and poor urine output.

Liver

During septic shock, the liver may be damaged by periods of hypotension and redis- tribution of fluid away from it. This is reflected in a sharp rise in liver enzymes in the blood and worsening coagulation profile. With adequate fluid and oxygen resus- citation this damage is often self-limiting and reversible.

Gastrointestinal tract

An empty gut may worsen sepsis and other organ dysfunction by increased bacterial translocation across inflamed or damaged intestinal mucosa. H

-antagonists and proton pump inhibitors have been used to reduce mucosal damage in adults.

Though no controlled clinical trials are available in the newborn they are frequently used in neonatal units. Use of these drugs has the disadvantage of reducing gastric acidity allowing bacterial overgrowth hence their routine use is not recommended.

It is very important to make every effort to provide the septic infant with some enteral feed (trophic feeding) except when there is clear evidence of gut injury, e.g., necrotizing enterocolitis.

Boosting Host Defense by Immunomodulation

Most neonates, preterm infants in particular, have deficiencies both in their innate and adaptive immunity. Their immune deficiency is directly proportional to the degree of prematurity. Immunological immaturity is inversely related to gestational age [9]. Sepsis (endotoxin/exotoxin) induces immune paralysis, which is frequently seen in the newborn and results in further reduction in the ability of their macro- phages and neutrophils to kill pathogens. To boost these functions various immuno- modulatory therapies have been tried:

Colony Stimulating Factors

Both granulocyte and granulocyte-macrophage colony stimulating factors (G-CSF,

GM-CSF) have been used as adjuncts to standard therapy in the treatment of neona-

tal sepsis. While the use of these factors has been shown to increase the number of

circulating white cells, their use has not been shown to reduce mortality from neo-

natal sepsis or septic shock [34].

Steroids

Although steroid therapy has been found to be useful in adults and children with severe sepsis, there are no studies of their use in neonates with sepsis.

Protein C and activated protein C

Protein C concentrations reach adult levels around three years of age. Sepsis depresses protein C levels, hence it is an attractive idea to provide protein C supple- mentation in sepsis. To date there are no randomized clinical trials using recombi- nant activated protein C in neonates with sepsis.

Pentoxifylline

This carbonic anhydrase inhibitor has been shown to improve white cell function. In one randomized controlled trial in premature infants, pentoxifylline, was shown to significantly reduce mortality [35].

Intravenous Immunoglobulin (IVIG)

Polyclonal and IgM-enriched IVIG have been shown to reduce mortality from sep- sis in newborn infants [36]. In the most recent Cochrane review [37], of nine stud- ies involving 553 neonates with suspected infection, six (n=318) reported mortality.

The use of IVIG was associated with a statistically significant reduction in mortality in infants with proven sepsis (RR 0.63 [95 % CI –0.40 – 1.00]). Treatment in seven trials (n = 262) of cases with subsequently proven infection also resulted in a statis- tically significant reduction in mortality following IVIG therapy (RR 0.55 [95 %CI –0.31 – 0.98]). Similarly, reports [36] using IgM-enriched IVIG have shown signi- ficant reductions in mortality from sepsis in the newborn (RR 0.35 [95 %CI –0.23 – 0.54]).

Conclusion

Neonatal sepsis is common and mortality from sepsis in very low birth weight infants remains high despite the use of broad-spectrum antibiotics and intensive care. To reduce this excessive loss of life, there needs to be a better understanding of pathophysiology of sepsis, severe sepsis, and septic shock in the newborn. It also needs an approach to management which involves a whole package (Table 3), which includes killing the pathogen, correcting the sequel of sepsis caused by pathogens and the body’s own activated defense systems, and boosting host defenses.

Table 3. Sepsis management package ) Clinical suspicion of sepsis (risk factors)

) Appropriate sepsis screen (inclusion of cytokines and PCR) ) Start appropriate antibiotic therapy (short duration)

) If perfusion is poor AND serum lactate

5 mmol/l give 20 ml/kg of colloid or crystalloid (earlier the better). If still hypotensive, start inotropes early

) Maintain Hb

10 g/dl

) Maintain calorie intake

100 kcl/day or

80 kcl/day if on TPN ) Maintain oxygen saturation between 90–94

) Consider adjuvant IVIG therapy

TPN: total parenteral nutrition; IVIG: intravenous immunoglobulin; Hb: hemoglobin

It is recognized that while this article may be static, the understanding, diagnosis and optimum management of severe sepsis and septic shock is a dynamic process.

It is hoped that the currently established interventions will, over a period of time, be based on evidence or abandoned and newer interventions developed and proven.

Wisdom is not what you know But what you do with what you know.

Anonymous

Acknowledgement: I am grateful to Tina Hill for typing the manuscript.

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