Aggressive fluid resuscitation is a mainstay of therapy for septic patients as this population tends to be severely hypovolemic related to multiple mechanisms, venodilation from altered vascular tone leads to pooling of blood in the capacitance vessels. (McGee & Jodka. 2002; Kumar, 2009, Teule 1984) Septic patients also have extravasation of fluid into the interstitium related to increased permeability of the capillary endothelium (Rivers 2008;

findings of the above trials.

Shoemaker, 1988 Supraphysiologic values as

patients

Hayes, 1994 Dobutamine to increase cardiac

consumption

Gattinoni, 1995 Achieving supranormal values for

< 70%

**1.3 Physiological derangements**

Table 1. Summary of Studies on Goal Directed Therapy

Rivers, 2001 Early goal directed therapy with CVP

< 65 mmHg following fluid resuscitation, ScvO2 ≥ 70%, dobutamine and red blood cells to keep hematocrit at least 30% if ScvO2 Pieracci 2011). These phenomena result in decreased preload, cardiac output and inadequate oxygen delivery. It remains essential to restore volume status and improve cardiac performance. Additionally, the body's inflammatory response is further modulated by cellular hypoxia brought about by the decline in bulk oxygen delivery (Rivers, 2007) may compound the physiologic derangement.

Concurrent with the needs to restore adequate preload and circulating blood volume, septic patients often demonstrate myocardial depression. This dysfunction is related to the presence of myocardial depressant factors early in the septic process, not decreased myocardial perfusion, and include cytokines, tumor necrosis factor alpha (TNF-α) and interleukin one beta (IL-1β) acting synergistically. (Court, 2002; Pathan, 2002) Additionally, nitric oxide generation, interstitial myocarditis, calcium trafficking, endothelin receptor antagonists and apoptosis likely all contribute to the ongoing process of myocardial depression. (Fernandes, 2008). This is manifest as a low cardiac output concurrent with a decrease in ejection fraction and oxygen delivery despite adequate filling pressures. Ventricular interdependence and impairment of left ventricular filling may be an important concern especially with concomitant ARDS and RV dysfunction/dilatation. (Michard, 2010; von Ballmoos, 2010)

The use of echocardiogram plays an important role in quantifying the degree of dysfunction as it is used to assess biventricular contractility and identifies hemodynamically unstable patients who will benefit from either inotropic support or further volume expansion (Griffee, 2010; Beaulieu, 2007). Dobutamine is a typical first line inotropic agent when myocardial depression of sepsis is confirmed and the goal is to establish adequate oxygen delivery or tissue perfusion as measured by ScvO2. No benefit is seen using inotropes to create a supra-physiologic state though studies achieving this did not have echocardiogram data to determine what proportion of subjects had impaired contractility (Hayes, 1994; Gattinoni, 1995). Sepsis induced myocardial depression usually resolves completely over the course of the illness for survivors. (Griffee, 2010; Parker, 1984).

#### **1.4 Role of red blood cells**

Controversy exists as to the ideal hemoglobin concentration for septic patients undergoing EGDT as the risks of transfusion often outweigh the benefits. (Hebert, 1999; Marik, 2008; Fuller, 2010) The goal of transfusion of red blood cells is to improve DO2. There is no impact on the sublingual microcirculation as detected by an orthogonal polarization spectral device in septic patients receiving a red blood cell transfusion (Sakr, 2007). Further, transfusing anemic, septic patients does not improve either regional or global oxygen utilization as determined by either the Fick equation or indirect calorimetry and may increase pulmonary vascular resistance, further hindering right ventricular function. (Fernandes, 2001; Bone, 1993) At this time unless there is active myocardial ischemia, it is difficult to define exact triggers for transfusion of red blood cells in septic patients undergoing active resuscitation. (Pieracci, 2011)

#### **1.5 Avoiding volume overload**

An aggressive, early intervention targeted at improving hemodynamic performance in septic patients improves outcomes and is now recognized as the standard of care. The trigger to transfuse red blood cells during the early resuscitation of septic patients remains controversial and is a major criticism of EGDT, especially given the known complications of

Applied Physiology and the Hemodynamic Management of

↑**RV Afterload**

↓**RV Preload**

**Positive Pressure Breath**

↑ **Intrathoracic Pressure**

**Delayed** ↓↓ **SV**

and afterload induced by positive pressure ventilation is shown.

intravascular volume status where it may not be.

Fig. 3. The phasic change in blood pressure and its timing to the ventilatory cycle is illustrated with four positive pressure breaths and the simultaneously displayed arterial waveform directly below it. Blood pressure goes up during the inspiratory phase of mechanical ventilation and decreases during expiration. The swings in blood pressure (pulse pressure variation, PPV) are generated by the change in stroke volume SV (stroke volume variation, SVV) effected by positive pressure ventilation. The variability is

respirophasic as this figure illustrates. The impact on right (RV) and left ventricular (LV) pre

In those clinical settings where SVV or PPV does not predict volume responsiveness how can this be determined? As long as stroke volume can be measured this question can be answered. This represents a huge advantage of the technologies that allow measurement of stroke volume and cardiac output, FloTrac/Vigileo, PICCO, and LiDCO, over those that simply provide pulse pressure variation, which is now readily available on bedside monitors that display an arterial waveform (IntelliVue MP90, 2006). This physiology also explains why this literature has been primarily developed in the operating room where ideal conditions often exist for the measurement and application of dynamic parameters, namely controlled mechanical ventilation with a large enough tidal volume to induce a significant change in pleural pressure to impact venous return. A threshold value for tidal volume of 8 cc per kilogram ideal body weight has been determined in several studies that evaluated the tidal volume necessary to meaningfully impact venous return. (Feissel, 2001; Tavernier, 1998; Michard, 2000; Perel, 1987) Across a heterogeneous population, this may be true, although there will be specific examples depending on the patient's lung compliance and

**Empty Pulmonary Venous System**

**MECHANISM OF SVV**

Septic Shock Utilizing the Physiologic Optimization Program 261

Pressure

Pressure

Arterial

Time

Airway

↑**LV Preload**

**Acute** ↑**SV**

providing transfusions to critically ill patients. Critical care practitioners need to recognize both the importance of implementing EGDT and avoiding the deleterious effects of fluid overload. When septic patients have a more positive fluid balance both early in the resuscitation process and cumulatively over 4 days there is an associated increased risk of mortality (Boyd, 2011). The importance of carefully managing fluids is further illustrated in patients with acute lung injury or ARDS as those with a lower cumulative fluid balance demonstrate improved outcomes. (Murphy, 2009; the NHLBI ARDSNet, 2006) When complicated by acute kidney injury, fluid overload further impacts mortality in critically ill patients (Payen, 2008; Bouchard, 2009)

#### **2. Applied physiology for the management of severe sepsis/septic shock**

The foundation of all resuscitation strategies for severe sepsis and septic shock is volume therapy. Early goal directed therapy is complicated by the requirement for central venous access which is not always available especially during the initial patient evaluation, and the use of a CVP target which has been called in to question as a meaningful measure of preload responsiveness. (Michard, 2002; Marik, 2008;Osman, 2007) Additionally although rapid resuscitation is important excess volume that does not improve cardiac performance is potentially contributing to complications; excess length of stay (Wiedemann, 2006) and mortality (Murphy, 2009). Generally as the goal of any volume therapy in the critically ill is to improve cardiac performance, we propose physiology based hemodynamic therapy for the severely septic patient that considers the pathophysiology already described.

#### **2.1 Physiologic optimization program for sepsis resuscitation, dynamic variables of volume responsiveness**

Utilizing dynamic variables of volume responsiveness to guide resuscitation allows precise titration of preload with clear endpoints for fluid resuscitation to minimize the risk of inappropriate fluid overload. Dynamic variables of volume responsiveness, stroke volume variation (SVV) and pulse pressure variations (PPV) exploit the physiology of the heart/lung interaction during positive pressure ventilation that relates the variation of stroke volume or pulse pressure to the degree of volume responsiveness. The respirophasic change in blood pressure (commonly observed in the arterial pressure tracing) of hypovolemic patients is a well known example. (McGee, 2009) (Figure 3).

The available devices quantify the variability and display the variation as a primary output. This variation is highly correlated with the degree of volume responsiveness, i.e., the greater the variation, the greater the expected response to a volume challenge. (Figure 4).

This approach is available only for patients with controlled positive pressure ventilation without a significant dysrhythmia as the utility of SVV or PPV to assess volume responsiveness is not valid beyond these conditions. The use of the dynamic variables SVV and PPV, especially during early resuscitation prior to intubation is generally not possible. Resuscitation of these patients, however, is straight forward and relies on titration of volume against cardiac performance measured by SV and CO. This approach provides assurance that preload optimization has occurred prior to implementation of pharmacotherapy. Our preference is to use the indexed values in an attempt to normalize targets across variability in body surface area. This may be problematic in the super obese (McGee, 2006). (Figure 5).

providing transfusions to critically ill patients. Critical care practitioners need to recognize both the importance of implementing EGDT and avoiding the deleterious effects of fluid overload. When septic patients have a more positive fluid balance both early in the resuscitation process and cumulatively over 4 days there is an associated increased risk of mortality (Boyd, 2011). The importance of carefully managing fluids is further illustrated in patients with acute lung injury or ARDS as those with a lower cumulative fluid balance demonstrate improved outcomes. (Murphy, 2009; the NHLBI ARDSNet, 2006) When complicated by acute kidney injury, fluid overload further impacts mortality in critically ill

**2. Applied physiology for the management of severe sepsis/septic shock**

The foundation of all resuscitation strategies for severe sepsis and septic shock is volume therapy. Early goal directed therapy is complicated by the requirement for central venous access which is not always available especially during the initial patient evaluation, and the use of a CVP target which has been called in to question as a meaningful measure of preload responsiveness. (Michard, 2002; Marik, 2008;Osman, 2007) Additionally although rapid resuscitation is important excess volume that does not improve cardiac performance is potentially contributing to complications; excess length of stay (Wiedemann, 2006) and mortality (Murphy, 2009). Generally as the goal of any volume therapy in the critically ill is to improve cardiac performance, we propose physiology based hemodynamic therapy for the severely septic patient that considers the pathophysiology already described.

**2.1 Physiologic optimization program for sepsis resuscitation, dynamic variables of**

hypovolemic patients is a well known example. (McGee, 2009) (Figure 3).

the variation, the greater the expected response to a volume challenge. (Figure 4).

Utilizing dynamic variables of volume responsiveness to guide resuscitation allows precise titration of preload with clear endpoints for fluid resuscitation to minimize the risk of inappropriate fluid overload. Dynamic variables of volume responsiveness, stroke volume variation (SVV) and pulse pressure variations (PPV) exploit the physiology of the heart/lung interaction during positive pressure ventilation that relates the variation of stroke volume or pulse pressure to the degree of volume responsiveness. The respirophasic change in blood pressure (commonly observed in the arterial pressure tracing) of

The available devices quantify the variability and display the variation as a primary output. This variation is highly correlated with the degree of volume responsiveness, i.e., the greater

This approach is available only for patients with controlled positive pressure ventilation without a significant dysrhythmia as the utility of SVV or PPV to assess volume responsiveness is not valid beyond these conditions. The use of the dynamic variables SVV and PPV, especially during early resuscitation prior to intubation is generally not possible. Resuscitation of these patients, however, is straight forward and relies on titration of volume against cardiac performance measured by SV and CO. This approach provides assurance that preload optimization has occurred prior to implementation of pharmacotherapy. Our preference is to use the indexed values in an attempt to normalize targets across variability in body surface area. This may be problematic in the super obese

patients (Payen, 2008; Bouchard, 2009)

**volume responsiveness**

(McGee, 2006). (Figure 5).

Fig. 3. The phasic change in blood pressure and its timing to the ventilatory cycle is illustrated with four positive pressure breaths and the simultaneously displayed arterial waveform directly below it. Blood pressure goes up during the inspiratory phase of mechanical ventilation and decreases during expiration. The swings in blood pressure (pulse pressure variation, PPV) are generated by the change in stroke volume SV (stroke volume variation, SVV) effected by positive pressure ventilation. The variability is respirophasic as this figure illustrates. The impact on right (RV) and left ventricular (LV) pre and afterload induced by positive pressure ventilation is shown.

In those clinical settings where SVV or PPV does not predict volume responsiveness how can this be determined? As long as stroke volume can be measured this question can be answered. This represents a huge advantage of the technologies that allow measurement of stroke volume and cardiac output, FloTrac/Vigileo, PICCO, and LiDCO, over those that simply provide pulse pressure variation, which is now readily available on bedside monitors that display an arterial waveform (IntelliVue MP90, 2006). This physiology also explains why this literature has been primarily developed in the operating room where ideal conditions often exist for the measurement and application of dynamic parameters, namely controlled mechanical ventilation with a large enough tidal volume to induce a significant change in pleural pressure to impact venous return. A threshold value for tidal volume of 8 cc per kilogram ideal body weight has been determined in several studies that evaluated the tidal volume necessary to meaningfully impact venous return. (Feissel, 2001; Tavernier, 1998; Michard, 2000; Perel, 1987) Across a heterogeneous population, this may be true, although there will be specific examples depending on the patient's lung compliance and intravascular volume status where it may not be.

Applied Physiology and the Hemodynamic Management of

**cardiac performance cardiac performance**

**Sweet Spot**

**SVI**

Septic Shock Utilizing the Physiologic Optimization Program 263

SVI Targeted Resuscitation SVI Targeted Resuscitation

**Preload dependent:**

**Preload Independent:**

**Less variability SVV is low < 13%**

**More variability SVV is high >13%**

Fig. 5. The goal of volume therapy during resuscitation is to optimize the use of preload augmentation of cardiac function. Stroke volume variation is a very useful parameter to allow rapid safe resuscitation. When this parameter is not useful (dysrhythmia, small tidal volume, spontaneous breathing), simply targeting the maximum stroke volume index (SVI), is another means to guide volume therapy. Independent of which Frank-Starling Curve the patient is on ,the goal of volume therapy is always the same during resuscitation; to obtain the most benefit from the preload dependent portion of the Frank-Starling Curve. These techniques have the additional benefit of more precisely targeting the "sweet spot" of the

**2.2 Stroke volume index targeted resuscitation: Obtaining the sweet spot on the**

Increase the tidal volume to at least 8-10 cc/kg and look for the change in SVV. For volume responsive patients, once beyond a threshold value for tidal volume, volume responsiveness becomes apparent as the SVV will increase to greater than 10-13%, a reliable cutoff above which patients are generally volume responsive. The time responsiveness of these technologies is fairly rapid and tidal volume needs to be increased for only a short period of time, typically less than 5 minutes. Physician presence at the bedside during this maneuver

b. Assure that the pressure encountered with the ventilation change is not harmful to the patients. If this change in tidal volume results in SVV becoming greater than 10-13%, a

**Preload**

Frank-Starling Curve without excessive volume overload.

**Frank-Starling curve (figure 5)**  1. Recruitable stroke volume:

is important to:

a. View the change; and

**Optimization of Optimization of preload dependent preload dependent**

## **Magnitude of SVV is Related to LV Magnitude of SVV is Related to LV Preload Preload**

**Change in preload related to positive Change in preload related to positive pressure ventilation pressure ventilation**

Fig. 4. Legend: A and B represent different locations on the Starling Curve. The change in preload induced by the ventilator is identical. The impact on SV is not. The change in SV induced by one positive pressure breath is proportional to SVV. SVV determines the magnitude of preload dependency. Patients with higher SVV are more volume responsive (A – preload dependent) functioning on the steeper portion of the Frank Starling curve. SVV decreases as preload dependent LV function is optimized (B – preload independent). In these patients (B) volume can be safely removed as cardiac performance is not influenced by changes in preload. SVV/SVI pairs allow individual discrimination of a patient's Starling curve that can determine when volume is required to improve cardiac performance and conversely when volume can be safely removed. SV (stroke volume) SVV (stroke volume variation)

At lower tidal volumes, false negatives where stroke volume variation is low, and the patient is still significantly volume responsive occur. Extreme examples of this were encountered during the H1N1 flu epidemic in the fall of 2009, where many patients were being oscillated at very high frequencies but with minimal tidal volume and hence pleural pressure change. These patients could be significantly volume responsive with essentially no stroke volume or pulse pressure variation because of the very small change in pleural pressure induced with this strategy of ventilation. Similarly, patients being ventilated using a low tidal volume strategy for ALI/ARDS may manifest a similar phenomenon. In those patients, teasing out volume responsiveness utilizing physiology is fairly simple. Listed below are three possible strategies to ascertain volume responsiveness when SVV is unable to provide direction: (DeBacker, 2005)

**Magnitude of SVV is Related to LV Magnitude of SVV is Related to LV**

**Preload PreloadChange in preload related to positive Change in preload related to positive**

**pressure ventilation pressure ventilation**

**Preload**

Equal change in Filling with positive Pressure breath

Fig. 4. Legend: A and B represent different locations on the Starling Curve. The change in preload induced by the ventilator is identical. The impact on SV is not. The change in SV induced by one positive pressure breath is proportional to SVV. SVV determines the magnitude of preload dependency. Patients with higher SVV are more volume responsive (A – preload dependent) functioning on the steeper portion of the Frank Starling curve. SVV decreases as preload dependent LV function is optimized (B – preload independent). In these patients (B) volume can be safely removed as cardiac performance is not influenced by changes in preload. SVV/SVI pairs allow individual discrimination of a patient's Starling curve that can determine when volume is required to improve cardiac performance and conversely when volume can be safely removed. SV (stroke volume) SVV (stroke volume

At lower tidal volumes, false negatives where stroke volume variation is low, and the patient is still significantly volume responsive occur. Extreme examples of this were encountered during the H1N1 flu epidemic in the fall of 2009, where many patients were being oscillated at very high frequencies but with minimal tidal volume and hence pleural pressure change. These patients could be significantly volume responsive with essentially no stroke volume or pulse pressure variation because of the very small change in pleural pressure induced with this strategy of ventilation. Similarly, patients being ventilated using a low tidal volume strategy for ALI/ARDS may manifest a similar phenomenon. In those patients, teasing out volume responsiveness utilizing physiology is fairly simple. Listed below are three possible strategies to ascertain volume responsiveness when SVV is unable

**A**

**B**

**SVV high >13%**

to provide direction: (DeBacker, 2005)

variation)

**SV**

**SVV low <13%**

Fig. 5. The goal of volume therapy during resuscitation is to optimize the use of preload augmentation of cardiac function. Stroke volume variation is a very useful parameter to allow rapid safe resuscitation. When this parameter is not useful (dysrhythmia, small tidal volume, spontaneous breathing), simply targeting the maximum stroke volume index (SVI), is another means to guide volume therapy. Independent of which Frank-Starling Curve the patient is on ,the goal of volume therapy is always the same during resuscitation; to obtain the most benefit from the preload dependent portion of the Frank-Starling Curve. These techniques have the additional benefit of more precisely targeting the "sweet spot" of the Frank-Starling Curve without excessive volume overload.

#### **2.2 Stroke volume index targeted resuscitation: Obtaining the sweet spot on the Frank-Starling curve (figure 5)**

#### 1. Recruitable stroke volume:

Increase the tidal volume to at least 8-10 cc/kg and look for the change in SVV. For volume responsive patients, once beyond a threshold value for tidal volume, volume responsiveness becomes apparent as the SVV will increase to greater than 10-13%, a reliable cutoff above which patients are generally volume responsive. The time responsiveness of these technologies is fairly rapid and tidal volume needs to be increased for only a short period of time, typically less than 5 minutes. Physician presence at the bedside during this maneuver is important to:

Applied Physiology and the Hemodynamic Management of

**2.3 Physiologic optimization program (figure 7)**

2010; McGee, 2009)

therapy (Figure 5).

performance measure.

(McGee, 2009).

therapy.

**2.4 Assessment of oxygen delivery**

Septic Shock Utilizing the Physiologic Optimization Program 265

improvement in cardiac performance may in fact be detrimental to the patient. (Cavallaro,

3. Volume challenges: As long as there is a cardiac performance measure, stroke volume or cardiac output, simply giving a fluid bolus and assessing its impact on cardiac performance is a reasonable way to assess volume responsiveness for patients where we suspect that additional volume will not be injurious, i.e. clear lungs and without renal failure. If cardiac performance does not improve, volume is not the correct

It is important to recognize when the patient is on the flat part of the Frank-Starling Curve and not responding to volume. Excess volume therapy has been associated with increased length of stay, increased time on mechanical ventilation, and mortality. (Boyd, 2011; Murphy, 2009; the NHLBI ARDSNet, 2006; Payen, 2008;Bouchard, 2009; Maitland, 2011) The major impact of using these technologies well is that we now have the ability for precise titration of volume management in the majority of critically ill patients. The simple premise underlying volume therapy in the ICU or OR is to affect a change in cardiac performance. This simply is not possible without a cardiac

Figure 7 illustrates the use of dynamic parameters of volume responsiveness for the hemodynamic management of patients with severe sepsis or septic shock. Volume responsive patients SVV > 13% receive volume therapy titrated against both SVV and SVI. For non-volume responsive patients, the physiology is interrogated at the level of cardiac performance on a beat to beat basis. Ultimately and with this approach rapidly a majority of patients will develop a SVI > normal (pathway 1). This represents resuscitated septic shock and these patients may be safely placed on a vasopressor, knowing that volume resuscitation has been accomplished. Precise volume titration can be maintained but once SVI is supraphysiologic (pathway 3) volume therapy is stopped and diuretics might be warranted for that population who go on to develop ALI/ARDS typically after the initial resuscitation phase. Approaches to the patient in pathway 2 will be discussed in the text

Non-volume responsive patients (SVV < 13%) with low SVI or CO are a particularly challenging population. DO2 adequacy must be determined on an individual basis. This will also apply to some patients with normal SVI or CO. O2 extraction is particularly useful in this regard facilitating determination of the adequacy of bulk oxygen transport. When extraction is low or normal (<33%) augmentation of DO2 has not been shown to be helpful. (Gattinoni, 1995, Hayes 1994) Alternatively, high extraction (>40%) usually precipitates some attempt at DO2 optimization, although this approach has not been rigorously evaluated, it remains the basis of all resuscitation strategies. It is clear that as O2 extraction increases, physiologic reserve is compromised, lactic acidosis ensues, and mortality results. Using O2 extraction as an endpoint further refines hemodynamic care of this severely ill group of patients and is the physiologic foundation of early goal directed

fluid bolus is then given after the patient has been returned to the initial ventilator settings.

Two additional strategies are also useful for non-ventilated patients or those with significant dysrhythmias.

2. The passive leg raising maneuver (PLR) ((Cavallaro, 2010, Monnet, 2006) (Figure 6.)

#### Fig. 6.

The patient is placed flat and the legs are elevated to 45 degrees and the change in stroke volume and cardiac output is recorded. Those patients that have a positive response usually defined as greater than 12-15% increase in cardiac output are then given a fluid challenge, typically 250-500 cc of colloid or crystalloid. This can be done numerous times until the indicator of volume responsiveness disappears or an adequate stroke volume/cardiac output is reached. Although the change in SV using aortic flow is fully apparent within 30 seconds, the increase in venous return that this maneuver induces in cardiac performance requires the legs be elevated for roughly 120 seconds to allow for the time constraints of the pulse contour technology. (Teboul, 2009; Biais, 2009) In numerous studies, this has been shown to be essentially a perfect test as a measure of volume responsiveness as long as the improvement in stroke volume/cardiac output is the cardiac performance parameter of interest. (Cavallaro, 2010) Simply looking at the change in blood pressure is not helpful. (Monnet, 2006) This technique works well especially in those patients who are either spontaneously breathing or have a significant dysrhythmia. This reversible volume challenge is most useful in patients with acute lung injury or ARDS or those with either acute or chronic renal failure, where giving a volume challenge that does not result in

Two additional strategies are also useful for non-ventilated patients or those with significant

**Passive Leg Raising**

**Baseline PLR**

Patients who respond to the PLR maneuver will also respond to a fluid bolus. Response described in text.

The patient is placed flat and the legs are elevated to 45 degrees and the change in stroke volume and cardiac output is recorded. Those patients that have a positive response usually defined as greater than 12-15% increase in cardiac output are then given a fluid challenge, typically 250-500 cc of colloid or crystalloid. This can be done numerous times until the indicator of volume responsiveness disappears or an adequate stroke volume/cardiac output is reached. Although the change in SV using aortic flow is fully apparent within 30 seconds, the increase in venous return that this maneuver induces in cardiac performance requires the legs be elevated for roughly 120 seconds to allow for the time constraints of the pulse contour technology. (Teboul, 2009; Biais, 2009) In numerous studies, this has been shown to be essentially a perfect test as a measure of volume responsiveness as long as the improvement in stroke volume/cardiac output is the cardiac performance parameter of interest. (Cavallaro, 2010) Simply looking at the change in blood pressure is not helpful. (Monnet, 2006) This technique works well especially in those patients who are either spontaneously breathing or have a significant dysrhythmia. This reversible volume challenge is most useful in patients with acute lung injury or ARDS or those with either acute or chronic renal failure, where giving a volume challenge that does not result in

Data recorded after 120s

2. The passive leg raising maneuver (PLR) ((Cavallaro, 2010, Monnet, 2006) (Figure 6.)

settings.

dysrhythmias.

Fig. 6.

fluid bolus is then given after the patient has been returned to the initial ventilator

improvement in cardiac performance may in fact be detrimental to the patient. (Cavallaro, 2010; McGee, 2009)

3. Volume challenges: As long as there is a cardiac performance measure, stroke volume or cardiac output, simply giving a fluid bolus and assessing its impact on cardiac performance is a reasonable way to assess volume responsiveness for patients where we suspect that additional volume will not be injurious, i.e. clear lungs and without renal failure. If cardiac performance does not improve, volume is not the correct therapy (Figure 5).

It is important to recognize when the patient is on the flat part of the Frank-Starling Curve and not responding to volume. Excess volume therapy has been associated with increased length of stay, increased time on mechanical ventilation, and mortality. (Boyd, 2011; Murphy, 2009; the NHLBI ARDSNet, 2006; Payen, 2008;Bouchard, 2009; Maitland, 2011) The major impact of using these technologies well is that we now have the ability for precise titration of volume management in the majority of critically ill patients. The simple premise underlying volume therapy in the ICU or OR is to affect a change in cardiac performance. This simply is not possible without a cardiac performance measure.

#### **2.3 Physiologic optimization program (figure 7)**

Figure 7 illustrates the use of dynamic parameters of volume responsiveness for the hemodynamic management of patients with severe sepsis or septic shock. Volume responsive patients SVV > 13% receive volume therapy titrated against both SVV and SVI. For non-volume responsive patients, the physiology is interrogated at the level of cardiac performance on a beat to beat basis. Ultimately and with this approach rapidly a majority of patients will develop a SVI > normal (pathway 1). This represents resuscitated septic shock and these patients may be safely placed on a vasopressor, knowing that volume resuscitation has been accomplished. Precise volume titration can be maintained but once SVI is supraphysiologic (pathway 3) volume therapy is stopped and diuretics might be warranted for that population who go on to develop ALI/ARDS typically after the initial resuscitation phase. Approaches to the patient in pathway 2 will be discussed in the text (McGee, 2009).

#### **2.4 Assessment of oxygen delivery**

Non-volume responsive patients (SVV < 13%) with low SVI or CO are a particularly challenging population. DO2 adequacy must be determined on an individual basis. This will also apply to some patients with normal SVI or CO. O2 extraction is particularly useful in this regard facilitating determination of the adequacy of bulk oxygen transport. When extraction is low or normal (<33%) augmentation of DO2 has not been shown to be helpful. (Gattinoni, 1995, Hayes 1994) Alternatively, high extraction (>40%) usually precipitates some attempt at DO2 optimization, although this approach has not been rigorously evaluated, it remains the basis of all resuscitation strategies. It is clear that as O2 extraction increases, physiologic reserve is compromised, lactic acidosis ensues, and mortality results. Using O2 extraction as an endpoint further refines hemodynamic care of this severely ill group of patients and is the physiologic foundation of early goal directed therapy.

Applied Physiology and the Hemodynamic Management of

approach or more aggressive resuscitation. (Figure 8)

SVI/cardiac output and ultimately oxygen delivery.

**2.5 Total physiologic assessment for septic shock**

easily and safely obtained (McGee, 2009).

performed.

**3. References**

of severe sepsis and septic shock.

Care Med 35, No. 5 Suppl: S235 – S249.

Septic Shock Utilizing the Physiologic Optimization Program 267

For those patients with extraction greater than normal but not excessively elevated (>33% to < 40%). Best clinical management remains unclear. DO2 should be determined as a first step. Clinical assessment of physiology as it relates to the individual patient along with frequent reassessment of other clinical parameters would typically lead to a watchful waiting

O2 extraction data helps assess the adequacy of O2 delivery. If adequate (extraction <33%) a vasopressor depending on the blood pressure or no further therapy is generally appropriate. Other possible interventions are shown in Figure 8, all titrated against a change in

In applying these algorithms at the bedside, the use of sound physiologic principles guides management in a group of patients in whom advanced hemodynamic monitoring can be

When possible but especially for those patients in whom we desire a more complete picture of cardiac performance typically those with normal or decreased stroke volume/cardiac output; echocardiography with assessment of biventricular function and ventricular interdependence along with pulmonary artery pressure allows for a complete description of cardiac performance and suggests possible therapies for augmentation if necessary. Inotropes for pure left ventricular failure or diagnosis and treatment of impairment of left ventricular filling from right ventricular distension as two common examples of how this additional cardiac functional anatomic data refines clinical care. Numerous other etiologies are possible and beyond the scope of this manuscript, but functional biventricular assessment is perhaps the final piece to a complete hemodynamic assessment of the critically ill septic shock patient. Flow (SV/CO and DO2), preload responsiveness (SVV/PPV), perfusion (ScVO2 and calculation of O2 extraction) along with biventricular function (echo) can all be obtained reasonably safely for a majority of critically ill patients who routinely have arterial and central venous catheters and often have echocardiography

Goal directed therapy saves lives of patients with severe sepsis. Application of physiology based volume management for the care of these patients further refines therapy while providing assurance that preload optimization is accomplished while minimizing the impact of excess volume. Titrated hemodynamic management using applied physiology has further potential to improve outcomes over more traditional approaches to the management

Beaulieu Y. (2007) Bedside echocardiography in the assessment of the critically ill. Crit

Biais M, Vidil L, Sarrabay P et al: (2009) Changes in stroke volume induced by passive leg

echocardiography and Vigileo/FloTrac device. Crit Care 13(6):R195.

raising in spontaneously breathing patients: comparison between

Fig. 7.

Fig. 7.

Fig. 8.

For those patients with extraction greater than normal but not excessively elevated (>33% to < 40%). Best clinical management remains unclear. DO2 should be determined as a first step. Clinical assessment of physiology as it relates to the individual patient along with frequent reassessment of other clinical parameters would typically lead to a watchful waiting approach or more aggressive resuscitation. (Figure 8)

O2 extraction data helps assess the adequacy of O2 delivery. If adequate (extraction <33%) a vasopressor depending on the blood pressure or no further therapy is generally appropriate. Other possible interventions are shown in Figure 8, all titrated against a change in SVI/cardiac output and ultimately oxygen delivery.

In applying these algorithms at the bedside, the use of sound physiologic principles guides management in a group of patients in whom advanced hemodynamic monitoring can be easily and safely obtained (McGee, 2009).

#### **2.5 Total physiologic assessment for septic shock**

When possible but especially for those patients in whom we desire a more complete picture of cardiac performance typically those with normal or decreased stroke volume/cardiac output; echocardiography with assessment of biventricular function and ventricular interdependence along with pulmonary artery pressure allows for a complete description of cardiac performance and suggests possible therapies for augmentation if necessary. Inotropes for pure left ventricular failure or diagnosis and treatment of impairment of left ventricular filling from right ventricular distension as two common examples of how this additional cardiac functional anatomic data refines clinical care. Numerous other etiologies are possible and beyond the scope of this manuscript, but functional biventricular assessment is perhaps the final piece to a complete hemodynamic assessment of the critically ill septic shock patient. Flow (SV/CO and DO2), preload responsiveness (SVV/PPV), perfusion (ScVO2 and calculation of O2 extraction) along with biventricular function (echo) can all be obtained reasonably safely for a majority of critically ill patients who routinely have arterial and central venous catheters and often have echocardiography performed.

Goal directed therapy saves lives of patients with severe sepsis. Application of physiology based volume management for the care of these patients further refines therapy while providing assurance that preload optimization is accomplished while minimizing the impact of excess volume. Titrated hemodynamic management using applied physiology has further potential to improve outcomes over more traditional approaches to the management of severe sepsis and septic shock.

#### **3. References**

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**Part 6**

**Pediatric Sepsis**

Von Ballmoos MW, Takala J, Roeck M et al: (2010) Pulse-pressure variation and hemodynamic response in patients with elevated pulmonary artery pressure: a clinical study. Critical Care 14:R111.

**Part 6**

**Pediatric Sepsis**

272 Severe Sepsis and Septic Shock – Understanding a Serious Killer

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**13**

Martin C. J. Kneyber

*The Netherlands*

**Management of Septic Shock in Children**

*University Medical Center Groningen, University of Groningen, Groningen*

Paediatric septic shock is a frequently occurring disease condition that is associated with high morbidity and mortality (Watson et al, 2003). Shock is an acute, complex state of circulatory dysfunction resulting in failure to deliver oxygen (DO2) and nutrients to meet metabolic demands (VO2) which are usually increased during shock. If left untreated, multiple organ failure and ultimately death will occur (Smith et al, 2006). This strongly points out the importance of early recognition and aggressive treatment of children with shock. Comparable to adults, such an approach – termed early-goal directed therapy (EGDT) – has been shown to significantly reduce mortality in paediatric septic shock. Paediatric studies have pointed out that the risk of death showed a two-fold increase with each hour delay in the reversal of shock (Carcillo et al, 2009; Han et al, 2003; Inwald et al,

Hypovolaemic shock and septic shock are the most common forms of shock in children. Hypovolaemic shock is characterized by a decrease in intravascular blood volume to such an extent that effective tissue perfusion cannot be maintained. In children hypovolaemic shock is mainly caused by fluid and electrolyte loss due to vomiting and diarrhea or acute haemorrhage. Septic shock is actually a combination of distributive shock (i.e. a decreased total vascular resistance and maldistribution of blood flow in the microcirculation) and relative as well as a absolute hypovolaemia. Furthermore, impairment of myocardial fuction

The great majority of children with septic shock will not be presented in hospitals with PICU facilities. Furthermore, from a pathophysiologic perspective paediatric shock does not resemble adult septic shock. This strongly suggests that every physician that could be faced with these children needs to understand how to recognize paediatric shock and have basic knowledge of the principles of primary management. This chapter summarizes the pathophysiology, clinical manifestations and primary management of paediatric septic

The balance between DO2 and VO2 is the key factor in the pathophysiology of shock. DO2 is also in children determined by the cardiac output (CO) and arterial oxygen content (CaO2)

**1. Introduction**

2009; Rivers et al, 2001).

shock.

according to the formula

may occur with symptoms of cardiogenic shock.

**2. Pathophysiology of paediatric shock**

*Department of Paediatric Intensive Care, Beatrix Children's Hospital*

## **Management of Septic Shock in Children**

#### Martin C. J. Kneyber

*Department of Paediatric Intensive Care, Beatrix Children's Hospital University Medical Center Groningen, University of Groningen, Groningen The Netherlands*

#### **1. Introduction**

Paediatric septic shock is a frequently occurring disease condition that is associated with high morbidity and mortality (Watson et al, 2003). Shock is an acute, complex state of circulatory dysfunction resulting in failure to deliver oxygen (DO2) and nutrients to meet metabolic demands (VO2) which are usually increased during shock. If left untreated, multiple organ failure and ultimately death will occur (Smith et al, 2006). This strongly points out the importance of early recognition and aggressive treatment of children with shock. Comparable to adults, such an approach – termed early-goal directed therapy (EGDT) – has been shown to significantly reduce mortality in paediatric septic shock. Paediatric studies have pointed out that the risk of death showed a two-fold increase with each hour delay in the reversal of shock (Carcillo et al, 2009; Han et al, 2003; Inwald et al, 2009; Rivers et al, 2001).

Hypovolaemic shock and septic shock are the most common forms of shock in children. Hypovolaemic shock is characterized by a decrease in intravascular blood volume to such an extent that effective tissue perfusion cannot be maintained. In children hypovolaemic shock is mainly caused by fluid and electrolyte loss due to vomiting and diarrhea or acute haemorrhage. Septic shock is actually a combination of distributive shock (i.e. a decreased total vascular resistance and maldistribution of blood flow in the microcirculation) and relative as well as a absolute hypovolaemia. Furthermore, impairment of myocardial fuction may occur with symptoms of cardiogenic shock.

The great majority of children with septic shock will not be presented in hospitals with PICU facilities. Furthermore, from a pathophysiologic perspective paediatric shock does not resemble adult septic shock. This strongly suggests that every physician that could be faced with these children needs to understand how to recognize paediatric shock and have basic knowledge of the principles of primary management. This chapter summarizes the pathophysiology, clinical manifestations and primary management of paediatric septic shock.

#### **2. Pathophysiology of paediatric shock**

The balance between DO2 and VO2 is the key factor in the pathophysiology of shock. DO2 is also in children determined by the cardiac output (CO) and arterial oxygen content (CaO2) according to the formula

Management of Septic Shock in Children 277

pulses ("warm shock". If the shock is not reversed, signs of failure of the compensatory mechanisms can be noted including cold extremities and prolonged capillary refill time ("cold shock"). Of note, the capillary refill time has little discriminative value in paediatric shock. Hypovolaemic children may still have a capillary refill time that is within the normal

0 – 7 days 180 50 59 8 – 28 days 180 40 69 1 – 12 months 180 34 74 1 – 5 years 140 22 75 6 – 12 years 130 18 83 13 – 18 years 110 14 90 Table 1. Age-related reference values for vital parameters in children (derived from reference values by age, height and weight). Values above the 95th percentile (for heart rate and respiratory rate), and below the 5th percentile (for systolic blood pressure) are abnormal.

Respiratory rate /min (95th percentile)

Systolic blood pressure mmHg (5th percentile)

limit (2 seconds).

Age Heart rate /min

Adapted from (Anonymous, 2004).

(95th percentile)

Symptoms of septic shock General symptoms Tachycardia

 Hypothermia or fever Decreased consciousness Decreased urinary output

Shortened capillary refill time

Capillary refill time > 2 secons

 Cold extremities, mottled skin Hypotension (not necessarily)

hypoperfusion, metabolic alterations and production of cytotoxic substances.

urinary output and hyperventilation to compensate for the metabolic acidosis.

Many children with fever have tachycardia and warm extremities on physical examination. Not all of these children are in shock. For early recognition of shock it is then absolute necessary to evaluate the mental state of the child. In general, children in shock are lethargic and have decreased consciousness, but the opposite (i.e. agitation, restless, anxious) also occurs. Underlying mechanisms include most likely a combination of cerebral

Oxygen debt will occur when the shock is not recognized and thus not treated properly. Clinically, the child suffers from depressed consciousness, poor skin perfusion, decreased

Widened blood pressure

"Warm shock"

"Cold shock"

Weak pulses

Table 2. Symptoms of paediatric septic shock

Bounding pulses

#### DO2 = CO \* (Haemoglobin \* 1.36 \* SaO2) + (0.003 \* PaO2) (1)

The CO is determined by the heart rate (HR) and stroke volume (SV), the latter is determined by the pre-load, afterload and contractility of the heart.

The VO2 is increased in septic shock. Hence, the body will try to compensate for this by increasing the DO2 through various mechanisms including increasing the HR and the venous vascular tone to optimize cardiac pre-load. Tachycardia is one of the earliest compensatory mechanisms. If this compensation is inadequate to meet cellular oxygen demands, the systemic vascular resistance (SVR) will be increased allowing perfusion of vital organs such as the heart and brain. In addition, oxygen extraction will be increased. Of importance, children are able to maintain normal blood pressure. This phase of shock is termed *compensated shock*.

Oxygen debt will occur if these mechanisms fail when the shock is not reversed. Under normal conditions oxygen debt will occur when the ratio DO2 : VO2 is 3 : 1. However, as a result of the increase in VO2 during septic shock oxygen debt will occur already at DO2 : VO2 2 : 1. Microvascular perfusion becomes marginal and cellular function deteriorates, affecting all organ systems (*uncompensated shock*). If not adequately managed, *irreversible shock* will occur. Vital organs will be damaged to such an extent that death is inevitable.

There are considerable differences in the pathophyiology of septic shock between children and adults. Vasomotor paralysis is the predominant cause of mortality in adults (Parker et al, 1987). Myocardial dysfunction in adult septic shock manifests mainly as decreased ejection fraction with either normal or increased CO. This is because adults are capable of increasing their CO by tachycardia in combination with ventricular dilatation allowing an increase in SV (Parker et al, 1984). In contrast, paediatric septic shock is mainly characterized by severe hypovolaemia; the decrease in CO and not SVR is associated with mortality (Carcillo et al, 2002). This is because especially younger children have higher baseline HR's compared to adults; hence they cannot increase their HR without impairing CO. Furthermore, children are not capable of increasing their SV (Feltes et al, 1994). This means that children need to be resuscitated with fluids aggressively. Nevertheless, the haemodynamic response of fluid-resuscitated children is different from adults. Ceneviva and co-workers evaluated 50 children with fluid-refractory, dopamine resistant septic shock (Ceneviva et al, 1998). The majority had low CO in combination with high SVR, but 22% had low CO and low SVR. Furthermore, haemodynamic profiles changed frequently during the first 48 hours.

Another interesting difference between children and adults relates to the VO2. The VO2 is mainly determined by oxygen extraction in adults, whereas in children is it mainly determined by the DO2 (Carcillo et al, 1989). This indicates that all efforts must be made to maintain adequate DO2.

#### **3. Symptoms of paediatric shock**

The early diagnosis of paediatric shock warrants a high index of suspicion and knowledge of disease conditions that predispose children to shock. It is imperative to understand the reference values for vital parameters in children.

Early signs of septic shock may be subtle and easily missed. Tachycardia is the earliest presenting symptom. Blood pressure will be normal during compensated shock, but the pulse pressure is widened. Children will have plethora, warm extremities and bounding

 DO2 = CO \* (Haemoglobin \* 1.36 \* SaO2) + (0.003 \* PaO2) (1) The CO is determined by the heart rate (HR) and stroke volume (SV), the latter is

The VO2 is increased in septic shock. Hence, the body will try to compensate for this by increasing the DO2 through various mechanisms including increasing the HR and the venous vascular tone to optimize cardiac pre-load. Tachycardia is one of the earliest compensatory mechanisms. If this compensation is inadequate to meet cellular oxygen demands, the systemic vascular resistance (SVR) will be increased allowing perfusion of vital organs such as the heart and brain. In addition, oxygen extraction will be increased. Of importance, children are able to maintain normal blood pressure. This phase of shock is

Oxygen debt will occur if these mechanisms fail when the shock is not reversed. Under normal conditions oxygen debt will occur when the ratio DO2 : VO2 is 3 : 1. However, as a result of the increase in VO2 during septic shock oxygen debt will occur already at DO2 : VO2 2 : 1. Microvascular perfusion becomes marginal and cellular function deteriorates, affecting all organ systems (*uncompensated shock*). If not adequately managed, *irreversible shock* will occur. Vital organs will be damaged to such an extent that death is inevitable. There are considerable differences in the pathophyiology of septic shock between children and adults. Vasomotor paralysis is the predominant cause of mortality in adults (Parker et al, 1987). Myocardial dysfunction in adult septic shock manifests mainly as decreased ejection fraction with either normal or increased CO. This is because adults are capable of increasing their CO by tachycardia in combination with ventricular dilatation allowing an increase in SV (Parker et al, 1984). In contrast, paediatric septic shock is mainly characterized by severe hypovolaemia; the decrease in CO and not SVR is associated with mortality (Carcillo et al, 2002). This is because especially younger children have higher baseline HR's compared to adults; hence they cannot increase their HR without impairing CO. Furthermore, children are not capable of increasing their SV (Feltes et al, 1994). This means that children need to be resuscitated with fluids aggressively. Nevertheless, the haemodynamic response of fluid-resuscitated children is different from adults. Ceneviva and co-workers evaluated 50 children with fluid-refractory, dopamine resistant septic shock (Ceneviva et al, 1998). The majority had low CO in combination with high SVR, but 22% had low CO and low SVR. Furthermore, haemodynamic profiles changed frequently during the

Another interesting difference between children and adults relates to the VO2. The VO2 is mainly determined by oxygen extraction in adults, whereas in children is it mainly determined by the DO2 (Carcillo et al, 1989). This indicates that all efforts must be made to

The early diagnosis of paediatric shock warrants a high index of suspicion and knowledge of disease conditions that predispose children to shock. It is imperative to understand the

Early signs of septic shock may be subtle and easily missed. Tachycardia is the earliest presenting symptom. Blood pressure will be normal during compensated shock, but the pulse pressure is widened. Children will have plethora, warm extremities and bounding

determined by the pre-load, afterload and contractility of the heart.

termed *compensated shock*.

first 48 hours.

maintain adequate DO2.

**3. Symptoms of paediatric shock**

reference values for vital parameters in children.

pulses ("warm shock". If the shock is not reversed, signs of failure of the compensatory mechanisms can be noted including cold extremities and prolonged capillary refill time ("cold shock"). Of note, the capillary refill time has little discriminative value in paediatric shock. Hypovolaemic children may still have a capillary refill time that is within the normal limit (2 seconds).

Table 1. Age-related reference values for vital parameters in children (derived from reference values by age, height and weight). Values above the 95th percentile (for heart rate and respiratory rate), and below the 5th percentile (for systolic blood pressure) are abnormal. Adapted from (Anonymous, 2004).

Table 2. Symptoms of paediatric septic shock

Many children with fever have tachycardia and warm extremities on physical examination. Not all of these children are in shock. For early recognition of shock it is then absolute necessary to evaluate the mental state of the child. In general, children in shock are lethargic and have decreased consciousness, but the opposite (i.e. agitation, restless, anxious) also occurs. Underlying mechanisms include most likely a combination of cerebral hypoperfusion, metabolic alterations and production of cytotoxic substances.

Oxygen debt will occur when the shock is not recognized and thus not treated properly. Clinically, the child suffers from depressed consciousness, poor skin perfusion, decreased urinary output and hyperventilation to compensate for the metabolic acidosis.

Management of Septic Shock in Children 279

delay in administration of antibiotic treatment (Kumar et al, 2006). Electrolyte disturbances

After 15 minutes it is evaluated if the clinical targets have been met. If not, the shock is classified as "fluid-resistant". The next step then would be to refer the patient to a PICU facility. It now depends upon the haemodynamic profile of the child what the next therapeutic intervention would be. If the child has a haemodynamic profile that is compatible with "cold shock", fluid administration is continued and dopamine 10 microgram/kg/minute is started via a peripheral line while in the mean time a central venous line is inserted. If the child has a haemodynamic profile that is compatible with "warm shock", fluid administration is continued and norepinephrine 0.1 microgram/kg/minute is started. Fluid administration will be continued until the liver becomes palpable enlarged or crackles are noted at pulmonary auscultation. Nevertheless, cumulative fluid administration up to 200 mL/kg may be necessary (Maar, 2004). Fluid administration should not be discontinued because of assumed possible development of pulmonary oedema, acute respiratory distress syndrome (ARDS) or cerebral oedema (Brierley et al, 2009). As an alternative to crystalloids, colloids such as albumin may be

Also, endotracheal intubation and initiation of mechanical ventilation should be strongly considered in order to optimize DO2. As discussed, in paediatric shock VO2 is dependent upon DO2.  Also, VO2 may rise with 15 – 30% due to increased work of breathing during septic shock (Butt, 2001; Carcillo et al, 1989). Last, but not less important, sedation and mechanical ventilation may be needed to facilitate invasive procedures such as insertion of central lines. Also, increased intrathoracic pressure reduces left ventricular afterload that may be beneficial when there is a low CI/high SVR state. Nevertheless, early intubation may still be subject of debate. One of the arguments often used is the vasodilatory effect of agents used for induction. This effect may further compromise DO2 in the septic child. We advocate the use of ketamine as induction agent (Yamamoto, 2000). Ketamine is a centrally acting Nmethyl-D-aspartate (NMDA) receptor antagonist allowing cardiovascular stability. We would also advocate refraining from the use of etomidate because of its negative effects on

The use of corticosteroids and sodium bicarbonate during the first hour of primary management of paediatric shock is also subject of heavy scientific debate. Corticosteroids are definitely indicated for children with purpura fulminans, or children with a recent history of prolonged corticosteroid use of proven abnormalities in the hypothalamicpituitary-adrenal gland axis (Langer et al, 2006). In addition, the use of corticosteroids may be considered when children do not respond to infusion of vaso-active drugs (*"catecholamine-resistant shock"*) (Brierley et al, 2009). Sodium bicarbonate is usually administered to correct metabolic acidosis as it is presumed that vaso-active drugs function less well in an acidic environment (Tabbutt, 2001). However, the metabolic acidosis is caused by insufficient tissue perfusion. This indicates that is necessary to optimize tissue perfusion rather than correcting the acidosis with sodium bicarbonate (Dellinger et al, 2008). Also, two studies performed in critically ill adults with septic shock and pH ≥ 7.15 have shown no beneficial effect on haemodynamic variables when patients were treated with

or hypoglycaemia is corrected in this first phase of primary management.

**4.2 Management after the first 15 minutes**

considered at this stage (Boluyt et al, 2006).

adrenal gland function (Brierley et al, 2009).

The contribution of laboratory tests is limited. In contrast with adult septic shock, blood gasses and serum lactate levels are not diagnostic for paediatric shock but may be used for monitoring the effectiveness of treatment (Brierley et al, 2009). Repeated evaluation and monitoring of the patient remains the most effective physiologic monitor.

#### **4. Management of paediatric shock**

The American College of Critical Care Medicine (ACCM) has published clinical guidelines for the haemodynamic support of neonates and children with septic shock in 2002 and revised them in 2009 (Brierley et al, 2009; Carcillo et al, 2002). These guidelines advocate amongst others early recognition, adequate fluid resuscitation and timely and appropriate antibiotic therapy. Notwithstanding the fact that the efficacy of these guidelines has not been confirmed in a randomized clinical trial, data strongly suggests that adherence to these guidelines results in improved survival (de Oliveira et al, 2008; Dellinger et al, 2008; Han et al, 2003). Han and co-workers evaluated 91 patients with septic shock who were referred to their PICU (Han et al, 2003). Shock reversal within 75 minutes and adherence with the ACCM guidelines was associated with > 90% survival. Worrisome however was that adherence to these guidelines was only achieved in < 30% of all patients. A study of 200 children with severe sepsis in the United Kingdom showed a drop from 25% to 6% in mortality when shock was reversed, although only 8% of patients were managed according to the ACCM guidelines (Inwald et al, 2009).

The primary goal of the primary management of paediatric shock is to prevent organ failure caused by oxygen debt through optimalisation of and balancing DO2 and VO2. This means that is important to maintain blood pressure above the critical point which below flow cannot be effectively maintained. Thus, shock should be clinically diagnosed before hypotension occurs. Clinical targets include age-appropriate HR and blood pressure, normalisation of the capillary refill time, normal consciousness and adequate urinary output (> 1 mL/kg/hour) (Figure 1) (Brierley et al, 2009). After each intervention it is evaluated whether or not these clinical targets have been achieved.

#### **4.1 Recognition and management during the first 15 minutes**

Within the first five minutes the child is evaluated according to the Paediatric Advanced Life Support approach – i.e. a structural approach examining Airway, Breathing and Circulation (Figure 1). The diagnosis septic shock is confirmed when tachycardia, fever and symptoms of inadequate tissue perfusion are present. These symptoms include altered consciousness, as well as shortened capillary refill time, bounding pulses and widened pulse pressure (in case of "warm shock") or prolonged capillary refill time, weak pulses, mottled skin and decreased urinary output (in case of "cold shock").

The next step then is to administer 100% oxygen via a non-rebreathing mask (flow 10 – 15 L/min) and to insert two peripheral lines. Blood is drawn for haematological, biochemical studies and blood culture. Subsequently, aggressive fluid resuscitation is mandated (Carcillo et al, 1991). This means that within 15 minutes three fluid boluses of 20 mL/kg (max 500 mL) are administered. Crystalloid fluids are the first choice. After each bolus the child is evaluated if the clinical targets have been met. Rapid and sufficient fluid administration is significantly associated with improved survival (Ceneviva et al, 1998).

Of importance, antibiotics must be administered within the first 15 minutes. Although not confirmed in paediatric studies, adult data indicated that mortality doubled for each hour

The contribution of laboratory tests is limited. In contrast with adult septic shock, blood gasses and serum lactate levels are not diagnostic for paediatric shock but may be used for monitoring the effectiveness of treatment (Brierley et al, 2009). Repeated evaluation and

The American College of Critical Care Medicine (ACCM) has published clinical guidelines for the haemodynamic support of neonates and children with septic shock in 2002 and revised them in 2009 (Brierley et al, 2009; Carcillo et al, 2002). These guidelines advocate amongst others early recognition, adequate fluid resuscitation and timely and appropriate antibiotic therapy. Notwithstanding the fact that the efficacy of these guidelines has not been confirmed in a randomized clinical trial, data strongly suggests that adherence to these guidelines results in improved survival (de Oliveira et al, 2008; Dellinger et al, 2008; Han et al, 2003). Han and co-workers evaluated 91 patients with septic shock who were referred to their PICU (Han et al, 2003). Shock reversal within 75 minutes and adherence with the ACCM guidelines was associated with > 90% survival. Worrisome however was that adherence to these guidelines was only achieved in < 30% of all patients. A study of 200 children with severe sepsis in the United Kingdom showed a drop from 25% to 6% in mortality when shock was reversed, although only 8% of patients were managed according

The primary goal of the primary management of paediatric shock is to prevent organ failure caused by oxygen debt through optimalisation of and balancing DO2 and VO2. This means that is important to maintain blood pressure above the critical point which below flow cannot be effectively maintained. Thus, shock should be clinically diagnosed before hypotension occurs. Clinical targets include age-appropriate HR and blood pressure, normalisation of the capillary refill time, normal consciousness and adequate urinary output (> 1 mL/kg/hour) (Figure 1) (Brierley et al, 2009). After each intervention it is evaluated

Within the first five minutes the child is evaluated according to the Paediatric Advanced Life Support approach – i.e. a structural approach examining Airway, Breathing and Circulation (Figure 1). The diagnosis septic shock is confirmed when tachycardia, fever and symptoms of inadequate tissue perfusion are present. These symptoms include altered consciousness, as well as shortened capillary refill time, bounding pulses and widened pulse pressure (in case of "warm shock") or prolonged capillary refill time, weak pulses, mottled

The next step then is to administer 100% oxygen via a non-rebreathing mask (flow 10 – 15 L/min) and to insert two peripheral lines. Blood is drawn for haematological, biochemical studies and blood culture. Subsequently, aggressive fluid resuscitation is mandated (Carcillo et al, 1991). This means that within 15 minutes three fluid boluses of 20 mL/kg (max 500 mL) are administered. Crystalloid fluids are the first choice. After each bolus the child is evaluated if the clinical targets have been met. Rapid and sufficient fluid administration is significantly associated with improved survival (Ceneviva et al, 1998). Of importance, antibiotics must be administered within the first 15 minutes. Although not confirmed in paediatric studies, adult data indicated that mortality doubled for each hour

monitoring of the patient remains the most effective physiologic monitor.

**4. Management of paediatric shock**

to the ACCM guidelines (Inwald et al, 2009).

whether or not these clinical targets have been achieved.

**4.1 Recognition and management during the first 15 minutes**

skin and decreased urinary output (in case of "cold shock").

delay in administration of antibiotic treatment (Kumar et al, 2006). Electrolyte disturbances or hypoglycaemia is corrected in this first phase of primary management.

#### **4.2 Management after the first 15 minutes**

After 15 minutes it is evaluated if the clinical targets have been met. If not, the shock is classified as "fluid-resistant". The next step then would be to refer the patient to a PICU facility. It now depends upon the haemodynamic profile of the child what the next therapeutic intervention would be. If the child has a haemodynamic profile that is compatible with "cold shock", fluid administration is continued and dopamine 10 microgram/kg/minute is started via a peripheral line while in the mean time a central venous line is inserted. If the child has a haemodynamic profile that is compatible with "warm shock", fluid administration is continued and norepinephrine 0.1 microgram/kg/minute is started. Fluid administration will be continued until the liver becomes palpable enlarged or crackles are noted at pulmonary auscultation. Nevertheless, cumulative fluid administration up to 200 mL/kg may be necessary (Maar, 2004). Fluid administration should not be discontinued because of assumed possible development of pulmonary oedema, acute respiratory distress syndrome (ARDS) or cerebral oedema (Brierley et al, 2009). As an alternative to crystalloids, colloids such as albumin may be considered at this stage (Boluyt et al, 2006).

Also, endotracheal intubation and initiation of mechanical ventilation should be strongly considered in order to optimize DO2. As discussed, in paediatric shock VO2 is dependent upon DO2.  Also, VO2 may rise with 15 – 30% due to increased work of breathing during septic shock (Butt, 2001; Carcillo et al, 1989). Last, but not less important, sedation and mechanical ventilation may be needed to facilitate invasive procedures such as insertion of central lines. Also, increased intrathoracic pressure reduces left ventricular afterload that may be beneficial when there is a low CI/high SVR state. Nevertheless, early intubation may still be subject of debate. One of the arguments often used is the vasodilatory effect of agents used for induction. This effect may further compromise DO2 in the septic child. We advocate the use of ketamine as induction agent (Yamamoto, 2000). Ketamine is a centrally acting Nmethyl-D-aspartate (NMDA) receptor antagonist allowing cardiovascular stability. We would also advocate refraining from the use of etomidate because of its negative effects on adrenal gland function (Brierley et al, 2009).

The use of corticosteroids and sodium bicarbonate during the first hour of primary management of paediatric shock is also subject of heavy scientific debate. Corticosteroids are definitely indicated for children with purpura fulminans, or children with a recent history of prolonged corticosteroid use of proven abnormalities in the hypothalamicpituitary-adrenal gland axis (Langer et al, 2006). In addition, the use of corticosteroids may be considered when children do not respond to infusion of vaso-active drugs (*"catecholamine-resistant shock"*) (Brierley et al, 2009). Sodium bicarbonate is usually administered to correct metabolic acidosis as it is presumed that vaso-active drugs function less well in an acidic environment (Tabbutt, 2001). However, the metabolic acidosis is caused by insufficient tissue perfusion. This indicates that is necessary to optimize tissue perfusion rather than correcting the acidosis with sodium bicarbonate (Dellinger et al, 2008). Also, two studies performed in critically ill adults with septic shock and pH ≥ 7.15 have shown no beneficial effect on haemodynamic variables when patients were treated with

sodium bicarbonate. Recent adult recommendations indicate to use sodium bicarbonate

It is unclear if optimizing haemoglobin (Hb) levels through transfusion of red blood cells (RBC) is beneficial. One group of investigators could not confirm a beneficial effect on VO2 despite optimalisation of CaO2 in paediatric shock (Mink et al, 1990). Nevertheless, it is currently recommended to maintain Hb > 10 g/dL (Brierley et al, 2009). Fresh Frozen Plasma (FFP) is indicated for active haemorrhage or a prolonged activated partial thromboplastin time (APTT); in clinical practice usually twice the age-dependent reference

One hour after presentation it is determined whether or not the shock has been reversed. If not, then the patient is recognized as having a fluid refractory dopamine-resistant shock. The patient is managed in the PICU. Treatment goals in this phase are similar to the golden hour (i.e. age-appropriate HR and blood pressure, normalisation of the capillary refill time, normal consciousness and urinary output > 1 mL/kg/hour), but now also include maintainance of age-appropriate perfusion pressure (mean airway pressure minus central venous pressure), cardiac index (CI) between 3.3 and 6.0 L/min/m2, central venous oxygen saturation (SvO2) > 70%, normal anion gap and normal lactate. Fluid replacement should be

The type of haemodynamic support depends upon the haemodyamic profile of the child (i.e. low CO/high SVR, high CO/low SVR, or low CO/low SVR) (Figure 2). It seems therefore rational to use haemodynamic monitoring devices such as pulse contour analysis or Doppler ultrasound to assess the haemodynamic profile especially since frequently change. Irrespective of haemodynamic profile, support should be targeted at a CI between 3.3 and 6.0 L/min/m2. Pollack and co-workers have shown that a CI within this range was associated with the best outcome in paediatric shock (Pollack et al, 1985). Also, SvO2 should be maintained > 70%. The SvO2 can be used as a surrogate marker of the CO. Oliveira and co-workers randomized 102 children with septic shock to be managed using the ACCM guidelines with or without monitoring the SvO2 (de Oliveira et al, 2008). Their SvO2 goaldirected therapy resulted in less mortality (28-day mortality 11.8% vs. 39.2%, p = 0.002), and fewer new organ dysfunctions (p = 0.03). However, this strategy was associated with more crystalloid (28 (20-40) vs. 5 (0-20 ml/kg, p<0.0001), blood transfusion (45.1% vs. 15.7%, p =0.002) and inotropic (29.4% vs. 7.8%, p = 0.01) support in the first 6 hours of admission. For patients with low CI, normal blood pressure and high SVR (i.e. "cold shock" with normal blood pressure), it is recommended to reduce ventricular afterload. This can be achieved using either epinephrine or dobutamine. Some have argued to additionally use a short-acting vasodilator such as nitroprusside or nitroglycerin to recruit the microcirculation. Alternatively, the use of type III phosphor-diesterase inhibitors such as milrinone may be considered (Barton et al, 1996). These agents have a synergistic effect with beta-adrenergic agents because they stimule intracellular cyclic adenosine monophosphate. Patients with low CI, low blood pressure and low SVR (i.e. "cold shock with low blood pressure) it is recommended to titrate vasopressor therapy. In general, dopamine is the firstline vasopressor therapy. At high infusion rates, the alpha-adrenergic effects of dopamine predominate. Alternatively, norepinephrine or high dosage epinephrine may be considered. Once adequate blood pressure is achieved, a vasodilator can be added to improve the SvO2

when pH < 7.00 (Boyd et al, 2008).

value (Brierley et al, 2009).

**4.3 Management after the first hour**

continued and directed at these endpoints.

by recruiting the microcirculation.

sodium bicarbonate. Recent adult recommendations indicate to use sodium bicarbonate when pH < 7.00 (Boyd et al, 2008).

It is unclear if optimizing haemoglobin (Hb) levels through transfusion of red blood cells (RBC) is beneficial. One group of investigators could not confirm a beneficial effect on VO2 despite optimalisation of CaO2 in paediatric shock (Mink et al, 1990). Nevertheless, it is currently recommended to maintain Hb > 10 g/dL (Brierley et al, 2009). Fresh Frozen Plasma (FFP) is indicated for active haemorrhage or a prolonged activated partial thromboplastin time (APTT); in clinical practice usually twice the age-dependent reference value (Brierley et al, 2009).

#### **4.3 Management after the first hour**

One hour after presentation it is determined whether or not the shock has been reversed. If not, then the patient is recognized as having a fluid refractory dopamine-resistant shock. The patient is managed in the PICU. Treatment goals in this phase are similar to the golden hour (i.e. age-appropriate HR and blood pressure, normalisation of the capillary refill time, normal consciousness and urinary output > 1 mL/kg/hour), but now also include maintainance of age-appropriate perfusion pressure (mean airway pressure minus central venous pressure), cardiac index (CI) between 3.3 and 6.0 L/min/m2, central venous oxygen saturation (SvO2) > 70%, normal anion gap and normal lactate. Fluid replacement should be continued and directed at these endpoints.

The type of haemodynamic support depends upon the haemodyamic profile of the child (i.e. low CO/high SVR, high CO/low SVR, or low CO/low SVR) (Figure 2). It seems therefore rational to use haemodynamic monitoring devices such as pulse contour analysis or Doppler ultrasound to assess the haemodynamic profile especially since frequently change. Irrespective of haemodynamic profile, support should be targeted at a CI between 3.3 and 6.0 L/min/m2. Pollack and co-workers have shown that a CI within this range was associated with the best outcome in paediatric shock (Pollack et al, 1985). Also, SvO2 should be maintained > 70%. The SvO2 can be used as a surrogate marker of the CO. Oliveira and co-workers randomized 102 children with septic shock to be managed using the ACCM guidelines with or without monitoring the SvO2 (de Oliveira et al, 2008). Their SvO2 goaldirected therapy resulted in less mortality (28-day mortality 11.8% vs. 39.2%, p = 0.002), and fewer new organ dysfunctions (p = 0.03). However, this strategy was associated with more crystalloid (28 (20-40) vs. 5 (0-20 ml/kg, p<0.0001), blood transfusion (45.1% vs. 15.7%, p =0.002) and inotropic (29.4% vs. 7.8%, p = 0.01) support in the first 6 hours of admission.

For patients with low CI, normal blood pressure and high SVR (i.e. "cold shock" with normal blood pressure), it is recommended to reduce ventricular afterload. This can be achieved using either epinephrine or dobutamine. Some have argued to additionally use a short-acting vasodilator such as nitroprusside or nitroglycerin to recruit the microcirculation. Alternatively, the use of type III phosphor-diesterase inhibitors such as milrinone may be considered (Barton et al, 1996). These agents have a synergistic effect with beta-adrenergic agents because they stimule intracellular cyclic adenosine monophosphate.

Patients with low CI, low blood pressure and low SVR (i.e. "cold shock with low blood pressure) it is recommended to titrate vasopressor therapy. In general, dopamine is the firstline vasopressor therapy. At high infusion rates, the alpha-adrenergic effects of dopamine predominate. Alternatively, norepinephrine or high dosage epinephrine may be considered. Once adequate blood pressure is achieved, a vasodilator can be added to improve the SvO2 by recruiting the microcirculation.

Management of Septic Shock in Children 283

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Finally, patients with persisting high CI and low SVR despite fluid administration and norepinephrine may benefit of agents such as vasopressin or phenylephrine. Of importance, CO may be reduced when these agents are used so close monitoring of the CO and/or SvO2 is mandated.

When the shock cannot be reversed and co-morbidities that fuel the shock (such as pericardial effusion, pneumothorax, hypoadrenalism, ongoing blood loss, increased intraabdominal pressure, or necrotic tissue) high-flow veno-arterial extra-corporeal membrane oxygenation (ECMO) or high-flux continues renal replacement therapy (CRRT) with flows > 35 mL/kg/hour may be considered. Yet, these modalities may be qualified as last resort and their effects on final outcome need to be established.

#### **5. Conclusion**

Early recognition and aggressive primary management of paediatric septic shock is significantly associated with improved patient survival. Tachycardia, fever and altered consciousness are the first clinical manifestations of paediatric septic shock. Primary management includes aggressive fluid resuscitation, adequate oxygen delivery through early intubation and mechanical ventilation, and early referral to a paediatric intensive care unit. Future research should be directed towards obtaining stronger scientific evidence to confirm the components of the ACCM guidelines.

#### **6. References**

Finally, patients with persisting high CI and low SVR despite fluid administration and norepinephrine may benefit of agents such as vasopressin or phenylephrine. Of importance, CO may be reduced when these agents are used so close monitoring of the CO and/or SvO2

When the shock cannot be reversed and co-morbidities that fuel the shock (such as pericardial effusion, pneumothorax, hypoadrenalism, ongoing blood loss, increased intraabdominal pressure, or necrotic tissue) high-flow veno-arterial extra-corporeal membrane oxygenation (ECMO) or high-flux continues renal replacement therapy (CRRT) with flows > 35 mL/kg/hour may be considered. Yet, these modalities may be qualified as last resort and

Early recognition and aggressive primary management of paediatric septic shock is significantly associated with improved patient survival. Tachycardia, fever and altered consciousness are the first clinical manifestations of paediatric septic shock. Primary management includes aggressive fluid resuscitation, adequate oxygen delivery through early intubation and mechanical ventilation, and early referral to a paediatric intensive care unit. Future research should be directed towards obtaining stronger scientific evidence to

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their effects on final outcome need to be established.

confirm the components of the ACCM guidelines.

Report, pp. 555-576,

is mandated.

**5. Conclusion**

**6. References**

**14**

*Italy*

**Septic Shock in Neonates**

Armando D'Angelo2, Nunzia Decembrino3, Paolo Manzoni4,

*2Coagulation Sevice & Thrombosis Research Unit, Scientific Institute HS. S. Raffaele Milan 3Neonatal Intensive Care Unit Fondazione MBBM San Gerardo Monza, Neonatology*

Every year 1.6 million of newborn infants die from sepsis (Lawn et al 2000). The prevalence of sepsis, meningitis, and other confirmed bacterial infections has been estimated to range between 1 to 5/1000 live births. Preterm infants are 20 times more likely to get infection than term infants with a prevalence of 1/230 (Haque KN 2003). Very low birth weight infants, evaluated and treated for infections are around 50% of all admissions to neonatal intensive

Sepsis is responsible for 30–80% increased risk of neuro-developmental impairment and 30–100% increase in odds for poor head growth and long term morbidity (Stoll et al 2004). 45% of late deaths in the Neonatal Intensive Care Unit (NICU) are caused by an infectiouse disease (Ince 2005). Despite assistance progress, mortality rates from sepsis have not

While the incidence of sepsis is known, the true incidence of septic shock in neonates has not been well documented. It is estimated to be around 1–5% of all infants with proven severe sepsis (Haque 2004). Kermorvant-Duchemin E. et al.(2008) reported septic shock in 1.3% of extremely low birth weight newborns with an associated mortality peaking at 71%.

Infection, far from being a homogeneous condition, reflects a continuum from fetal inflammatory response syndrome to sepsis, severe sepsis, septic shock, multiorgan failure, and death. The difficulty for the clinician is to define precisely the phase in which his/her patient is at any given moment as the patient may move from one phase to another

Definition of sepsis derives from the international consensus definitions that have been adapted for pediatric and neonatal use, including term neonates (0-7 days) and newborns (1 week to 1 month) (Carcillo et al 2002, Goldestein et al 2005) (tab 1 and 2). Sepsis is a complex entity, with wide variations in clinical, laboratory parameters and outcome. Septic shock is a

**1. Introduction**

care (Stoll et al 2003).

declined over the last three decades (Haque 2003).

**2. Definition and risk factors**

imperceptibly (Haque 2007).

Lidia Decembrino1 ,Giulia Ruffinazzi1,

Agata Boncimino1 and Mauro Stronati1 *1Neonatology and Neonatal Intensive Care Unit Fondazione IRCCS Policlinico San Matteo, Pavia*

*4Neonatal Intensive Care Unit. S.Anna Hospital Torino*

## **Septic Shock in Neonates**

Lidia Decembrino1 ,Giulia Ruffinazzi1, Armando D'Angelo2, Nunzia Decembrino3, Paolo Manzoni4,

Agata Boncimino1 and Mauro Stronati1

*1Neonatology and Neonatal Intensive Care Unit*

*Fondazione IRCCS Policlinico San Matteo, Pavia*

*2Coagulation Sevice & Thrombosis Research Unit, Scientific Institute HS. S. Raffaele Milan 3Neonatal Intensive Care Unit Fondazione MBBM San Gerardo Monza, Neonatology 4Neonatal Intensive Care Unit. S.Anna Hospital Torino Italy*

#### **1. Introduction**

284 Severe Sepsis and Septic Shock – Understanding a Serious Killer

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epidemiology of severe sepsis in children in the United States. *Am.J.Respir.Crit Care*

Every year 1.6 million of newborn infants die from sepsis (Lawn et al 2000). The prevalence of sepsis, meningitis, and other confirmed bacterial infections has been estimated to range between 1 to 5/1000 live births. Preterm infants are 20 times more likely to get infection than term infants with a prevalence of 1/230 (Haque KN 2003). Very low birth weight infants, evaluated and treated for infections are around 50% of all admissions to neonatal intensive care (Stoll et al 2003).

Sepsis is responsible for 30–80% increased risk of neuro-developmental impairment and 30–100% increase in odds for poor head growth and long term morbidity (Stoll et al 2004). 45% of late deaths in the Neonatal Intensive Care Unit (NICU) are caused by an infectiouse disease (Ince 2005). Despite assistance progress, mortality rates from sepsis have not declined over the last three decades (Haque 2003).

While the incidence of sepsis is known, the true incidence of septic shock in neonates has not been well documented. It is estimated to be around 1–5% of all infants with proven severe sepsis (Haque 2004). Kermorvant-Duchemin E. et al.(2008) reported septic shock in 1.3% of extremely low birth weight newborns with an associated mortality peaking at 71%.

#### **2. Definition and risk factors**

Infection, far from being a homogeneous condition, reflects a continuum from fetal inflammatory response syndrome to sepsis, severe sepsis, septic shock, multiorgan failure, and death. The difficulty for the clinician is to 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 (Haque 2007).

Definition of sepsis derives from the international consensus definitions that have been adapted for pediatric and neonatal use, including term neonates (0-7 days) and newborns (1 week to 1 month) (Carcillo et al 2002, Goldestein et al 2005) (tab 1 and 2). Sepsis is a complex entity, with wide variations in clinical, laboratory parameters and outcome. Septic shock is a

Septic Shock in Neonates 287

contributing to hypoperfusion that eventually results in tissue damage and organ dysfunction. On the other hand, consumption of coagulation factors and platelets promotes a bleeding tendency that may clinically manifest as petechiae, ecchymoses, and sometimes hemorrhages, all of which are associated to increased mortality. (Fourrier et al 1992, Kenet et l 2008, Levi 2010). The immune system and coagulation are closely related. Cytokines mediating neutrophils activation and migration to the tissues and extravascular compartment, generate the thrombin and fibrin deposit formation, triggering tissue factor, that is considered the main both septic shock and diffuse tissue injury mediator. That's why, disseminated intravascular coagulation (DIC) is not so rare in septic shock, resulting from the sustained thrombin generation. Thrombin, in turn, stimulates more inflammatory mediators' formation. Fibrin formation stabilizes platelet plugs, in addition to its important role in pathogens' adhesion to the leukocyte surface, facilitating phagocytosis (Levi et 2010). The Toll-like receptors (TLRs), found in immune system cells, have a fundamental role in the septic shock pathophysiology. They can interfere with the cardiovascular system depending on the systemic inflammatory response to pathogen. They are able to detect pathogens-associated molecular patterns (PAMPs), causing the induction of proinflammatory and anti-inflammatory mediators, particularly cytokines.(Gao et al 2008Gao et al 2005, Fleer et al 2007). TLRs, present in endothelial cells, alveolar epithelium cells, and cardiomyocytes, may induced TNFα and IL-1β production, responsible for the early myocardial dysfunction in gram-negative (TLR4) and gram-positive (TLR2) germs severe sepsis.(Zhang et al 2007). Unlike in adults, TLRs genetic polymorphisms and signaling proteins (MYD88) regulating the host response to infection and different septic shock patterns,

are less characterized in neonates. (Zhang et al 2007, Cornell et al 2010).

compensated, uncompensated, and irreversible shock. (Jones et al 2008).

normal range due to compensatory mechanisms (Cayabyab et al 2009).

shock hypotension is not permissive and need a therapeutical intervent.

contraction (Brierley et al 2008).

In septic shock the action of inflammatory mediators leads to damage of the capillary wall with loss of vascular tone, resulting in vasodilatation and reduction of systemic vascular resistance with low to normal blood pressure and increased systemic blood flow. Thanks to the compensatory heart rate increase, skin is well perfused and warm (warm shock). In the late phase of shock there is a reduction of myocardial contractility that leads to vasoconstriction, decreased systemic blood flow, decreased pulse volume, cold periphery, prolonged capillary refill time, and increased vascular tone in an attempt to centralize the circulation (cold shock). Shock, that is not recognized and treated, progresses from early to late stages, referred to as

The hemodynamic response to sepsis of a newborn is markedly different from that of an adults or an older child with relevant difference between the preterm and the term newborn owing to the different anatomical structure, the functional activity and excitation–

In the neonates, the absence of hypotension does not precludes shock that is mainly related with blood flow rather than blood pressure as the mean blood pressure may be in the

In the evaluation of blood pressure, the physiological variability with age and gestational age should be taken in account (Silveira et al 2010). Despite this, 30 mmHg should be considered the absolute minimum tolerable of in the extremely premature infants. (Munro et al 2004). Furthermore in critically ill prematures, refractory hypotension may be related to patent ductus arteriosus, intraventricular hemorrhage and poor prognosis. (Carcillo et al 2002). While in healthy prematures lower mean blood pressure levels may be accepted being associated with appropriate cerebral perfusion and normal cardiac output (30), in septic

condition of inadequate tissue perfusion secondary to cardiovascular dysfunction occurring in the course of suspected or certain systemic infection, requiring fluid resuscitation or inotropic support (Goldstein et al 2005, Haque 2007). This definition, valid for newborns born > 37 weeks gestation, is problematic for preterms due to immaturity of organ systems and transitional physiology (Jones 2008). For these reasons, the hemodynamic response to septic shock and optimum clinical interventions in preterm neonates are not well understood.

Risk factors for a neonate to develop septic shock have not been described in detail, but they overlap those for sepsis. Prenatal risk factors include maternal intrapartum fever, chorioamnionitis or prolonged rupture of membranes, treatment with steroids, group B *Streptoccocci* recto-vaginal colonization. A few days after aspiration of infected amniotic fluid during the birth, the neonate may manifest with signs and symptoms of neonatal shock. Gram-positive germs as group B *Streptococci* are those most frequently described as causative agents in early neonatal sepsis, even if, more recently, some gram-negative agents have been frequently described (*Escherichia coli*, *Klebsiella spp., Enterobacter spp*.). This probably is due to the intrapartum use of antibiotics directed against gram-positive pathogens that allows gram-negative flora's outbreak (Schrag et al 2007). Other microbes include *Listeria monocytogenes, coagulase-negative staphylococci* (ConS) (22%) and *nonpyogenic streptococci* (9%) (Muller-Pebody et al. 2011).

Post-natal risk factors include: male gender, birth weight less than 1000 g, hypogammaglobulinemia, parenteral nutrition, central venous catheters, steroids or drugs that decrease gastric acidity, prolonged duration of mechanical ventilation, hand contamination of health care personnel, mother and other family members, aspiration of feeds, and disruption of skin integrity. *Staphylococcus aureus* is the most frequent germ in late sepsis. Gram negative and ConS, almost half the isolates (45%), are the predominant pathogens associated with late severe sepsis or septic shock ((Muller-Pebody et al. 2011).). Also viruses (*herpes simplex, enteroviruses*) or fungi (*candida albicans*) have been associated with fulminant neonatal sepsis.  (Stoll et al 2002, Gordon et al 2006).

#### **3. Pathophysiology**

The development of septic shock is associated with elevated levels of proinflammatory cytokines including IL-1β, IL-6, IL-8 and TNFα (Lynch et al 2008). The inflammatory cytokine response to sepsis in neonates is more pronounced and faster than in adults and associated with an increase in early mortality (<48 hours), while the compensatory antiinflammatory response system appears to be immature, with both term and preterm infants demonstrating profoundly decreased IL-10 production and a lower amount of transforming growth factor beta-positive lymphocytes, than do adults, after lipopolysaccharide (LPS) stimulation (Langer et al 2006). In addition, in the neonate eosinophils, macrophages and polymorphonuclear neutrophils have reduced surface binding components and have defective opsonization, phagocytosis and antigen-processing capabilities, leading to a generally less robust response to pathogen exposure (Urlichs et al 2006, Marodi et al 2006). Several studies indicate that the mechanisms of sepsis include excessive activation of the coagulation cascade, inhibition of endogenous natural anticoagulants, and impaired fibrinolysis (Short 2004). Within the microcirculation, this leads to fibrin deposition,

condition of inadequate tissue perfusion secondary to cardiovascular dysfunction occurring in the course of suspected or certain systemic infection, requiring fluid resuscitation or inotropic support (Goldstein et al 2005, Haque 2007). This definition, valid for newborns born > 37 weeks gestation, is problematic for preterms due to immaturity of organ systems and transitional physiology (Jones 2008). For these reasons, the hemodynamic response to septic shock and optimum clinical interventions in preterm neonates are not well

Risk factors for a neonate to develop septic shock have not been described in detail, but they overlap those for sepsis. Prenatal risk factors include maternal intrapartum fever, chorioamnionitis or prolonged rupture of membranes, treatment with steroids, group B *Streptoccocci* recto-vaginal colonization. A few days after aspiration of infected amniotic fluid during the birth, the neonate may manifest with signs and symptoms of neonatal shock. Gram-positive germs as group B *Streptococci* are those most frequently described as causative agents in early neonatal sepsis, even if, more recently, some gram-negative agents have been frequently described (*Escherichia coli*, *Klebsiella spp., Enterobacter spp*.). This probably is due to the intrapartum use of antibiotics directed against gram-positive pathogens that allows gram-negative flora's outbreak (Schrag et al 2007). Other microbes include *Listeria monocytogenes, coagulase-negative staphylococci* (ConS) (22%) and *nonpyogenic*

Post-natal risk factors include: male gender, birth weight less than 1000 g, hypogammaglobulinemia, parenteral nutrition, central venous catheters, steroids or drugs that decrease gastric acidity, prolonged duration of mechanical ventilation, hand contamination of health care personnel, mother and other family members, aspiration of feeds, and disruption of skin integrity. *Staphylococcus aureus* is the most frequent germ in late sepsis. Gram negative and ConS, almost half the isolates (45%), are the predominant pathogens associated with late severe sepsis or septic shock ((Muller-Pebody et al. 2011).). Also viruses (*herpes simplex, enteroviruses*) or fungi (*candida albicans*) have been associated with fulminant neonatal sepsis.  (Stoll et

The development of septic shock is associated with elevated levels of proinflammatory cytokines including IL-1β, IL-6, IL-8 and TNFα (Lynch et al 2008). The inflammatory cytokine response to sepsis in neonates is more pronounced and faster than in adults and associated with an increase in early mortality (<48 hours), while the compensatory antiinflammatory response system appears to be immature, with both term and preterm infants demonstrating profoundly decreased IL-10 production and a lower amount of transforming growth factor beta-positive lymphocytes, than do adults, after lipopolysaccharide (LPS) stimulation (Langer et al 2006). In addition, in the neonate eosinophils, macrophages and polymorphonuclear neutrophils have reduced surface binding components and have defective opsonization, phagocytosis and antigen-processing capabilities, leading to a generally less robust response to pathogen exposure (Urlichs et al 2006, Marodi et al 2006). Several studies indicate that the mechanisms of sepsis include excessive activation of the coagulation cascade, inhibition of endogenous natural anticoagulants, and impaired fibrinolysis (Short 2004). Within the microcirculation, this leads to fibrin deposition,

understood.

*streptococci* (9%) (Muller-Pebody et al. 2011).

al 2002, Gordon et al 2006).

**3. Pathophysiology**

contributing to hypoperfusion that eventually results in tissue damage and organ dysfunction. On the other hand, consumption of coagulation factors and platelets promotes a bleeding tendency that may clinically manifest as petechiae, ecchymoses, and sometimes hemorrhages, all of which are associated to increased mortality. (Fourrier et al 1992, Kenet et l 2008, Levi 2010). The immune system and coagulation are closely related. Cytokines mediating neutrophils activation and migration to the tissues and extravascular compartment, generate the thrombin and fibrin deposit formation, triggering tissue factor, that is considered the main both septic shock and diffuse tissue injury mediator. That's why, disseminated intravascular coagulation (DIC) is not so rare in septic shock, resulting from the sustained thrombin generation. Thrombin, in turn, stimulates more inflammatory mediators' formation. Fibrin formation stabilizes platelet plugs, in addition to its important role in pathogens' adhesion to the leukocyte surface, facilitating phagocytosis (Levi et 2010).

The Toll-like receptors (TLRs), found in immune system cells, have a fundamental role in the septic shock pathophysiology. They can interfere with the cardiovascular system depending on the systemic inflammatory response to pathogen. They are able to detect pathogens-associated molecular patterns (PAMPs), causing the induction of proinflammatory and anti-inflammatory mediators, particularly cytokines.(Gao et al 2008Gao et al 2005, Fleer et al 2007). TLRs, present in endothelial cells, alveolar epithelium cells, and cardiomyocytes, may induced TNFα and IL-1β production, responsible for the early myocardial dysfunction in gram-negative (TLR4) and gram-positive (TLR2) germs severe sepsis.(Zhang et al 2007). Unlike in adults, TLRs genetic polymorphisms and signaling proteins (MYD88) regulating the host response to infection and different septic shock patterns, are less characterized in neonates. (Zhang et al 2007, Cornell et al 2010).

In septic shock the action of inflammatory mediators leads to damage of the capillary wall with loss of vascular tone, resulting in vasodilatation and reduction of systemic vascular resistance with low to normal blood pressure and increased systemic blood flow. Thanks to the compensatory heart rate increase, skin is well perfused and warm (warm shock). In the late phase of shock there is a reduction of myocardial contractility that leads to vasoconstriction, decreased systemic blood flow, decreased pulse volume, cold periphery, prolonged capillary refill time, and increased vascular tone in an attempt to centralize the circulation (cold shock). Shock, that is not recognized and treated, progresses from early to late stages, referred to as compensated, uncompensated, and irreversible shock. (Jones et al 2008).

The hemodynamic response to sepsis of a newborn is markedly different from that of an adults or an older child with relevant difference between the preterm and the term newborn owing to the different anatomical structure, the functional activity and excitation– contraction (Brierley et al 2008).

In the neonates, the absence of hypotension does not precludes shock that is mainly related with blood flow rather than blood pressure as the mean blood pressure may be in the normal range due to compensatory mechanisms (Cayabyab et al 2009).

In the evaluation of blood pressure, the physiological variability with age and gestational age should be taken in account (Silveira et al 2010). Despite this, 30 mmHg should be considered the absolute minimum tolerable of in the extremely premature infants. (Munro et al 2004). Furthermore in critically ill prematures, refractory hypotension may be related to patent ductus arteriosus, intraventricular hemorrhage and poor prognosis. (Carcillo et al 2002). While in healthy prematures lower mean blood pressure levels may be accepted being associated with appropriate cerebral perfusion and normal cardiac output (30), in septic shock hypotension is not permissive and need a therapeutical intervent.

Septic Shock in Neonates 289

count with differential, glucose, electrolytes, albumin, creatinine, urea, lactate, blood pyruvate, coagulationparameters, serum and urine osmolarity, cultures with susceptibility

Research offers an increasing number of biological markers for early detection of sepsis, but many of them failed to differentiate between sepsis and other non septic critical illness. The

Procalcitonine (PCT) revealed superior to C reactive protein (CRP) to differentiate children with sepsis from those with septic shock (Simon et al 2006), mainly at admission and 12 h later (Fioretto et al 2010). Baruti Garufi et al. (2010) found that the increase of PCT levels was related to the severity, course and prognosis of disease. Procalcitonin values were significantly increased in neonates with septic shock (92.5 ng/mL) compared to those with systemic inflammatory response syndrome- SIRS (41 ng/mL), neonatal sepsis (10,26 ng/mL) and purulent meningitis (9,80 ng/mL). CRP was increased without statistical differences in all stages. Casado-Flores et al. (2006) observed a stronger correlation between PCT and PRISM score in septic shock than RCP, possibly due to the kinetics of this mediator that after an approximately 2 h latency period from initial stimulus, rises to a plateau within

Serum lactate level is considered an important biomarker to distinguish sepsis from septic shock. Normally a small amount of lactate is produced and all healthy tissue have the capacity to convert it, in aerobic condition, to pyruvate, used for cellular metabolism. When sepsis-associated multisystem organ failure occurs, this metabolic capacity, in anaerobic condition, is decreased and lactate levels rise. In the past the lactate levels were used to distinguish between state of adeguate perfusion and poor oxygen delivery. At present, as has been that lactate could be increased by others factors like adrenergic stimuli and lung injury, it became important to consider the increase lactate levels in the general clinical context while a reduction of serum lactate is still advocated as a target for treatment (Arnold

Among imaging techniques: chest X-ray, ECG, ultrasound scans of brain, heart and kidney

Minimally invasive monitoring like central vein access and arterial presuure monitoring, and non invasive tools like echocardiography are considered necessary in septic neonates. Hemodynamic variables including (perfusion pressure mean arterial pressure [MAP], minus central venous pressure [CVP]), and cardiac output (CO) should guide resuscitation

The systemic circulation is represented by CO = (MAP - CVP)/SVR (systemic vascular

Measurement of urine output and creatinine clearance can be also used as an indicator of adequate blood flow and perfusion pressure. Because blood pressure does not necessarily reflect CO, it is recommended that normal CO and/or SVC (superior vena cava) flow, measured by Doppler echocardiography, be a primary goal as well. (Carcillo et al 2002,

Measurement of CO and O2 consumption were proposed as being of benefit in patients with persistent shock because a cardiac index (CI) between 3.3 and 6.0 L/min/m2 and O2 consumption >200 mL/min/m2 are associated with improved survival (Pollack et al 1985). Because low CO is associated with increased O2 extraction, ScvO2 saturation can be used as an indirect indicator of whether CO is adequate to meet tissue metabolic demand. If tissue

resistance). This relationship is important for organ perfusion.

Brieley et al 2009, Kluckow 2001, Kluckow et al 2000, Kluckow et al 2000 )

most commonly available and used markers are shown in table 3 (Haque 2005).

testing (blood culture, urine culture, culture catheters or drainage).

12–48 h and then slowly declines.

et al 2009, Jones et al 2010).

are proposed.

treatment.

The neonate is enable to increase the stroke volume or myocardial contractility in case of sepsis, due to different physiologic abnormalities: a relatively decreased left ventricular muscle mass (Joyce et al 2004), an impaired left ventricular diastolic function and alterations in mid-wall left ventricular fractional shortening (Kozak-Barany et al 2001). These differences may be mediated by alterations in calcium channel expression and activity, in ATP-sensitive potassium channel function and in β-receptor coupling (Huang et al 2006, Morrissey et al 2005).

These developmental alterations make the neonates critically dependent on increasing the heart rate to generate increased cardiac output, but unable to compensate in this manner because of their relatively higher baseline heart rate (Carcillo et al 2009).

The development of cardiovascular disfunction and septic shock make newborn infants susceptible to sudden cardiac deterioration, also because left ventricular sistolic performance is highly dependent on afterload. So the reopening of a patent ductus arteriosus and the development of persistent pulmonary hypertension (Carcillo et al 2002) may complicate the cardiovascular response to sepsis.

#### **4. Clinical features**

Septic shock should be suspected in any newborn with tachycardia, respiratory distress, poor feeding, poor tone, poor color, tachypnea, diarrhea or reduced perfusion particularly in the presence of prenatal risk factors like chorionamnionitis or prolonged rupture of membranes. (Kisson et al 2010)