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Personal Practice

Indian Pediatrics 1999; 36:265-288 

Management of Shock


Sunit Singhi
 

From the Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India.

Reprint requests: Dr. Sunit Singhi, Additional Professor, Pediatric Emergencies and Intensive Care, Department of Pediatrics, Advanced Pediatric Center, PGIMER, Chandigarh 160012 India.  E-mail: medinst@pgi.chd.nic.in

"Shock" is a clinical syndrome that results from an acute circulatory dysfunction and consequent failure to deliver sufficient oxy­gen and other nutrients to meet the metabolic" demands of tissue beds. The syndrome is characterized by signs of hemodynamic instability, namely, tachycardia, poor peripheral perfusion (poor pulse volumes, decreased skin temperature, poor capillary refill, often relative or absolute hypotension), and in later stages evidence of major organ hypoperfusion such as diminished urine output, changes in mental status, coagulopathy and acute respira­tory distress syndrome (ARDS).

In this article I have discussed manage­ment of shock as practiced in our unit. Referepce has been made 'to other available alternatives and future directions in therapy. A discussion on physiology and pathophysiology of circulation and determinants of tissue perfusion is included with a view to enhance understanding of various management strategies.

Physiology

The primary goal of cardiovascular and
circulatory system is to move blood and oxy­gen saturated hemoglobin to various parts of body, and deliver O2 and nutrients to vital organs. The interaction between blood flow and systemic and local vascular tone generates a perfusion pressure which determines tissue perfusion.

Cardiac output (CO): Cardiac output is the" most important determinant of tissue perfusion. It is defined as volume of blood ejected by the heart per minute. It is the pro­duct of stroke-volume and the heart rate. An increase in heart rate within physiological limits results in an increase in cardiac output, but an excessively high rate may limit diastolic filling time. In young 'children and infants, "elevation of heart rate is the most important compensatory mechanism for increasing cardiac output. However, because of higher resting heart rates, the proportional increase in heart rate in children is more. than that of adults, leaving them with little reserve to adapt to low cardiac output state.

The stroke volume is determined by preload, afterload and myocardial contract­ility. Preload refers to the volume of blood fillng the ventricle at the onset of diastole. It is determined by the volume of venous return to the heart and myocardial end diastolic fiber length. Any reduction in circulating blood volume, or an increase in venous capacitance as seen in distributive shock, or increase intrathoracic pressure which results in decreased venous return to heart, decreases stroke volume and cardiac output.

Myocardial contractility is determined by the total mass of functioning-ventricular muscle, myocardial perfusion, intrinsic and extrinsic neurocirculatory control mechanisms and the presence of physiologic and pharmacologic stimulants or depressants. Acidosis, hypoxia, hypoglycemia, hypokalemia, toxins, sepsis and primary myocardial disease all decrease contractility. Increase in contractility (positive inotropy) is affected by endogenous catecholamines and exogenous inotropic agents. The central factor in muscle contraction however, is the availability of the cytoplasmic calcium. All inotropic agents appear to depend ultimately on the ability to increase cytoplasmic calcium levels.

Afterload is best understood as the sum of forces that the ventricle must overcome in order to eject blood. It is determined by systemic vascular resistance. Increase in sys­temic vascular resistance causes an increase in the work of heart and a decrease in cardiac output. Infants and children are more suscep­tible to increase in afterload. Afterload may be manipulated by vasodilator therapy.

Distribution of blood flow: The distribution of blood flow is under local and neural control. Vascular factors determine the transcapillary exchange of gases and nutrients within tissue beds and the resistance to flow of blood through an organ bed. The latter depends upon the viscosity of blood and by length and cross-sectional area of blood vessels perfusing that organ.

Higher viscosity leads to increased resis­tance to blood flow and hence poor perfusion of tissue bed.

Neuronal control is exercised through sympathoadrenal discharge to the circulatory system and is regulated by vasomotor center of the brainstem. Activity of these neurons is modulated by afferent impulses originating from various receptors which include arterial and cardiopulmonary baroreceptors, chemoreceptors, and somatic receptors in skeletal muscle. When cardiac output is insufficient interaction of these receptors with the sympa­thetic and parasympathetic output affects se­lective vasoconstriction which helps in shunt­ing away the blood from less essential area such as skin, kidneys and gastrointestinal tract to vital organs namely brain and heart. In chil­dren there is a parasympathetic predominance (bradycardia with hypoxemia and hypovolemia) and immature sympathetic innervation of heart.

Many circulating humoral agents play an important role in cardiovascular homeostasis directly and indirectly. These are renin, vaso­pressin, adrenal steroids, prostaglandins, kinins, atrial natriuretic factor and catechol­amines.

Pathophysiology and Causes

A decrease in oxygen delivery to meet tissue oxygen requirement can be caused by any of the three basic abnormalities:

1. Hypovolemia (decreased circulating volume)

2. Cardiac function impairment (decreased myocardial contractility)

3. Inappropriate distribution of cardiac output secondary to abnormal vasodilatation.

Pathophysiology of shock based on these functional etiologies are discussed below. A schematic presentation of various events during shock is given in Fig. 1.

Hypovolemic shock: Hypovolemic shock is the most common form of shock in children(1) and continues to claim millions of lives each year(2) in true hypovolemia there is an actual sudden loss of circulating blood volume, as a consequence of loss of fluid and electrolytes (diarrhea, vomiting) or acute blood loss (internal or external). Relative hypovolemia occurs secondary to peripheral pooling of blood volume and 'third space' losses caused by loss of vascular tone and increased capillary permeability(3). It is most often seen in septic shock. It must be appreci­ated that because of small size the total volume of fluid blood loss that may cause shock is much less in a child as compared to an adult.

Fig. 1. Schematic diagram of pathophysiologic events in shock

Fig. 1. Schematic diagram of pathuphysiologic events in shock.

Important aspects of hypovolemic shock are the extent and the rapidity with which hypovolemia occurs. The loss of circulating blood volume is followed by a series of cardiac and peripheral homeostatic adjustments directed at restoration of systemic arterial blood pressure and perfusion of critical organs such as heart and brain. Whether these adjustments are adequate to maintain cardiovascular homeostasis is determined by patient's preexisting hemodynamic status.

Cardiogenic shock: Cardiogenic shock is best viewed as a 'pump failure'. The common causes of cardiogenic shock in children are shown in Table I. The common event is an inadequate stroke volume mostly as a result of decreased myocardial contractility and infre­quently due to mechanical obstruction to the flow of blood. Low cardiac output, decreased blood pressure and poor tissue perfusion, produce a rapid downhill spiral of inadequate oxygen delivery to tissues and microcirculatory failure. Children rarely go through a compensated phase of cardiogenic shock.

Distributive shock: In this type of shock there is maldistribution of the blood volume. Common to all the conditions causing this form of shock is massive injury to capillary endothelium resulting in loss of its integrity and leakage of fluid to interstitium or so­called "third-space". Septic shock is a classi­cal example of this type. Other causes are listed in Table I. Septic shock is a consequence of overwhelming bacteremia and/or sepsis most often caused by Gram negative organisms. However, it may also occur following Gram positive as well as fulminant viral infections. It is more often seen in hospitalized chil­dren and is one of the most common causes of mortality in pediatric intensive care units.

TABLE I- Causes of Shock

A. Hypovolemic

Fluid and electrolyte loss: Diarrhea, vomiting, excessive sweating, pathologic renal loss, diuretics, heart stroke Blood loss: External-Laceration, Internal-Ruptured visceras, GI bleed, Intracranial bleed (esp. Neonates), Post­surgery

Plasma loss: Burns, leaky capillaries-sepsis, nephrotic syndrome, sepsis "third space loss", intestinal obstruction, peritonitis

Endocrine: Diabetes mellitus, diabetes insipidus, adrenal insufficiency

B. Cardiogenic

Myocardial insufficiency: Congestive heart failure (Congenital, or acquired heart disease), Cardiomyopathies, myocarditis, Arrhythmias: Supraventricular tachycardia.

Metabolic: Hypothermia, drugs, toxins, myocardial depressant effect of hypoglycemia, acidosis, hypoxia, Poor myocardial perfusion - Kawasaki disease, congenital coronary abnormalities

Outflow obstruction: Cardiac tamponade, Pneumopericardium, Tension pneumothorax, Pulmonary embolism.

C. Distributive

Septic shock, anaphylaxis, neurogenic shock, drugs/toxins, tissue injury, prolonged hypoxia or ischemia

The pathophysiologic events in septic shock are as a result of complex interplay between microbial products and host (Fig. 2). Of the microbial factors, the most important is Gram negative lipopolysaccharide (LPS). Among host responses that have been implicated are components of coagulation cascade, complement and kinin systems as well as fac­tors released from stimulated macrophages and neutrophils like tumor necrosis factor-α (TNF) , and interleukins. Interaction of host with these mediators produces a series of metabolic alterations at the cel1ular and subcellular levels, the end result of which is multiple organ system failure.

The critical event as shown if1 Fig. I, in all forms of shock is poor perfusion of vital organs and other body tissues and inability of those tissues to utilize essential nutrients. The common final sequence of events is altered cellular and subcellular metabolism and energy production. The release of proteolytic enzymes and other toxic products as a result of cellular injury further alters cellular function and structure in the adjoining and distant tissue beds.

Clinical Progression and Stages of Shock

Shock is a progressive disorder. The progression may be fulminant within minutes, such as after a massive hemorrhage. More of­ten it evolves over a span of hours. This progression has been arbitrarily divided into two stages:

1. "Early", "Compensated" shock; and

2. "Progressive", "decompensated" shock.

Fig. 2 Schematic diagram of pathophysiology of septic shock and its mediators


'Early', 'Compensated' shock implies that
vital organ function is maintained by intrinsic compensatory mechanisms such as venoconstriction, fluid shift from interstitial to intravascular space and arteriolar vasoconstriction. At this stage symptoms and signs of hemodynamic impairment which one commonly observed in adults have the potential to remain subtle in children for a longer period of time, leading to delays in recognition and un­derestimation of shock states(4). Because of this a high degree of clinical suspicion is required to identify shock in children. Blood pressure (BP) is usual1y maintained, heart rate is increased, pulse pressure is narrow and signs of peripheral vasoconstriction (de­creased skin temperature and impaired capil­lary refill >3 seconds) are present. Children with dehydration exhibit in addition, signs of interstitial hypovolemia such as sunken anterior fontanel1e, sunken eyes, dry buccal mucosa, poor skin turgor. Children with "capillary leak" because of sepsis on the other hand may have none of above signs. Children may attempt to compensate for the metabolic acidosis and decreased tissue oxygen supply by increasing respiratory rate and work of breathing. If shock is identified and vigorously treated at this stage, the syndrome may often be successfully reversed.

The "progressive", "decompensated'" stage appears with persistence of shock, especial1y when an additional stress is imposed. In this stage despite intense arteriolar constriction and increased heart rate, blood pressure and cardiac output declines. This leads to lowered perfusion pressure, progressive blood stagnation, anaerobic metabolism and release of proteolytic and vasoactive substances. Platelet aggregation and release of tissue thromboplastin produce hypercoagulability and disseminated intravascular-coagulation.

Patient may demonstrate impairment of major organ perfusion which may manifest as altered mentation (impaired cerebral perfusion), oliguria (renal hypoperfusion) and myocardial ischaemia (coronary flow impair­ment). The external appearance of patient reflects excessive sympathetic drive with acrocyanosis, peripheral vasoconstriction and cold and clammy extremities. Child may attempt to compensate for the metabolic aci­dosis and decreased tissue oxygen supply by increasing respiratory rate and work of breath­ing. It is evident at this point that the patient has deteriorated. Rapid aggressive interven­tion is required to halt the progression of shock to irreversible stage.

Not all forms of shock progress in similar manner or go through these stages. Neuro­genic shock is characterized by hypotension at onset due to diminished or absent sympathetic activity and loss of vascular tone. The classic example is shock following transection of the spinal cord in the cervico-thoracic region. Reduced peripheral vascular tone leads to pool­ing of blood in the extremities and inadequate venous return. Initially the patient has warm extremities, low diastolic pressure and a very wide pulse pressure. Ultimately perfusion pressure falls and acidosis develops.

Septic shock often follows a trimodal pattern of hemodynamic presentation. In the early stages, there is a decrease in systemic vascular resistance and an increase in cardiac output ("Warm" shock). Hemodynamically it is characterized by low cardiac filling pres­sures, increased cardiac output, tachycardia, and decreased whole body oxygen consump­tion. The latter effect is due to impaired mito­chondrial oxygen utilization and deficient oxygen delivery to cells despite an increase in overall cardiac output (maldistribution of cardiac output). Late in sequence of septic shock there is a decline in cardiac output and profound hypotension with severe acidosis, hypoxemia and hypoxia ("Cold" shock). Frequently there is pulmonary and/or cerebral edema as a result of endothelial disruption. The end stage of septic shock is often associated with multiple organ system failure with profound derangements in cardiovascular, pulmonary and renal systems.

"Irreversible" shock is a term that is applied to the clinical situation in which even correction of hemodynamic derangement does not halt the downward spiral. The prolonged hypoperfusion of brain, heart and kidneys leads to ischemic cell death in these organs with progressive worsening of coma, renal failure and pulmonary edema, and onset of adult respiratory distress syndrome (ARDS).

Management-Objectives

The major objectives in the management of shock are:

1. Rapid recognition of shock' state and resuscitation (airway, breathing)
2. Correction of initial insult, if possible.
3. Correction of secondary consequences of
shock through volume replacement, vasoactive drug therapy, RBC transfusion: 4. Protection, support and maintenance of vital organs function.
5. Identification and correction of aggravating factors.
6. Monitoring of cardiovascular and hemodynamic response and oxygen.

All the objectives are approached simultaneously in an organized way so as to ensure optimal therapy.

Recognition and Assessment

The early diagnosis of shock requires a high index of suspicion and a knowledge of which conditions predispose to shock. The age of the child, previous medical conditions such as congenital heart disease, immuno deficiencies, suspected ingestions and a history of trauma all should raise the suspicion. Children who are febrile, have an identifiable source of infection or are hypovolemic from any cause are at a greater risk of developing shock. It may be often difficult to determine which children have crossed over from a state of being dehydrated and febrile to a state of fully developed shock. Table II summarizes physical signs of shock.       

TABLE II

Physical Signs of Shock

A. Signs of autonomic response to low cardiac output
(i) Tachycardia (most important early sign)
(ii) Tachypnea
(iii) Blood pressure - normal
B. Signs of decreased tissue perfusion
(Helpful but can not be relied upon)
(i) Color: Pale, ashen grey
(ii) CapiUary refilling time (:2:3sec)
(iii) Decreased skin surface temperature
(iv) Increas.ed difference between core and peripheral temperature >2oC
C. Signs of major organ dysfunction
Brain              :Agitaiton, stupor-coma, ischemic brain injury
Kidneys          : Acute renal failure, oliguria
GIT                 : Erosive gastritis, ischemic pancreatitis.
Liver                :Ischemic hepatitis-elevation of transminases and biliurbin
Hematologic    :Coagulation abnormality, elevated PT, PTTK in all forms of shock,
                       severe DIC and thrombocytopenia

 

On physical examination it is possible to identify signs reflecting the underlying physiologic process. True tachycardia is noticed well before any notable alterations in blood pressure. The respiratory rate (RR) is usually elevated. The changes in heart rate and blood pressure also depend on the acuteness of the underlying events. An acute volume deficit of 10% may be marked by an increase in pulse rate by 20 beats/min. Signs of decreased tissue perfusion are decreased skin temperature, impaired capillary refill (>3 seconds) and im­paired function of several organs. Cold extremities or increased peripheral to core temperature gradient (>2°C) indicate intact homeostatic mechanisms compensating for hypovolemia by cutaneous vasoconstriction. Serial determination at frequent intervals of these signs may provide an excellent indication of response to treatment. Blood pressure is remarkably well preserved in hypovolemic shock until there is sudden decompendation. A rough estimate of a minimum acceptable systolic blood pressure is: Systolic pressure = 70 + (age in year x 2). A gradual 10-15% loss of volume produces minimal changes; hypotension may not occur until 30% volume loss. Therefore, in the assessment of shock, blood pressure may be helpful but cannot be overvalued as an overall indicator. In animal models of hemorrhagic shock hypotension was not evident until 50% decrease in blood volume(5).

"Vital organ hypopeifusion" can be assumed to occur if oliguria from renal hypoperfusion coexists, or if child develops clouded sensorium with disorientation, lethargy, confusion or hallucinations.

The physical findings of early septic shock are different from other types of shock as the patient may have fever, chills. The peripheral tissues are initially welI perfused and warm. Peripheral pulse. rate and volume are increased. Pulse pressure is widened: precordium is hyperdynamic and diastolic pres­sure is low. Presence of acidosis supports the diagnosis of early septic shock. Once multiple organ system failure sets in, the patient becomes cold, has decreased pulse volume, low blood pressure and signs of decompensated shock. More recent opinion does not use the term 'early' septic shock instead a grading of severity of sepsis is proposed for the all ages. Table III gives the terminology and definition of sepsis and septic shock given by Society of Critical Care Medicine, USA.

TABLE III
Terminology for Systemic Inflammatory Response, Sepsis and Septic Shock (Modified from Society of Critical Care Medicine Consensus Conference)(6)

Term Definition
Systemic Inflammatory Response Syndrome (SIRS)

Two or more of the following:
. Tachypnea (respiration>age appropriate breaths/min or PaC02<32 torr)
. Tachycardia (heart rate>age appropriate beats/min)
. Hyperthermia or hypothermia: Core or rectal temperature >IOI"F (>38"C) or <96.1"F «35.S-C) .
. WBC > 12,000 cells/mm3, <4000 cells/mm3, or > 10% band cells

Sepsis SIRS with clinical evidence of infection
Severe sepsis

Sepsis, plus evidence of altered organ dysfunction, hypoperfusion or hypotension (including one or more of the following):
.  Acute changes in mental status
.  PaOiFi02<280 (without other pulmonary or cardio-vascular disease as the cause)
. Increased lactate (more than upper limits of normal for the Laboratory)
. Oliguria (documented urine output <0.5 ml/kg body weight for at least I h (in patients with bladder catheter in place)

Septic shock

Sepsis with hypotension [systolic BP <70 mm Hg+ (age x 2) or fall in mean arterial pressure by >10 mm Hg from baseline] and perfusion abnormalities that is responsive to fluids resuscitation

Refractory or nonresponsive septic shock

Sepsis with hypotension that lasts for >1h, not responsive to IV fluids (20 mil kg of normal saline over 30 min) or pharmacologic intervention (requiring vasopressors: e.g., dopamine >10 μg/kg/min)

Laboratory investigations to assess the function of various organ 'system to plan support therapy, and determine underlying cause of shock should be obtained as outlined in Table IV. It may however be remembered that use of laboratory values to predict fluid deficit has not been supported(7). The definition and diagnosis of multiple organ failure based on clinical and laboratory criteria given by Society of Critical Care Medicine(6) are shown in Table V.

Echocardiography may be particularly valuable to assess ventricular function in new­born and infants with cardiogenic shock. It provides an unique window to anatomy of heart, which dictates the pathophysiology, and gives tremendous insight into management of these patients.

 

TABLE IV - Laboratory Measurements in Shock Patients

Cardiovascular System Gastrointestinal
ECG Stool-occult blood
Chest X-ray Gastric pH
Blood gases Liver function test
 Echo-cardiogram Pancreatic functions
Respiratory System Metabolic
Blood gases - Arterial and
mixed venous
Serum Na, K, Ca, Mg
Phosphorus
Lung function tests
 
Blood glucose
Serum  proteinalbumin
Renal System Infection Screen
Urine-Specific gravity, Na Cultures-Blood, CSF,
Sediments, protein, sugar, Serum urea and creatinine urine, stool, pus
 
Hematologic System
 
Toxicology Screen
(if suspected)
Blood counts Common poisons
Coagulation parameters Anticonvulsants
Platelets counts, fibrinogen
degradtion products
Heavy metals
 

Oxygen

The initial resuscitation involves securing patent-airway, administration of oxygen and establishment of intravenous access. Oxygen must be administered initially to all patients in shock, in view of impaired peripheral oxygen delivery. An attempt should be made to achieve an arterial oxygen saturation of 90% or higher. Continuous assessment of oxygen­ation can be guided by the use of pulse oximetry, but significant alterations in man­agement must be based upon direct assess­ment of arterial blood gases.

Venous Access

Vascular access must be obtained immedi­ately. First attempt should be made at a large peripheral vein (anticubital vein, saphenous vein anterior to medial malleolus, cephalic vein posterolateral to wrist, external jugular). Intraosseous (IO) route may be used for administration of fluids and drugs when IV access is not obtained within 1-2 minutes in children 6 years of age. A luer-Iocked bone marrow needle is placed in the proximal tibial shaft (Fig. 3). The intramedullary space is contiguous with the intravenous compartment, so fluid and drugs readily pass to the central circulation following 10 use. Rapid fluid administration may require manual "pushing" or the application of a pressure bag to the IV set up. If a peripheral IV access has failed or can not be obtained immediately, a percutaneous central venous access should be obtained by an experienced person either in femoral, or subclavian vein(8,9). A short catheter with a large radius will allow most rapid flow rate.

Fluid Therapy

Restoration of effective circulating volume by replacement of fluid is the key step in man­agement of hypovolemic and distributive shock. Volume replacement improves cardiac output by increasing venous' return and pre­load and improves perfusion of vital organs. Fluid therapy should be initiated before establishing a line for monitoring the CVP and with­out a fear of fluid overload. In the patients with otherwise normal cardiorespiratory function, volume overload resulting in pulmonary edema is rare.

Fig. 3. lntraosseous illfusion: Sites of illfusion and method.

A.  Lower end of femur : 2-3 cm above the external condyles in midline.
B. Upper end of tibia: on the antero-medial surface, 1-2 cm below the centre-point of the horizontal line connecting tibial tuberosity and medial border. The needle is inserted at an angle of90. to the long axis of the bone or slightly caudal. Needle entry into the marrow is accompanied by a loss of resistance, sus­tained erect posture of needle without support and free fluid infusion.
C. Lower end of tibia: on medial surface proximal to medial "malleolus.

Choice of fluid: The choice of fluid includes crystalloid, colloids and blood products (Table VI). Initially, Ringer's lactate solution or normal saline is given in a bolus of 20 ml/kg in less than 10 minutes. This may be repeated according to response. Blood may be needed to replace with blood loss.

Amount of fluid: The amount of fluid arid time over which it should be given is often debated topic. The volume to be administered depends upon the patient's volume status and ongoing losses. In severe shock 60 ml/kg may be required extremely rapidly and up to 120 ml/kg in first 6 hours. A clinical study in septic shock has noted significant reduction in mortality when patients received  40 ml/kg within first hour(10).                                               "

Crystalloid v/s Colloid Therapy: Crystal­loid solutions stay in circulation briefly; only 25% remain in intravascular component after 4 hours, rest will move to interstitial and other extracellular compartments( 11). Large volumes of crystalloid can therefore contribute to interstitial and pulmonary edema. Attempts have been made to decrease interstitial and pulmonary edema by supplementing Ringer's lactate with colloid (albumin, and hydroxyethyl starch solutions). Colloids however are 40-60 times more expensive than equivalent volumes of crystalloid. There is little evidence from studies in adults that such combinations increase patient survival. Studies evaluating colloids in pediatric patients are needed. We however, prefer to give colloids in patients with septic shock after 40-60 ml/kg of crystalloids.

TABLE V - Definition and Criteria for Diagnosis of Multiorgan Failure (MOF) Associated with Shock(6).

MOF Criteria for diagnosis
Disseminated intravascular coagulation

(i) A confirmatory test is positive (FOP> 1 :40 or D-Dimers <2.0).
(ii) AbnormalIy low values for platelets (or a >25% decrease from a previously documented value); and
(iii) Either prolonged prothrombin time or partial thromboplastin time or clinical evidence of bleeding. a

Adult respiratory distress syndrome

Unexplained hypoxemia in the presence of a predisposing factor such as sepsis. Bilateral pulmonary infiltrates consistent with pulmonary edema and PaOiFi02<175.h

Acute Renal Failure

Serum creatinine becomes abnormal and urinary sodium is >40 mmol/L in a spot specimen, or serum creatinine increase by 2.0 mg/dl (176 umol/L) in a patient with previous renal insuffi­ciency, and is not prerenal in nature (e.g., associated with dehy­dration or gastrointestinal bleeding) or due to rhabdomyolysis (preferably no diuretics within 2 h of obtaining urinary sodium levels).

Hepatobiliary dysfunction

Serum bilirubin exceeds 2.0 mg/dl (34 Jlmol/l), and alkaline phosphatase, gamma glutamyl transpeptidase (GGT), SGOT, or SGPT exceed twice the upper limit of normal, in the absence of confounding disease.

Central nervous system dysfunction


 

Glasgow Coma Scale (Pediatric adaptation) score <15 in patients with normal baseline CNS function, or at least one point lower than a baseline Glasgow Coma Scale score in patients with baseline CNS impairment."

aThese abnormalities. must occur in the absence of clinical evidence of bleeding, medicalIy significant confounding factors such as liver failure, major hematoma, or anticoagulant therapy.

bThese factors must occur in the absence of congestive heart failure or primary lung disease. Pulmonary artery occlusion pressure, when measured must be <18 mm Hg.

cTo assess Glasgow Coma Scale scores, patients should not have been treated with paralyzing or sedating "agents in the dose that can alter their Glasgow Coma Scale scores.

TABLE VI - Choice of Fluids-Crystalloids Versus Colloids

Intravenous Fluids Guidelines for Use
Crystalloids


 

* 0.9% sodium chloride

1. Initial fluid of choice for shock of undertermined etiology

* Hypertonic sodium chloride 2. Can be used for upto 50% volume expansion
* Ringers lactate solution 3. Hypertonic saline used in bum patients
Caution: Avoid excess use in severe hypo-oncotic states and cardiogenic shock
Colloids  
* 5% serum albumin in 019% saline 1. Hypovolemic-hypoproteinemic patients with renal cardiac and respiratory failure
* 25% serum albumin in 0.9% saline 2. Refractory hypovolemic shock (combined with crystalloids)
* 10% dextran-40 in 5% dextrose  
* Hydroxyethyl starch in 0.9% saline Caution: Contraindicated in bums and severe capillary leaks
* Pentastarch  
Blood Products  
* Whole blood
 
1. Volume replacement in trauma or hemorrhage
* Packed red blood cells 2.  Packed RBCs in bum patients
* Fresh frozen plasma 3. Plasma in coagulopathies

Expected response to a fluid bolus includes an improvement in pulse volume, a decrease in capillary refill time, an improvement in sensorium, a decrease in tachycardia, elevation of an initially low blood pressure and the maintenance of an adequate urine output (1mI/kg/h). Almost all patients with hypo­volemic shock and neurogenic shock, and 20-30% patients with septic shock will respond well to fluids alone. If there is poor therapeutic response after two boluses or if there is evidence of renal or cardiac disease, CVP measurement (or pulmonary artery pressure monitoring) should be undertaken to evaluate the need and response to further fluid therapy. In shock, optimal CVP is somewhere between 10-]5 mm Hg (12-18 cm HP). The CVP should be interpreted in the light of clinical condition; it may be influenced. by rapid heart rate and increases in intrathoracic pressure.

Further fluid therapy: If the response to a fluid is adequate the child should receive nor­mal maintenance and further replacement of losses as follows:

Replacement of losses: One half the calculated loss is replaced along with maintenance fluid over the next 8 hours. 0.45 NS in 5% dextrose is the preferred solution. Potassium 20 mEq/L is added to fluid once urine output is established. Ongoing losses are replaced concurrently with a solution that matches the fluid being lost, either 0.45 NS + 40 mEq/L KCl or Ringer's lactate. The remainder of the calculated loss is replaced along with maintenance fluid over the next 16 hours. The pre­ferred solution is 0.45 NS in 5% dextrose with 20 mEq/L of potassium.

Provision of Maintenance Fluid and Electrolyte Requirements

* 4 ml/kg/hour for first 10 kg of body weight (100 ml/kg/day) 

* 2 ml/kg/hour for second 10 kg of body weight (50 mI/kg/day)

* 1 ml/kg/hour for each additional kg of body weight (20 ml/kg/day)

* 2-4 mEq/100 ml Na+ and 2-3 mEq/100 ml K+

Specific Therapy for Hemorrhagic Shock

Class I (blood loss <15%) hemorrhage should betreated by replacing the volume loss with a balanced salt solution (Ringer's lactate or normal saline). Administer 20 ml/kg as a bolus, replacing 3 ml of crystalloid for every 1 ml of circulating blood volume lost. The rationale for the "3 for 1" rule is that only 1/3 of the crystalloid infused remains in the intra­vascular space. More recently hypertonic saline 4 ml/kg has been suggested as "low volume" resuscitation fluid. Both 7.5% saline in 6% dextran 70 or 7.5% glucose saline have been used but no survival benefit have been shown so far.

Class II hemorrhage requires blood (10-15 ml/kg) as well as Ringer's lactate. Whole blood is preferred if it is available.

Classes III and IV (blood loss 30-40%, re­spectively) hemorrhage frequently requires blood replacement. Ongoing blood losses are replaced ml for ml with blood.

, A pneumatic anti-shock garment (MAST) may 'be necessary to raise blood pressure acutely.

Blood replacement therapy for the child in hemorrhagic shock should begin as soon as possible. Although all blood products (cells, platelets, fresh frozen plasma) are potentially contaminated with virus (hepatitis, HIV), this should not deter its life saving use. Fresh «48 hours) whole blood contains red blood cells, platelets, and clotting factors. When available and cross matched (which takes about one hour), it is the ideal replacement product. Otherwise stored ("banked") blood or compo­nents such as packed red blood cells, should be used.

Packed red blood 'Cells are red cell concentrates with a hematocrit between 50 and 70%. There are no platelets and very little Factor V and VIII in this solution. To maintain shelf life, packed cells are stored in solutions that bind calcium. Potassium levels may be high.

Vasopressor, Inotropic and Vasodilator Therapy

All shock states, even hypovolemic, have some form of impairment of myocardial func­tion whether this impairment is primary or secondary. Use of vasoactive drug therapy to optimize cardiac output is therefore, the cornerstone of shock therapy. Patients in septic shock in particular, may not show desirable response even after 60 ml/kg fluid (labelled as fluid refractory stock) and may require vasopressor support. They commonly have right and left ventricular dysfunction with depres­sion of ejection fraction and dilatation of ventricles, which is reversible over a 7-10 days period in survivors(12). A circulating myocardial depressant substance appears to be the cause of myocardial depression(13,14).

Who need it? In general, inotropic and vasodilator drugs should be used once volume resuscitation has been achieved. Even in cardiogenic shock if there is no sign of CCF (no jugular venous distension, pulmonary edema or hepatomegaly), Ringer's lactate in 5-10 ml/kg aliquots should be given while monitoring perfusion(15). Fluid is stopped if there is no improvement in perfusion or if signs of CCF- develop. However, in septic shock it is sometimes practical to start vasoactive drugs at the same time as the fluid infusion if patient has profound hypotension or end-organ failure.

Which Drugs? The vasoactive agents are aimed at increasing myocardial contractility (increased inotropy) and decreasing left ventricular afterload. Unfortunately no single agent appears to produce the desired effects in all forms of shock. Proper choice of drugs requires a knowledge about exact hemodynamic disturbance and pharmacology of these drugs (Table VIl). The sympathomimetic amines are the most potent positive inotropic agents available; besides inotropy they also possess chronotropic effects and complex effects on vascular beds of various organs (Table VII). Dopamine augments cardiac contractility through direct stimulation of β1 receptors. in heart and by inducing nor-epinephrine release at presynaptic terminals which results in stimulation of β-receptors. At higher dose it can result in stimulation of (XI-receptors which results in vasoconstriction. Dobutamine has primarily β1 and β2 effects which can lead to increased force of contraction and vasodilatation. The efficacy of dobutamine appear to be less at younger age, perhaps because of reduced β stimulation and higher level of circulating catecholamine. In higher doses sympathomimetic amines may have undesirable vascular actions or toxic effects on myocardium. Phosphodiesterase inhibitors, amrinone and milrinone, are another groups of inotropic agents available. These drugs decrease breakdown of cyclic AMP and increase calcium availability inside the cell, theraby increasing force of myocardial contraction and vasodila­tation. These drugs are useful in children in whom simultaneous reduction in right ventricular afterload is desirable(16). Unfortunately, these drugs are not regularly available in India. Hemodynamic effects at various doses, site of action and dosage for various sympathomimetic amines is given in Table Vlll.

How to give vasoactive agents? Most of the inotropic or vasoactive agents are given by continuous intravenous infusions through a central venous catheter. A standby peripheral catheter should be available in case of mal­function of primary catheter. Infusion should be given through an infusion pump and should never be interrupted because half life of these agents is only one or two minutes. Inadvertent flushing of catheter can be fatal because of sudden delivery of a bolus of these drugs. All infusions with their rates should be carefully labelled. The infusion rate should be calculated in microgram/kilogram/minute.

Choice of Initial therapy: Initial therapy should be undertaken with drugs with a mixed inotropic and vasopressor effect, e.g., dopa­mine, adrenaline, or noradrenaline. Addition of an inotropic agent, e.g., dobutamine may be considered if presence of myocardial dysfunction is suspected or confirmed. In our unit dopamine is first choice and usually started at a dose of 10 μg/kg/min. A rational choice may be made by remembering that dobutamine is believed to be a pure inotrope whereas dopamine may be a vasodilator, inotrope, or vasoconstrictor depending on the dose. In a patient who is in low output state and where blood pressure appears adequate, dobutamine may be the drug of choice. On the other hand, in hypotensive patients, pressor effects of dopamine may be required to augment. the cardiac output. Combination of inotropic concentrations of dobutamine with vasodilator concentration of dopamine are also highly effective. In patients who fail to respond to maximal increases in dopamine or dobutamine concentration more potent agents like, adrenaline, noradrenaline and isoproterenol must be considered. Adrenaline remains use­ful in patients with left ventricular dysfunction that remains refractory to dopamine and dobutamine. It is usually started at 0.1 Ilglkgl min and increased rapidly. Maximum dose should not exceed 2-3 μg/kg/min. Noradrenaline may improve arterial BP and urine flow when volume replacement and dopamine have failed to reverse hypotension in septic shock.

End-points/Objectives: Reversal of hypotension and endorgan dysfunction are the objectives of vasoactive therapy. However, reversal of hypotension with very high doses of vasopressor carries risk. Improvement in cerebral and renal functions may only be tran­sient and tissue hypoxia may worsen. The vasoactive therapy should therefore be moni­tored by clinical evaluation and determination of blood gases and lactate concentration.

Vasodilator drugs may improve cardiac performance by decreasing the afterload (the resistance against which heart must pump blood). Among these drugs, nitroprusside and nitroglycerin are the two for which there is greatest clinical experience. The use of these agents may be particularly indicated in shock where vasoconstriction is a prominent part of clinical picture. The protocol employed for treating hypotension at PICD, Chandigarh is summarized in Table IX. The management of neurogenic shock is depicted in Table X.

Correction of acidosis, hypoxia, hypocalcemia and hypokalemia or hyperkalemia and treatment of arrhythmia should be undertaken. Calcium supplementation may play an essen­tial role in augmenting left ventricular func­tions in pediatric patients(15). One may use atropine and isoproterenol for bradyarrhythmias, adenosine or verapamil (in older children) for supraventricular tachyarrhythmias and lidocaine for ventricular ectopy.

Supranormal Tissue Oxygen Delivery (D02) and Tissue Uptake Utilization (V02)

The ultimate problem surrounding shock involves alteration of oxygen utilization (V02) at the microscopic level, particularly the mitochondria, the actual site of cellular respiration. Accordingly, shock reflects con­sequence of glycolysis and inefficient ATP production.

TABLE IX
Protocol for Treating Hypotension at Pediatric Intensive Care Unit PGIMER, Chandigarh

. Fluid bolus (Normal saline) 20 ml/kg over 5-10 min, Insert CVP line

. Monitoring respiratory rate, pulse rate, blood pressure (BP) and CVP (must). Also send blood gases, glucose, calcium/phosphate and BCG

Hypotension persisting with

A. CVP<10 Cm H2O

. More fluid bolus-20 ml/kg repeat if setting of hypovolemia

. 10 ml/kg, if cardiogenic cause is suspected

. Arrange to give colloid (plasma, Gelatin, Hexastarch) 10 ml/kg/over 20 min as soon as possible.

B. CVP>15 cm of H2O

. Start Dopamine infusion 5-20 Ilg/kg/min, titrate from 10 Ilg/kg up or down

. Lasix I mg/kg/dose IV

. Add dobutamine if response inadequate

C. CVP 10-15 cm HP

. Dopamine - 5-15 Iμg/kg/min infusion

. Add dobutamine if response inadequate

Hypotension persists

. Infusion adrenaline - 0.1 μg/kg/min to 2-3 μg/kg/min (maximum)

To taper slowly over 12-24 h when BP is stable and CVP is normal for atleast 6 h

TABLE X

Management of Neurogenic Shock

1. Trendelenburg position (head down, legs elevated) and compressive leg wraps

2. Ringer's lactate or normal saline in 10-20 ml/kg aliquots

3. Vasopressor drugs: Phenylephrine (neosynephrine): Acts by direct (α-I adrenergic stimulation vasocon­striction), (α-I venous stimulation (venoconstiction and increased venous return)

Dose: 1-10 μg/kg, Continuous infusion: 1-10 μg/kg/minute
Duration: 5-10 minutes

In cell suspensions VO2 cytochrome oxidase and A TP turnover are all preserved above a PO2 of 15 torr. At PO2 < 15 torr but > 4 torr, these cells enter a phase of adapted hypoxia in which A TP turnover and VO2 are maintained at expense of increased cyto­chrome reduction. At PO2 < 4 torr cells exhibit "intact dysoxia" in which VO2 and cyto­chrome oxidation are decreased but cell maintains adequate A TP turnover via anaero­bic pathway. Finally, at some level below this, cells exhibit decreased function with decreased VO2 and A TP turnover(17). The anoxia finally wrecks the machinery.

It is suggested that merely attaining nor­mal physiological parameters during therapy of shock may not be adequate. Some studies in adults have suggested that 'survivors' of shock have supranormal cardiac output, oxy­gen consumption and elevated oxygen extraction (18-20). It is therefore suggested that after achieving an adequate blood pressure with normal mental status and satisfatory urine output, optimization of cardiac output should be attempted to attain supranormal DO2

Normal oxygen DO2 is 550-650 ml/min/m2 and VO2 120-200 ml/min/m2. Theoretically it is possible to increase DO2 and hence VO2 as we know:

DO2 = CaO2 x Cardiac Index

where CaO2 = Hb x 1.34 x oxygen saturation

+ (PaO2 x 0.003),

Cardiac Index = Cardiac output/m2, and

Cardiac output = Heart rate x stroke volume.

DO2 can therefore, be increased by in­creasing cardiac output, improving Hb con­tents, FiO2 and ventilation. In clinical practice this has been documented by several studies.

However, not all investigators agree that VO2 is dependent on DO2 in patients with septic shock(20). It is uncertain whether the oxy­gen transport relationship in children are same as adults(21). In one study in children blood transfusion increased DO2 but not VO2 and epinephrine infusion increased both VO2 and DO2(22). High dose inotropic therapy to obtain supranomal cardiac output is, therefore, not recommended(23).

Metabolic Correction

Acidosis: Severe acidosis impairs meta­bolic processes, impedes normal neurovas­cular interactions, and may prevent effective pharmacologic actions of various vasopressor and inotropic agents. Correction is indicated when marked metabolic acidosis exists (arterial blood pH <7.20). Sodium bicarbonate is usually given in an initial dose of 1 to 2 mEq/kg. Subsequent doses are based on body weight and base deficit (mEq = body weight in kilograms x base deficit x 0.3). Bicarbonate should be used only to partialy correct the pH to a level which do not pose a serious immedi­ate threat of life (7.15-7.20). Overcorrection may impair cardiac function and cause paradoxical CNS acidosis. There is no evidence that sodium bicarbonate during shock reduces risk of mortality.

Glucose: It is important to avoid hypo­glycemia and if present, treat it rapidly. At the same time if blood glucose concentration is 250-300 mg/dl, insulin (0.1 unit/kg) should be used to bring the concentration to normal.

Serum sodium: Disorders of serum so­dium concentration may cause cerebral injury. The levels should be monitored and main­tained within normal range.

Calcium: Sustained decrease in ionized calcium is seen in shock. It is a poor prognos­tic sign. Therapeutic intervention is justified when serum ionized calcium level falls below normal (=2.4 mg/dl). An intravenous infusion of 1-2 ml/kg of 10% calcium gluconate under cardiac monitoring is the usual dose.

Magnesium: Hypomagnesemia is frequently seen and should be corrected with IV MgSO4.

Organ System Support
Ventilatory Support

Abnormality of respiratory function is almost, always present in shock, especially septic shock. The work of breathing is sub­stantially increased, respiratory drive and lung mechanics may be abnormal. Pulmonary edema may occur. Respiratory failure can develop rapidly and is frequently the cause of death. Therefore, patients in refractory shock should be intubated early and treated with positive pressure ventilation. Indications for mechanical ventilation in the shock are:

 

1. Apnea or ventilatory failure (acute respiratory acidosis).

2. Failure to adequately oxygenate with high flow oxygen.

3. Respiratory fatigue.

During ventilation attempts should be made to achieve a minimum arterial oxygen concentration of 60-65 torr with an FiO2 of 0.6 or less. This may be facilitated by judicious use of positive end expiratory pressure (PEEP). Lung injury, air leaks and its sequelae are quite common in children therefore high pressures should be avoided. Frequent posture changes and vigorous physiotherapy to promote drainage of secretions and avoid atelectasis are essential.

CNS Protection

A voidance and rapid correction of hypoxia and hypoglycemia are mandatory. Hypercapnia may aggravate raised intracra­nial pressure. Mechanical ventilation should be used to correct it. Intracranial infection may induce septic sl1Ock; it should therefore be ruled out in all patients with septic shock through CSF analysis and CT scan.

Renal Salvage

Shock may lead to renal failure. Aggres­sive fluid replacement and inotropic and vasopressor support should be used to. correct hypotension and vasodilating doses (2-3 μg/kg/min) of dopamine may be used, as also mannitol, loop diuretics, etc. However, there is no convincing evidence that these drugs can prevent acute renal injury(24). Should hyperkalemia, refractory acidosis, hypervolemia and altered mental status occur, dialysis should be seriously considered. Nephrotoxic substances, e.g., aminoglycoside and amphotericin-B should be used very cautiously.

Gastrointestinal Support

Gastrointestinal disturbances after shock include stress bleeding and ileus. Hypokalemia should be corrected. Gastrointestinal blood loss can be prevented by using antacids, or an H2-receptor blocker such as ranitidine, or sucralfate. Attempts should also be made to maintain the patient normothermic in order to optimize tissue oxygen utilization.

Hematologic Support

Hematocrit should be maintained in the 35% to 40% range with the use of packed cells transfusions. DIC frequently complicates shock. The use of vitamin K 1 mg IV, fresh frozen plasma and platelet transfusion to correct coagulation parameters may be helpful.

Nutritional Support

Nutritional support is a frequently over­looked but extremely important aspect of the care of patients in shock. The metabolic derangement in shock is characterized by increased protein breakdown which is not suppressed by protein or energy intake, reprioritisation of protein synthesis with in­creased synthesis of acute phase reactants and decreased synthesis of structural proteins, glucose and lipid intolerance, insulin resistance, hyperglycemia, lipolysis and hypertrigly­ceridemia(25). Excessive catabolism with destruction of lean body plass is common.

Enteral nutrition is more physiological and preferred in crucially ill patients, over parenteral nutrition(26). It can be successfully accomplished despite the use of maximum ventilatory support, heavy sedation and muscle relaxants and inotropic support. The contraindications to enteral feeding are those which are applicable to any patient such as ileus, obstruction, active upper GI bleed, risk of necrotising enterocolitis and those specific to critically ill child: unstable hemodynamic status requiring escalation of vasoactive drug therapy or extubation within 4 hours(27). If. unable to achieve acceptable intake within 24­36 hours, parenteral supplementation should be given.

Nasogastric tube which is placed for gastric decompression initially is converted to gastric feeding tube. Transpyloric route is preferred these days. Close monitoring of daily caloric intake and determination of serum albumin, electrolytes and liver function tests should be done. Continuing administration of vitamin and essential trace metal level is important in long term care.

Additional Therapies for Septic Shock

1. Antibiotics

In suspected septic shock antibiotics should be initiated as soon as cultures are sent. It is preferable ,to provide empirical broad spectrum antibiotic coverage taking into con­siderations, primary site of infection, local bacterial sensitivity pattern and immunocompetence of the host. A general guide to antibiotic therapy in septic shock for various age groups is shown in Table XI. In addition, pus anywhere in the body should be drained surgically.

TABLE XI

Pathogens and Initial Antibiotic Therapy in Bacterial Sepsis

Age Pathogen Antibiotics Dose/day
Neonate Gram negative Ampicillin and 100 mg/kg
  Group-B steptrococcus Cefotaxime or Gentamicin 150 mg/kg
5-7.5mg/kg
Infants
(1mo-1yr)
H. influenzae
Strep. pneumoniae
Ampicillin and Chloramphenicol or cefotaxime or ceftriaxone 100 mg/kg
150 mg/kg
Older children Stept. pneumoniae C penicillin and  
  H. influenzae Chloromphenicol
or cefotaxime
or ceftriaxone
150 mg/kg
150 mg/kg

150 mg/kg
  Staph. aureus cloxacillin plus
Gentamicin
200 mg/kg
5-7.5 mg/kg
  Pseudomonas Ceftazidime 150 mg/kg
  Enterobacteriaceae    

2. Corticosteroids

The use of corticosteroids in septic shock remains controversial. Although a recent prospective, randomized controlled trial in adult patients has once again claimed a beneficial effect of hydrocortisone on hemodynamics and survival(28) there are no well controlled trials supporting the routine use of steroids in most forms of shock. Several trials have shown no benefit of corticosteroids in the management of septic shock. The only clear indication at present for corticosteroids administration in human shock is acute adre­nal crisis with cardiovascular collapse.

3. Adjunctive Immunotherapy

With the knowledge that septic shock is produced by systemic inflammatory response, triggered by endotoxemia and consequent release of cytokines (TNF α, and IL-β particularly) the treatment of septic shock was directed towards blocking the inflammatory response (sepsis response), and counteract del­eterious effects of endotoxin. Larged studies aimed at endotoxin blockade through anti LPS antibodies, anti- TNF-α monoclonal antibodies, inhibitors of TNF-α (soluble TNF-α­receptors), anti IL-1 have proved ineffective in reducing morality(29,30). Anti-inflammatory agents such as ibuprofen, pentoxi­phylline, immunoglobulins, PAF antagonists, imflammatory cytokines all are ineffective(30). In fact a combination of TNF-α­binding proteins and IL-1 receptor antagonist was uniformly fatal in septic animals(3).

Monitoring of Shock

Monitoring patients in shock should be done with the following objectives:

1. Definition of pathophysiologic stage of shock for diagnosis, to plan treatment and predict outcome.

2. Continuous assessment of vital organ function.

3. Assessment of the efficacy of therapeutic intervention(s).

4. Early recognition of correctable problems.

Nothing can substitute for a close, repeated and careful examination of the child's physiological status. It must be made by a competent observer. The emphasis must be on ongoing clinical assessment to determine alteration in peripheral perfusion (capillary refill color), presence of cyanosis, heart rate and rhythm, characteristics of the pulse, blood pressure, respiratory pattern and level of con­sciousness. The basic minimum monitoring of a child with shock or at risk for shock should include continuous pulse oximetry and ECG monitoring, and intermittently arterial blood gases, temperature (skin, great toe and rectal/core), blood pressure (noninvasive), urine output per hour and central venous pressure (CVP). Echocardiographic evaluation of ejection fraction and ejection volume of left ventricle if available, should be done periodically for more reliable indication of myocardial performance.

Invasive hemodynamic monitoring and cardiac output monitoring improves thera­peutic interventions by allowing for more precise management of drugs and interventions. Non-invasive (bioimpedance) method of car­diac output measurement still have technical problems which have to be overcome before its use in children. Balloon tipped pulmonary artery catheter [Swan-Ganz catheter] may be used to measure pulmonary artery occlusion pressure to assess left ventricular function and estimation of cardiac output.

The temperature of great toe should nor­mally be within 2.4°C of rectal temperature. The worse the state of perfusion the colder the toe and extremities become. The trend in change in temperature gradient is helpful in monitoring adequacy of response to therapy.

A central venous pressure catheter (or a pulmonary artery catheter) is placed when there is an inadequate response to the initial fluid challenges. Although right-sided filling pressures usually reflect volume status and left heart function, in certain conditions (pulmonary disease, pneumothorax, mitral stenosis or positive pressure ventilation) this is not true. The evp actually reflects right ventricular compliance rather than volume. A poorly compliant ventricle may be volume depleted ("empty") and yet have a high filling pressure. In such cases, a pulmonary artery catheter may be used to monitor pulmonary artery occlusion pressure (PAOP) and adequacy of LV function.

A high CVP > 15 cmH2O (or PAOP > 12 mmHg) commonly indicates tension pneumothorax, pericardial tamponade, or cardiac failure (cardiogenic shock, myocardial insufficiency, myocarditis).

A decreased CVP 10 cm H2O (or PAOP,12 mm Hg) with signs of poor perfusion warrants administration of crystalloid in 10 ml/kg aliquots. If the CVP does not increase more crystalloid should be given until perfusion improves or the CVP rises by 4-5 mm Hp.

Future Directions in Drug Therapies
Antioxidant Therapy

Reactive oxygen species (ROS) mediate fine balance between cellular physiology and pathophysiology. Disruption of cellular redox hemostasis by events related to ischemia­reperfusion and inflammation lead to adaptive changes which include altered transcription and translation of antioxidant enzymes, stress proteins and cytokines. Thus, ROS may initiate as well as amplify the cellular insult associated with shock in number of ways which include important contributions to inflammation as well as lytic and apoptotic cell death.

In future, an important therapeutic goal in shock may involve reestablishing cellular redox homeostasis not only to ensure cellular structural integrity but also to reestablish normal secondary cellular signal transduction mechanism(32). Following therapies have been tried with variable success:

(i) Xanthine oxidase inhibition with Allopurinol.

(ii) Superoxide dismutase (SOD) has been shown to reduce risk of organ failure and ICU stay.

(iii) Antioxidant vitamins:- Vitamin-E and its analogs, glutathione GSH, 21-aminosteroids, iron chelators: (desferrioxamine) are all being investigated.

(iv) N-acetyl cysteine.

It should be appreciated that a number of drugs used in shock (e.g., dopamine, adrenaline, doubtamine, noradrenaline) and in ICU patients (e.g., propofol, desferoxamine, N-acetylcysteine) have demonstrated antioxidant effect. Vitamin C, β-carotene, α-tocopherol and selenium may help foster ROS clearance.

Inhibition of cAMP production with help of amrinone and ATP-MgCI2 may have benefit.

Nitric Oxide Synthetase Inhibitors

Nitric oxide (NO) is an endogenous vasodilator. It is produced from the aminoacid arginine by enzyme nitric oxide synthetase (NOS). NOS exist in constitutive (cNOS) and inducible (cNOS) isoforms. It is believed that cNOS generated NO is responsible for hypotension in septic shock(33) and may also have a myocardial depressant role(34).,NO is released partly through TNF a dependent and TNF α-independent mechanism. Studies show that children with sepsis and hypo­tension have higher concentration of nitrite and nitrates(35). It has been suggested that in­hibition of NOS using N-amino-arginine might be of therapeutic benefit in treating hypotension(36). Much work needs to be done before NOS inhibition can be used routinely in management of septic shock.

Mechanical and Artificial Cardiopulmonary Assistance

Recent advances have made available various mechanical support devices for temporary management of patients with medically refractory shock of various etiolo­gies. These very costly devices fortunately are needed for a very small proportion of patients.

l. lntra-aortic balloon counter-pulsation may be used in management of certain types of cardiogenic shock.

2. Extracorporeal membrane oxygenation: Limited success has been reported with this technique in patients with refractory shock or cardiac arrest.

Prognosis and Outcome

Aggressive and early management of shock is associated with intact survival of a child. The mortality depends upon the under­lying etiology, being as high as 50% with septic shock. Outcome is improved in patients with increased cardiac output, elevated oxygen consumption and elevated oxygen extraction without significant pulmonary disease(18). On the other hand low body temperature (<37oC), pulmonary disease, low cardiac index (3.3 l/min/m2) and decreased oxygen utilization are all poor prognostic indicators in shock.

In conclusion early detection and aggressive management, application of conventional goals of resuscitation, i.e., "ABC" for airway breathing and circulation, added by "D" for increasing the delivery of oxygen to level that meets the metabolic demands of all tissues in body and protection of various organ systems and correction of metabolic function is likely to improve the outcome of shock.                    

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