Monograf´ del Semin. Matem. Garc´ de Galdeano. 27: 405–412, (2003).

ıas ıa

Classification of shock models in system reliability
F. Mallor, J. Santos
Departamento de Estad´ ıstica e Investigaci´n Operativa, Universidad P´blica de Navarra. o u

Abstract Shock models in system reliability are usually defined by the time between two consecutive shocks, the damage caused by a shock, the system failure and the dependence relationship among the above elements. The main purpose of this work is to review and classify the large set of shock models defined and studied in the literature in the last three decades. Furthermore, we introduce a new model which generalizes some of the classical ones that arise when the system is governed by independent and identically distributed pairs, {(An , Bn )}∞ , where An is the magn=0 nitude of the nth shock and Bn is the time between the (n − 1)th and the nth shock. Keywords: Reliability, Shock model. AMS Classification: 90B25, 60K10.



We consider systems subject to shocks that occur randomly in time. Shock models have been studied by several authors and provide a realistic formulation for modelling certain reliability systems situated in random environment. Various of the models collected here are physically motivated. For instance, the extreme and cumulative shock models may be appropriate descriptions for the fracture of brittle materials, such as glass, and for the damage due to the earthquakes or volcanic activity, respectively. The way in which the time between two consecutive shocks, the damage caused by a shock, the system failure and the relationships among all these elements are modelled, characterizes a shock model. In the literature, two major types are distinguished depending on whether the effect of the shock on the system is independent of its arrival time or not. These principal models are collected in Section 2 and Section 3, respectively. In Section 4, we introduce a new shock model which generalizes some of the classical ones. Finally, we end with some remarks and conclusions.



Classic shock models with independence assumption

When independence between the shock effect and the arrival time is assumed, a sequence ¯ ¯ of surviving probabilities {Pk } is defined, being Pk the probability that the system still run after the kth shock. According to the time between consecutive shocks, these models are divided into four kinds: - homogeneous Poisson process, that is, the times between two consecutive shocks are independent, identically distributed exponential random variables; - non-homogeneous Poisson process, that is, a counting process null at the origin with independent increments where the probability of a shock in (t+∆t] is λ(t)∆t+o(∆t), while the probability of more than one shock in (t + ∆t] is o(∆t); - non-stationary pure birth process, that is, a Markov process where, given that k shocks have occurred in (0, t], the probability of a shock in (t, t + ∆t] is λk λ(t)∆t + o(∆t), while the probability of more than one shock in (t, t + ∆t] is o(∆t); - or renewal process, that is, the times between two consecutive shocks are independent and identically distributed random variables. In the simplest case, homogeneous Poisson process, conditions on the prefixed sequence ¯ ¯ {Pk } are obtained to guarantee distribution properties of the survival function H(t). For more details, see Esary et al [6]. Some of these results are extended by A-Hameed and Proschan [1] in the case of the non-homogeneous Poisson process and by A-Hameed and Proschan [2], Klefsj¨ [13] and o [14] in the case of the non-stationary pure birth process. When the shocks occur according to a renewal sequence, Skoulakis [24] describes the system failure in such a way that generalizes the previous ones. In this model, we assume that the jth shock, independent of all else, has an intensity x randomly chosen from a distribution Gj , which is supported in [0, 1] and that it may cause the failure with probability x. This shock model also has the Ross’ model [20, p. 22], the R˚ ade’s model [18] and the Nakagawa’s model [17] as particular cases. In the renewal process case, the interest is focussed on the reliability function for a component and on the extension to multi-component systems. We point out that, along these last years, several authors have incorporated elements to turn the system more realistic. For instance, Finkelstein and Zarudnij [9] add the concept of recovery to allow the system to eliminate the consequence of each shock in the following way: a r.v. τ is defined for each shock, which models the recovery time 406

from the shock. Then, if a shock occurs before the recovery time from the previous one has elapsed, the system fails. For this particular model, Finkelstein and Zarudnij obtain the reliability function for times between consecutive shocks following a non-homogeneous Poisson process. Ageing is another element that has been incorporated to some models. Fan et al [7] include this ageing notion to a compound Poisson process shock, P (λ, x), that is, a shock model where the shocks have random magnitudes x and arrive according to an homogeneous Poisson process of rate λ. In the compound Poisson process, a shock is fatal to the system with probability 1 − exp(−x), where x is the shock’s magnitude. The incorporation of ageing is carried out by means of a constant δ, the rate of ageing, in such a way that the probability of failure due to a shock of magnitude x arriving at time u is 1 − exp(−δu − x). The reliability function is also obtained and an extension to multi-component systems is provided.


Classic shock models with a dependence structure

When there exists dependence between the effect of the shock and its arrival time, the damage caused by a shock is modelled in the Fan’s way, that is, by a random variable representing the shock’s magnitude. Three principal models are considered: extreme shock model, where the system breaks down as soon as the magnitude of an individual shock exceeds some given level; cumulative shock model, where the system fails when the cumulative shock magnitude exceeds some given level and run shock model, where the system works until k consecutive shocks with critical magnitude occur. However, Agrafiotis and Tsoukalas [3] define a shock model that is an extension of the cumulative shock model: the system failure depends on the cumulative damage of those shocks with a magnitude exceeding some pre-specified threshold. The general setup in these three main shock models is a family {(An , Bn )}∞ of i.i.d. n=0 two-dimensional vectors where An represents the magnitude of the nth shock and Bn the time between the (n − 1)st and the nth shock or, alternatively, the time between the nth and the (n + 1)st shock, called model I and model II respectively. Model II differs significantly from model I in that the magnitude An of the nth shock affects future events, that is, the time interval Bn until the (n + 1)st shock. Moreover, there exists a first shock at time t = 0 in model II while A0 and B0 are assumed to be zero in the model I. Let T be the time to the system failure and {N (t), t ≥ 0}, the counting process generated by the renewal sequence {Bn }∞ . Then, for a fixed threshold z > 0, we have n=0 that, in the extreme damage case, T ≤ t ⇔ max{An |0 ≤ n ≤ N (t)} > z; in the cumulative damage case, T ≤ t ⇔
N (t) n=0

An > z; in the run case, where z is the level which defines

a shock as critical, T ≤ t ⇔ min{n|An−j > z, j = 0, 1, . . . , k − 1} ≤ N (t). 407

Under the model I and model II, the two first failure models were studied by Shanthikumar and Sumita [22], [23], [25] and Gut [10] and [11], providing the reliability function, two first moments and some results about the asymptotic behaviour of the system failure time. In the case when the interarrival time Bn has infinite mean, Anderson, [4] and [5], obtains asymptotic results for the model I. Igaki et al [12] extend the extreme and cumulative shock model under the model I incorporating the influence of the external system state after the nth shock, Jn , on the correlation structure between the shock magnitudes and the shock interarrival times. More concretely, a trivariate stochastic process {An , Bn , Jn }∞ is defined satisfying the n=0 following Markov property for all n ∈ {0, 1, 2, . . . } and j ∈ S = {1, 2, . . . , N }: P {An+1 ≤ a, Bn+1 ≤ b, Jn+1 = j|A0 , . . . , An , B0 , . . . , Bn , J0 , . . . , Jn } = P {An+1 ≤ a, Bn+1 ≤ b, Jn+1 = j|Jn } Also, temporally homogeneity is assumed so that the right hand side of the above equation is independent of n. That is, the system state changes after each shock according to a Markov process and the joint distribution of {An , Bn } is affected by transitions of the system state. The third failure model was recently introduced by Mallor and Omey [15] obtaining properties of the distribution function of the system failure time and the limit behaviour when k tends to infinity or when the probability of entering a critical set tends to zero. All these models are summarized in the Table 1.
System failure Extreme damage / Critical region (An , Bn ) D.F. of Tz [22] {(An , Bn )}∞ n=0 i.i.d pairs of correlated variables Model I Moments of Tz [22], [11] Properties of Tz [23] Asymptotic behaviour •E[B] < ∞ [22], [11] •E[B] = ∞ [4] Random environment [12] {(An , Bn )}∞ n=0 i.i.d pairs of correlated variables Model II D.F. of Tz [22] Moments of Tz [22] Properties of Tz [23] Asymp. behaviour •E[B] < ∞ [3] {(An , Bn )}∞ n=0 independent but not necessarily identically distributed pairs of correlated variables Model I Asymp. behaviour [11] Cumulative damage P Ai > z D.F. of Tz [25], [3] Moments of Tz [25], [3] Properties of Tz [25] Asymp. behaviour •E[B] < ∞ [25], [10], [3] •E[B] = ∞ [5] Random environment [12] D.F. of Tz [25] Moments de Tz [25] Properties of Tz [25] Asymp. behaviour •E[B] < ∞ [25], [10] D.F. of Tz [15] Moments [15] Asymp. behaviour [15] k consecutive shocks with (A, B) ∈ R

Table 1: Correlated effect and interarrival shock time



Definition of a new general model

We consider a system subject to shocks. Let An denote the magnitude of the nth shock and Bn the time between the (n − 1)st and the nth shock. Let R ⊆ R be a prefixed real subset. We say that the nth shock is a critical shock if An ∈ R. Also, we say that k consecutive shocks form a critical run of length k if all of them are critical and they are not contained in any sequence of k + 1 consecutive critical shocks. We define a complete run of length k + 1 as a critical run of length k immediately followed by a non critical shock. In order to model the damage caused by a shock, we introduce a new set of random variables dj , j = 0, 1, . . . . The variable d0 represents the damage due to a non critical shock and we assume it to be zero. For j ≥ 1, the variable dj represents the damage caused by a shock when it occupies the jth place in a critical run. That is, the nth shock causes a damage dj if An−i ∈ R, for i = 0, 1, . . . , j − 1 and An−j ∈ R, / An ∈ R, / for n ≥ j ≥ 1; for j = 0.

The system fails as soon as the accumulated damage due to the random variables dj ’s exceeds a fixed threshold z > 0. For our model we suppose that the defined random variables verify the following stochastic assumptions: a) {dj }∞ is a family of nonnegative and independent but not necessarily identically j=0 distributed random variables. We also assume that d0 = 0; b) for each j ≥ 0, {(An , Bn , dj )}∞ are nonnegative, independent random vectors, all n=1 of them equally distributed as the random vector (A, B, dj ); c) we do not impose any condition of independence among the variables A, B and dj for all j ≥ 0. In brief, our model is governed by a sequence of random vectors of three correlated variables which represent the magnitude of the shock, the intershock time and the damage caused by the shock, respectively. Note that this general shock model extends the model I in the cases of cumulative damage, extreme damage and run damage. The distribution function of the system failure time and its mean value are provided via Laplace transforms in Mallor and Santos [16].



Final remarks and conclusions

The models where a probability is attached to each shock bring together the cumulative ¯ and extreme shock models defining adequately the sequence {Pk } and are studied as particular cases by A-Hameed and Proschan [1] and Esary et al [6]. Let Fj be the distribution function of the damage caused by the jth shock, then for the cumulative shock model ¯ ¯ Pk = F1 ∗ F2 ∗ · · · ∗ Fk (z) and for the extreme shock model Pk = k Fj (z).

As before, different elements are incorporated to get a more realistic model such as the assumption of a random threshold instead of a prefixed z and the stochastically decrease of the sequence {Fk }∞ . k=1

System Interarrival shock time failure

General failure model k Y ¯ Pk = (1 − pj )

Cumulative shock damage Xi i.i.d

Cumulative shock damage independent Xi and Fi (z) decreasing in i •Independent Xi and Fi (x) decreas. in i ¯ H(t) : IF R [6] • Ageing ¯ H(t) : IF R [6] and dual [6] • Random threshold [6] h(t) : log-concave Extreme shock damage

¯ Sufficient conditions on Pk ¯ H(t) : IF R, IF RA Homogeneous Poisson process of rate λ ∞ X (λt)k −λt ¯ ¯ e H(t) = Pk k! k=0 N BU, N BU E, DM RL h(t) : P F2 , P Fn and dual [6] ¯ H(t) : HN BU E, HN W U E [14] h(s + t) : SCn [6] • Ageing [7] • Recovery [9] Sufficient conditions on ¯ Pk and Λ(t) Non-homogeneous Poisson process ∞ X (Λ(t))k −Λ(t) ¯ e Pk k! k=0 ¯ H(t) : IF R, IF RA N BU, N BU E, DM RL h(t) : P F2 and dual [1] ¯ H(t) : HN BU E, HN W U E [14] • m components [21] • Recovery [9] Non-stationary Pure birth process ∞ X ¯ ¯ H(t) = sk (t)Pk h(t) =
∞ X k=0 k=0

¯ Pk = F (k) (z) ¯ H(t) : IF RA, IF R h(t) : P F2 [6] • Random threshold [6] ¯ H(t) : IF R, IF RA, N BU h(t) : P F2 • l kinds of shocks ind. [6] ¯ H(t) : IF RA

¯ Pk = F1 ∗ · · · ∗ Fk (z) ¯ H(t) : IF R, IF RA [6] h(t) : P F2 [6] • Random threshold [6] ¯ H(t) : N BU • Dependence [6] ¯ H(t) : IF RA

• m components in series ¯ H(t) : IF RA • m components in series with random threshold ¯ H(t) : IF RA, N BU and dual [1] ¯ H(t) : IF RA [19]

¯ H(t) =

¯ Conditions on Pk , λk , λ(t) ¯ H(t) : IF R, IF RA N BU, N BU E, DM RL h(t) : P F2 and dual [2] ¯ H(t) : HN BU E, HN W U E [13] ¯ H(t) : IF RA, DF RA [13] Reliability function for pk • indep. of k [18]

sk (t)λk λ(t)pk+1

sk (t) = P {k shocks in [0, t]}

Renewal process

• dep. of k [17] • indep. of k and random [20] • dep. of k and random [24]

Asymp. behaviour of Tz [25]

Table 2: Independence between the effect and interarrival shock time Ross [19] extends these two failure modes defining a new damage function Dt such that: - Dt (x1 , . . . , xn , . . . , 0) represents the damage at time t if exactly n shocks having magnitudes x1 , . . . , xn have occurred by time t, with 0 = (0, 0, . . . ); - Dt is nondecreasing in each of its arguments for t ≥ 0; 410

- Dt (x1 , . . . , xn , 0) = Dt (xi1 , . . . , xin , 0) whenever (i1 , . . . , in ) is a permutation of 1, 2, . . . , n for all n. By taking Dt (x1 , . . . , xn , 0) = max{x1 , . . . , xn } or Dt (x1 , . . . , xn , 0) = summarized in the Table 2. In this work, we have presented the main shock reliability models studied in the literature which, as far as we know, have not been analysed jointly. So, this task facilitates us to see what has been done and, what is more important, what is still to be done.
n i=1

xi , we

obtain the cumulative and the extreme shock model respectively. All these models are

[1] A-Hameed, M.S. and Proschan, F. (1973). Nonstationary shock models. Stochastic Processes and their Applications, Vol. 1, No. Oct.; 383-404. [2] A-Hameed, M.S. and Proschan, F. (1975). Shock models with underlying birth process. Journal of Applied Probability 12; 18-28. [3] Agrafiotis, G.K. and Tsoukalas, M.Z. (1995). On excess-time correlated cumulative processes. Journal of the Operational Research Society 46; 1269-1280. [4] Anderson, K.K. (1987). Limit theorems for general shock models with infinite mean intershock times. Journal of Applied Probability 24; 449-456. [5] Anderson, K.K. (1988). A note on cumulative shock models. Journal of Applied Probability 25; 220-223. [6] Esary, J.D., Marshall, A. W. and Proschan, F. (1973). Shocks models and wear processes. The Annals of Probability Vol. 1, No.17; 627-649. [7] Fan J., Ghurke S.G. and Levine R.A. (2000). Multicomponent lifetime distributions in the presence of ageing. Journal of Applied Probability 37, 521-533. [8] Feller, W. (1968). An Introduction to Probability Theory and its Applications, Vol. 1. New York. Wiley & Sons. [9] Finkelstein M.S. and Zarudnij V.I. (2001). A shock process with non-cumulative damage. Reliability Engineering & System Safety 71, 103-107. [10] Gut, A. (1990). Cumulative shock models. Advances in Applied Probability 22; 504-507. [11] Gut, A. (1999). Extreme shock models. Extremes 2:3; 295-307. [12] Igaki, N., Sumita, U. and Kowada, M. (1995). Analysis of Markov renewal shock models. Journal of Applied Probability 32; 821-831. ¨ [13] Klefsjo, B. (1981). Survival under the pure birth shock model. Journal of Applied Probability 18; 554-560.


¨ [14] Klefsjo, B. (1981). HNBUE survival under some shock models. Scandinavian Journal of Statistics 8; 39-47. [15] Mallor, F. and Omey, E. (2001). Shocks, Runs and Random Sums. Journal of Applied Probability 38; 438-448. [16] Mallor, F. and Santos, J. Reliability of systems subject to shocks with a stochastic dependence for the damages. Submitted. [17] Nakagawa, T. (1979). Further results of replacement problem of a parallel system in random environment. Journal of Applied Probability 16; 923-926. [18] R˚ ade, L. (1976). Reliabilty systems on random environment. Journal of Applied Probability 34; 407-410. [19] Ross, S.M. (1981). Generalized Poisson shock models. The Annals of Probability 9; 896-898. [20] Ross, S.M. (1983). Stochastic Processes. New york; John Wiley & Sons. [21] Savits T.H. (1988). Some multivariate distributions derived from a non-fatal shock model. J. Appl. Prob. 25, 383-390. [22] Shanthikumar, J.G. and Sumita, U. (1983). General shock models associated with correlated renewal sequences. Journal of Applied Probability 20; 600-614. [23] Shanthikumar, J.G. and Sumita, U. (1984). Distribution properties of the system failure time in a general shock model. Journal of Applied Probability 16; 363-377. [24] Skoulakis, G. (2000). A general shock model for a reliability system. Journal of Applied Probability 37; 925-935. [25] Sumita, U. and Shanthikumar, J.G. (1985). A class of correlated cumulative shock models. Advances in Applied Probability 17; 347-366.


SETHI, J. Anaesth. 2003; 47 (5) : 345-359 Indian SHARMA, MOHTA, TYAGI : SHOCK


Dr. A. K. Sethi1 Dr. Prakash Sharma2 Dr. Medha Mohta3 Dr. Asha Tyagi4
Introduction The syndrome of shock in humans is often the final pathway through which a variety of pathologic processes lead to cardiovascular failure and death. As such, shock is perhaps the most common and important problem with which the critical care physicians contend. It is one of the most common causes of death in the United States today and, together with respiratory failure, accounts for most emergent intensive care unit (ICU) admissions.1 The magnitude of the problem of shock is illustrated not only by absolute numbers of deaths but also in the high mortality percentages seen with various types of shock. History Despite recognition of a post traumatic syndrome by Greek physicians such as Hippocrates and Galen, the origin of the term shock is generally credited to the French surgeon Henri Francois Le Dran, who in 1737 defined the same as “A treatise of reflections drawn from experience with gunshot wounds” and coined the term choc to indicate a severe impact or jolt.2 An inappropriate translation by the English physician Clare, in 1743, led to the introduction of the word “shock” to the English language to indicate the sudden deterioration of a patient’s condition when major trauma has occurred.2 It was Edwin A. Moses,3 who began to popularize the term, using it in his article “A practical treatise on shock after operations and injuries” in 1867. Definition of Shock The definition of shock has evolved in parallel with our understanding of the phenomenon and many definitions of shock have appeared.5 Until the late 1800’s, the term shock was used to indicate the immediate response to massive trauma, without regard to a specific post trauma syndrome. Later, with the introduction of noninvasive blood pressure monitoring devices, most clinical definitions of shock added the requirement of
1. 2. 3. 4. M.D., D.A., Professor and Head M.D., D.N.B., Senior Resident M.D., Reader M.D., DNB, Lecturer Department of Anaesthesiology and Critical Care, U.C.M.S. and G.T.B. Hospital, Shahdara, Delhi, India - 110095 Correspond to : E-mail:

arterial hypotension.4 But current technology, which allows assessment of perfusion independent of arterial pressure, has shown that hypotension does not define shock. The emphasis in defining shock is on tissue perfusion in relation to cellular function. Thus, the most appropriate definition of shock is “the state in which profound and wide spread reduction of effective perfusion leads first to reversible, and then, if prolonged, to irreversible cellular injury.5 Classification A classification based on cardiovascular characteristics, which was initially proposed in 1972 by Hinshaw and Cox,6 is the most accepted one amongst many others that have been given. It divides the syndrome into four major categories: hypovolemic, cardiogenic, extracardiac obstructive and distributive (Table 1). However, this is just an artificial separation and there is a frequent, considerable initial mixing and overlap within these categories. (i) Hypovolemic Shock It is characterized by a loss in circulatory volume, which results in decreased venous return, decreased filling of the cardiac chambers, and hence a decreased cardiac output which leads to increase in the systemic vascular resistance (SVR). The haemodynamic profile on monitoring of flow pressure variables shows low central venous pressure (CVP), a low pulmonary capillary wedge pressure (PCWP), low cardiac output (CO) and cardiac index (CI), and high SVR. The arterial blood pressure may be normal or low. Cardiogenic Shock This is primarily dependent on poor pump function. Cardiogenic shock due to acute catastrophic failure of left ventricular pump function is characterized by high PCWP, low CO and CI, and generally a high SVR.


(iii) Distributive or Vasogenic shock This type of shock is associated with not only poor vascular tone in the peripheral circulation but maldistribution of blood flow to organs within the body also. The CO varies, but is usually raised. A common haemodynamic profile is a low or normal PCWP, a high CO, a low arterial blood pressure, and a low SVR.



Table - 1 : Classification of shock6
HYPOVOLEMIC (oligemic) • Hemorrhagic Trauma Gastrointestinal Retroperitoneal • Fluid depletion (nonhemorrhagic) External fluid loss Dehydration Vomiting Diarrhea Polyuria Interstitial fluid redistribution Thermal injury Trauma Anaphylaxis Increased vascular capacitance (venodilatation) Sepsis Anaphylaxis Toxins/Drugs

(iv) Extracardiac obstructive shock It is associated with a physical impairment to adequate forward circulatory flow involving mechanisms different than primary myocardial or valvular dysfunction. Several hemodynamic patterns may be observed, depending on the cause, from frank decrease in filling pressures (as in mediastinal compressions of great veins); to trends towards equalization of pressures in the case of cardiac tamponade; or to markedly increased right ventricular filling pressures with low PCWP in the case of pulmonary embolism. Cardiac output is usually decreased with increased SVR. Pathophysiology Shocks of all form involve common cellular metabolic processes that typically end in cell injury, organ failure and death.7 The pathogenesis of shock involves multiple interrelated factors including (a) cellular ischemia, (b) circulating or local inflammatory mediators, and (c) free radical injury. (a) Ineffective perfusion leading to cellular ischemia plays a major role in cellular injury in most forms of shock. Hypoperfusion decreases the delivery of nutrients to the cells leading to diminished ATP production.8 Essential ATP dependent intracellular metabolic processes that may be affected include maintenance of transmembrane potential, mitochondrial function9 and other energy-dependent enzyme reactions. Liver and kidney are particularly sensitive as intracellular levels of ATP fall and ATPdependent processes are impaired.8,10-13 Lysosomal disruption is the point of irreparable cell damage analogous to clinical irreversibility. Worsening of shock, organ failure, and death may result. The effect of inflammatory mediators on cellular metabolism is of prime importance in organ dysfunction resulting from sepsis and septic shock and also hemorrhagic shock associated with extensive trauma.14,18 Generally, it is the endotoxin from gram negative bacteria that triggers the inflammatory cascade but bacterial antigens and cell injury it self can also initiate the cascade. Macrophage production of cytokines such as TNF-a and IL-1b appear to be the prime mediators.19 Other substances involved in the inflammatory process include IL-2, IL-6, interferon-a, endothelin-1, leukotrienes, thromboxanes, prostaglandins and complement fragments C3a and C5a.19,20 Two other mediators, circulating myocardial depressant substance and nitric oxide have a role to play in septic shock.23,24,25

CARDIOGENIC • Myopathic Myocardial infarction Left ventricle Right ventricle Myocardial contusion (trauma) Myocarditis Cardiomyopathy Post ischemic myocardial stunning Septic myocardial depression Pharmacologic Anthracycline cardiotoxicity Calcium channel blockers • Mechanical Valvular failure Regurgitant Obstructive Hypertropic cardiomyopathy Ventricular septal defect Arrhythmic Bradycardia Sinus (e.g., vagal syncope) Atrioventricular blocks Tachycardia Supraventricular Ventricular

EXTRACARDIAC OBSTRUCTIVE • Impaired diastolic filling (decreased ventricular preload) Direct venous obstruction (vena cava) Intrathoracic obstructive tumors Increased intrathoracic pressure Tension pneumothorax Mechanical ventilation (with positive end-expiratory pressure [PEEP], autoPEEP or volume depletion) Asthma (with auto PEEP) Decreased cardiac compliance Constrictive pericarditis Cardiac tamponade Acute Post-MI free wall rupture Traumatic Hemorrhagic Chronic Malignant Uremic Idiopathic • Impaired systolic contraction (increased ventricular afterload) Right ventricle Pulmonary embolus (massive) Acute pulmonary hypertension Left Ventricle Saddle embolus Aortic dissection


DISTRIBUTIVE Septic (bacterial, fungal, viral, rickettsial) Toxic shock syndrome Anaphylactic, anaphylactoid Neurogenic (spinal shock) Endocrinologic Adrenal crisis Toxic (e.g., nitroprusside, bretyllium)




Free radical injury induced by reperfusion or neutrophil activity is another mechanism by which cell and organs suffer a damage.26,27 Tissue ischemia leads to accumulation of adenosine, inosine and hypoxanthine.28 With resuscutation, reperfusion of ischemic areas occurs. The availability of O2 generates superoxide (O2-) by xanthine oxidase which is converted to hydrogen peroxide (H2O2) which further reacts to produce the highly reactive tissue damaging hydroxyl radicals. These inturn interact with critical cell targets resulting in cell lysis and tissue injury. Oxidant activity, directly and through endothelial damage attracts and activates neutrophils causing amplification of superoxide generation and further tissue damage due to neutrophil protease release.27

absent. All compensatory responses to shock, whether hemodynamic, metabolic or biochemical, support oxygen delivery to vital organs. These responses are similar for varying classes of shock and are divided into four categories (Table 2): (a) (b) (c) (d) Maintenance of mean circulatory pressure Maximizing cardiac function Redistributing perfusion to vital organs Optimizing unloading of oxygen at tissues

Table - 2 : Cardiovascular/Metabolic compensatory responses to shock5
Maintain Mean Circulatory Pressure (venous pressure) • Volume - Fluid redistribution to vascular space From interstitium (Starling effect) From intracellular space (Osmotic effect) - Decreased renal fluid losses Decreased glomerular filtration rate (GFR) Increased aldosterone Increased vasopressin Pressure - Decreased venous capacitance Increased sympathetic activity Increased circulating (adrenal) epinephrine Increased angiotensin Increased vasopressin Maximize Cardiac Performance - Increased contractility Sympathetic stimulation Adrenal stimulation Redistribution of Perfusion - Extrinsic regulation of systemic arterial tone - Dominant autoregulation of vital organs (heart, brain) Optimize Oxygen Unloading - Increased RBC 2, 3 DPG - Tissue acidosis - Pyrexia - Decreased tissue PO2

Microvascular function in shock Microvessels (100-150mm diameter) is one of the key determinants of appropriate tissue perfusion during shock. Adequate cardiac output as well as normal local and systemic microvascular function ensure that specific tissues are effectively perfused. Distribution of cardiac output involves local intrinsic autoregulation and extrinsic regulation mediated by autonomic tone and humoral factors. Blood flow to individual organs may be affected by system wide changes in microarteriolar tone or by local alteration in metabolic activity. It is the precapillary arterioles and precapillary and postcapillary sphincters that are responsible for these tasks. During both irreversible hemorrhagic and septic shock, peripheral vascular failure results. The potential mechanisms are (a) tissue acidosis29 (b) catecholamine depletion and mediator related vascular resistance to catecholamine30,33 (c) release of arachidonic acid metabolites34-36 (d) nitric oxide generation23,37,38 and (e) decreased sympathetic tone due to altered central nervous system (CNS) perfusion.39 Other microvascular pathologic processes occurring in shock include disruption of integrity of endothelial cell barrier leading to loss of plasma proteins, decrease in plasma oncotic pressure, interstitial edema and fall in circulating volumel.40,41 In addition, there is microvascular clotting and microthrombi leading to further inadequate distribution of perfusion within tissue.42,43 Compensatory Responses to Shock With the onset of hemodynamic dysfunction, homeostatic compensatory mechanisms engage to maintain adequate tissue perfusion. At this stage, signs and symptoms of hemodynamic stress may be apparent (i.e., tachycardia, decreased urine output) but overt evidence of shock (i.e., hypotension, altered sensorium, metabolic acidosis) are

Mean circulatory pressure (and venous return) is sustained in early shock not only by sympathetic activation44,45 causing precapillary vasoconstriction but also by decrease in capillary hydrostatic pressure causing influx of interstitial fluid into the vascular compartment.46 The intravascular volume may also be supported by the osmotic activity of glucose generated by glycogenolysis.47 Intravascular volume is maintained by decreasing renal fluid looses and by release of rennin from juxtaglomerular apparatus.48 Rennin converts angiotensinogen into angiotensin I which is further metabolized to angiotensin II49 which causes aldosterone release. This in turn, increases sodium reabsorption in the distal tubules of the kidney. Angiotensin II is also a potent vasocontrictor particularly on mesenteric vessels and increases sympathetic



out flow and adrenal epinephrine release.49,50 Vasopressin released also causes water retention and vasoconstriction particularly of the splanchnic circulation.51 Cardiac functions are augmented by local release of norepinephrine by sympathetic nerves and systemic release of epinephrine, which stimulate cardiac a and b adrenergic receptors. During shock, increased sympathetic vasoconstrictor tone, systemic release of epinephrine from the adrenals, vasopressin and angiotensin II cause vasocontriction in all sensitive vascular beds, including skin, skeletal muscle, kidney and splanchnic organs. The vascular supply of the brain and heart is spared causing effective redistribution of flow to these vital organs.44,45 Tissue ischemia results in local acidemia, which causes a decreased affinity between oxygen and haemoglobin.56,57 Also, systemic alkalemia due to respiratory alkalosis leads to rapid increases of erythrocytes 2,3 diphosphoglycerate (DPG). Both of these cause rightward shift of oxyhaemolobin dissociation curve. Effect of shock on various organ systems (Table 3) (1) Brain - Though CNS neurons are extremely sensitive to ischemia, the vascular supply is highly resistant to extrinsic regulatory mechanisms. Patients without a primary cerebrovascular impairment, support their cerebral function well until the mean arterial pressure falls below approximately 50-60 mmHg.58,59 At this point, irreversible ischemic injury may occur to the most sensitive areas of the brain i.e., cerebral cortex and water shed areas of the spinal cord.58,59 Before such injury, an altered level of consciousness varying from confusion to unconsciousness may be seen depending on the degree of perfusion deficit. Electroencephalographic (EEG) recordings demonstrate non-specific changes compatible with encephalopathy. (2) Heart - The major clinically apparent manifestations of shock result from sympatho adrenal stimulation. Heart rate is usually increased except in case of severe haemorrhage where vagally mediated paradoxical bradycardia may occur.60,61 In addition, catecholamine driven supraventricular tachycardia and ventricular ectopy with ichaemic ECG changes (in patients predisposed to myocardia ischaemia) may be seen. Systemic hypotension compromises coronary perfusion leading to overt ischemia in high risk patients.62 Circulating myocardial depressant factors contribute to myocardial depression in septic21,22 and haemorrhagic shock. Unless shock is of cardiac origin, the heart usually plays a participatory role in which it is unable to compensate fully for arterial hypotension caused by hypovolemia, vasodilatation, or other factors.63

Table - 3 : Organ system dysfunction in shock5
Central Nervous System Heart Encephalopathy (ischemic or septic) Cortical necrosis Tachycardia, Bradycardia, Supraventricular tachycardia, Ventricular ectopy, Myocardial depression Acute respiratory failure, Adult respiratory distress syndrome Prerenal failure, Acute tubular necrosis Ileus Erosive gastritis, Pancreatitis, Acalculous cholecystitis, Colonic submucosal hemorrhage, Transluminal translocation of bacteria/antigens Ischemic hepatitis”Shock” liver intrahepatic cholestasis Disseminated intravascular coagulation, Dilutional thrombocytopenia Hyperglycemia, Glycogenolysis, Gluconeogenesis, Hypoglycemia (late), Hypertriglyceridemia Gut barrier function depression, Cellular immune depression, Humoral immune depression

Pulmonary Kidney Gastro-Intestinal

Liver Hematologic Metabolic Immune System


Respiratory system - Increased respiratory drive resulting from peripheral stimulation of pulmonary J receptors and carotid body chemoreceptors, as well as hypo-perfusion of the medullary respiratory center results in increased minute volume (tachypnea, hyperpnea), hypocapnia and primary respiratory alkalosis.64 With increased minute volume and decreased cardiac output, the V/Q ratio is increased. Coupled with an increased workload, respiratory and diaphragmatic muscle impairment caused by hypoperfusion may lead to early respiratory failure.65,66 If shock is not promptly reversed and the initiating condition controlled adult respiratory distress syndrome (ARDS) may develop. Kidney - Oliguria, as defined by a urinary output less than 0.5 mlkg-1hour is a cardinal manifestation of shock. Sympathetic stimulation, circulating catecholamines, angiotensin, and locally produced prostaglandin contribute to afferent arteriolar vasoconstriction and the redistribution of blood flow away from cortex to the medulla.63,67,68 The net effect is a decreased glomerular filtration rate. The three pathologic changes seen are (a) tubular necrosis (b) tubular obstruction by casts or debris and (c) tubular epithelial damage. It is because of these pathologic changes that restoration of normal hemodynamic function does not often lead to an immediate improvement in renal function. Urine produced during shock often reflects the pathophysiologic changes occurring in kidney. If




reflex vasoconstricting mechanisms predominate (i.e., hypovolemic and cardiogenic shock), the urine has an osmolality in excess of 450 mosmlL-1, sodium concentration of less than 20 mmolL-1, fractional excretion of sodium less than 1% and a urine to plasma creatinine ratio of over 40. However, with acute tubular necrosis the osmolality of urine decreases to less than 350 mosmlL-1, sodium concentration gets over 40 mmolL-1 with fractional excretion of sodium of over 2% and a urine to plasma creatinine ratio of less than 20.69 (5) Gastrointestinal - Typical clinical manifestations of hypoperfusion, sympathetic stimulation and inflammatory injury associated with shock includes ileus, erosive gastritis, pancreatitis, acalculous cholecystitis and colonic submucosal hemorrhage.70,71,72 Also, enteric bacteria and antigens translocate from the gut lumen into the systemic circulation during gut ischemia causing irreversible shock.73,74 Liver - Centrilobular injury with mild increases of transaminases and lactate dehydrogenase usually peaks within 1-3 days of ischemic insult and resolves over 3-10 days. ‘Shock liver’ associated with massive ischemic necrosis and a major elevation of transaminases is atypical in the absence of extensive hepatocellular disease.75 In both, only mild increases in bilirubin and alkaline phosphatase is seen in early shock. Though, the clnical manifestations are not apparent in early stages of shock, as the organ participates in the release of acute phase reactants but synthetic functions may be impaired with decreased generation of prealbumin, albumin and hepatic coagulation factors.76 Biliary stasis with increased bilirubin uptake and alkaline phosphatase may be seen after hemodynamic resolution of the shock. Hematologic - Disseminated intravascular coagulation (DIC) characterized by microangiopathic hemolysis, consumptive thrombocytopenia, consumptive coagulopathy and microthrombi with tissue injury is seen commonly in septic shock. Dilutional thrombocytopenia after volume replacement is associated with hemorrhagic shock.77 Metabolic - In early shock, sympathoadrenal activity is enhanced causing increased release of adreno corticotrophic hormones (ACTH), glucocorticolds and glucagons and decreased release of insulin.78 Also, glycogenolysis and gluconeogensis contribute to hyperglycemia. Later, glycogen depletion or failure of hepatic glucose synthesis leads to hypoglycemia.79

Fatty acid initially increase but later with hypoperfusion of adipose containing peripheral tissue, levels fall.80 Increased catecholamines, glucocorticoids and glucagon increase protein catabolism causing negative nitrogen balance.78,80 Catecholamine stimulation and reduced lipoprotein lipase expression also causes hypertriglyceridemia.78,81 (9) Immune system - Compromised immune functions are due to injury to barrier mucosa especially of the gut; parenchymal tissue injury from associated trauma, or free radical injury; and direct ischemic or mediator induced dysfunction of cellular and humoral immune system.82,83


Diagnostic Approach and Evaluation Shock is an end-stage of a continuum of progressive physiologic derangements. It is imperative, therefore, that clinicians recognize the early stages of shock at a time when it is more responsive to treatment. A monitored physiologic approach to therapy provides the best opportunity for successful outcome and avoidance of organ dysfunction. Not only the initial resuscitative technique but continuous evaluation of the patient’s condition is important. (Table 4)
Table - 4 : General Approach to Shock: Initial Diagnosis and Evaluation5
Clinical (primary diagnosis) Tachycardia, tachypnea, cyanosis, oliguria, encephalopathy (confusion), peripheral hypoperfusion (mottled extremities), hypotension (systolic blood pressure < 90 mm Hg; mean arterial pressure <65 mm Hg) Hemoglobin, WBC, platelets PT/PTT Electrolytes, arterial blood gases Ca, MgBUN, creatinine Serum lactate ECG Continuous ECG and respiratory monitors Arterial pressure catheter Central venous pressure monitor (uncomplicated shock) Pulmonary artery flotation catheter Cardiac output Pulmonary wedge pressure Mixed venous oxygen saturation (intermittent or continuous)* Oxygen delivery (Do2) and oxygen consumption (VO2)* Oximetry* Transcutaneous oxygen tension* Gastric intramucosal pH* Echocardiogram (functional assessment)* Chest radiograph Radiographs of abdomen* Computerized axial tomogram (CT scan), abdomen or chest* Echocardiogram (anatomic assessment)* Pulmonary perfusion scan*

Laboratory (confirmatory)







Clinical presentation This varies with the previous level of organ function, compensatory mechanisms, severity of organ dysfunctions and the cause of shock syndrome. Impending shock is characterized by the typical compensatory response to cardiovascular stress. Tachycardia, tachypnea and oliguria are the hall mark. Cool extremities are seen in hypodynamic shock. With progression, blood pressure falls and frank hypotension (MAP<60-65mmHg) ensues. With further progression, anuria, mottled, dusky extremities and altered sensorium occurs. (Table 5)
Table - 5 : Clinical Recognition of Shock5
ORGAN SYSTEM CNS SYMPTOM OR SIGN Mental status changes Pinpoint pupils Circulatory Heart Tachycardia Other dysrhythmias Hypotension CAUSES Decreased Cerebral perfusion Narcotic overdose Adrenergic stimulation, depressed contractility Coronary ischemia Depressed contractility secondary to ischemia or MDFs, right ventricular failure Valvular dysfunction, VSDDecreased SVR, decreased venous return Hypovolemia, decreased venous return Right heart failure Aortic dissection Pulmonary edema, respiratory muscle fatigue, sepsis, acidosis Hypoxemia Decreased perfusion, afferent arteriolar vasoconstriction Vasoconstriction, sympathetic stimulation Anaerobic metabolism, hepatic dysfunction Infection

detailed sediment analysis, serum amylase level; and arterial blood gases (ABG). Leucocyte count is frequently elevated early in shock caused by demargination of neutrophils. Leucopenia is found in sepsis and late shock. Haemoglobin level varies with the type of shock. Stress of circulatory shock increases platlet count initially but with proression thrombocytopenia occurs. BUN and creatnine rarely change after the acute creatinine onset of shock, even if renal injury is present. ABG determines the adequacy of oxygenation and acid base status. Serial serum lactate levels are used in the assessment of prognosis and levels of >2meqL-1 represent tissue ischemia. Pregnancy test should be performed in all females of child bearing age. A 12 lead ECG is critical for diagnosis of ischemic cardiac injury either as a primary cause of cardiogenic shock or secondary to hypotension associated with other shocks. Chest radiograph is also a must. Other studies should be considered in specific conditions and may include blood, sputum and urine gram stains and cultures in all cases of suspected sepsis. More detailed imaging studies like CT scans, abdominal radiographs or ultrasound, surface or transesophageal echocardiograms84,85 ventilation/perfusion scan, angiograms and cardiac isoenzymes86 may be ordered for as and when required. Typing and crossmatching for several units of packed RBC’s and fresh frozen plasma should be asked for when a significant blood loss is observed, anticipated, or suspected. Invasive hemodynamic monitoring Arterial pressure catheter is a must for all patient suspected of having circulatory shock. Marked peripheral vasoconstriction may make the assessment of blood pressure by manual sphygmomanometry or automated noninvasive oscillometric technique inaccurate.87 Also, continuous monitoring of the rapidly changing hemodynamic status of unstable patients and access for ABG samples is available with arterial catheter in place. Central venous pressure monitoring is not an accurate means of monitoring volume resuscitation and should be used only as a rough guide. An initially low CVP (i.e., less than 5mmHg) may indicate hypovolemia and a CVP more than 15mmHg with an absent Y descent suggests cardiac tamponade in the appropriate clinical setting. As a rule, CVP monitoring is inadequate for the hemodynamic assessment of critically ill patients and also it does not accurately estimate left ventricular preload in critically ill patients.88,89


New murmurs Hypotension Decreased JVP Increased JVP Disparate peripheral pulses


Tachypnea Cyanosis

Renal Skin Other

Oliguria Cool, clammy Lactic acidosis Fever

Laboratory studies There are used not only for confirmation of diagnosis of shock but also to know the etiologic factors. Initial laboratory tests should include a complete chemistry profile with serum electrolytes, creatinine, blood urea nitrogen (BUN), liver function tests, calcium, magnesium and phosphate levels, a complete blood count and differential; a platlet count; serum lactate levels; prothrombin and activated partial thromboplastin times, urinalysis with a



Flow directed ballon tipped pulmonary artery catheter with thermodilution cardiac output determination capability have become the standard practice for the hemodynamic assessment of circulatory shock.90,91,92 Continuous monitoring of central venous and pulmonary artery waveforms and pressures is also provided by them. It is also useful for etiologic classification of shock, determination of optimal management and response to the therapy. Mixed venous oxygen saturation provides an assessment of adequacy of resuscitation of low output states before the presence of anaerobic metabolism. Normal SVo2 falls within 65%-75% range. SVo2 rises with increases of perfusion above requirements and falls, with increasing oxygen extraction ratio, as perfusion become inadequate. Oxygen delivery and oxygen consumption variables can also be determined using pulmonary artery catheterderived data. But, the utility of this data is controversial when applied to individual patients. Recent modification to the standard pulmonary artery floatation catheter allows continuous monitoring of SVo2 or determination of right ventricular ejection fractions and volumes though they have no defined role at this time in clinical shock management. Ancillary monitoring techniques Pulse oximetry has a limited use in the acute management of circulatory shock and may be more helpful in the post resuscitation monitoring. Transcutaneous and transconjunctival oxygen tension measurements are newer noninvasive techniques for determining tissue oxygen tensions.93,93,95 Gastric mucosal pH is also a noninvasive method for assessment of adequacy of tissue oxygenation/ perfusion. It correlates well with systemic and organ oxygen consumption, organ failure and outcome in critically ill patients.96,97 Normalization of gastric mucosal pH is also one of the target during resuscitation of circulatory shock. Echocardiography in the ICU not only detects the anatomic lesions but also allows direct measurement of cardiac output, stroke volume, preload, systolic contractility, diastolic function and regional motion abnormalities.99 There are other promising noninvasive monitoring devices i.e, near-infrared spectroscopy to detect oxygen availability and utilization at tissue level and thoracic electrical bioimpedance for continuous cardiac output measurements. These could be used with high risk patients to detect “compensated states”, before clinical hemodynamic instability is evident. But, more studies and refinement are necessary before the ‘golden standard’ (pulmonary artery catheter with a thermistor tip) can be

challenged.100,101-105 Management and Therapy Patients in shock should be managed in ICU with continuous ECG monitoring and close nursing support. Invasive hemodynamic monitoring with arterial and pulmonary artery catheters should be instituted in those indicated i.e., patients in whom etiologic diagnosis is in doubt, whose hemodynamic instability does not quickly resolve with intravenous fluids etc., laboratory tests as mentioned before should be performed the earliest possible. Management of shock can be divided into specific therapy for triggering injury and general therapy of the shock syndrome. (Table 6)
Table - 6 : General approach to shock: Immediate goals5
Hemodynamic MAP>60-65 mm Hg (higher in the presence of coronary artery disease or chronic hypertension) PWP = 12 to 18 mm Hg (may be higher for cardiogenic shock) CI>2.1 Lmin-1m-2 for cardiogenic and obstructive shock>3.0 to 3.5 Lmin-1m-2 for septic and resuscitated traumatic/hemorrhagic shock. Hemoglobin >10 gdL-1 Arterial saturation>92% Svo2>60% Normalization of serum lactate (to <2.2 meqL-1) Reverse encephalopathy Maintain urine output >0.5 mlkg-1hr-1

Optimization of oxygen delivery

Reverse organ system dysfunction

Aims - The basic goal of circulatory shock therapy is the restoration of effective perfusion to vital organs and tissues before the onset of cellular injury. This in turn depends on cardiac index (CI) and mean blood pressure. The first specific resuscitative aim should be support of blood pressure greater than 60-65 mmHg in a baseline normotensive patient. The second aim, maintainence of CI greater than 2.1Lmin-1m-2 for cardiogenic and obstructive shock and greater than 3.0-3.5 Lmin-1m2 for septic and resuscitated hemorrhagic shock should be then looked after. Finally, maintaining perfusion sufficiently high to keep arterial lactate concentration <2.2 meqL-1 avoids anaerobic metabolism. The concept that augmenting O2 delivery (Do2) to “supranormal” levels increase oxygen consumption and thereby, decrease organ failure and mortality remains controversial. More recent investigations have cast doubts on this therapeutic approach of augmenting Do2.106-109 (a) Airway management and mechanical ventilation A critical first step in the treatment of shock is to ensure adequate alveolar ventilation and oxygenation. Most patients with the fully developed shock syndrome require tracheal intubation and mechanical ventilatory



support, even if acute respiratory failure has not yet occurred. Improvement may occur for several reasons. Mechanical ventilation allows blood flow to be redistributed, tends to reverse lactic acidosis and supports the patient until other therapeutic measures can be effective. Tracheal intubation also is indicated if mental status changes make airway unprotected or for inadequate respiratory compensation for metabolic acidosis.110 Initial guidelines include using calculated tidal volumes in the order of 7-10 mlkg-1 of lean body mass, an O2 concentration that results in arterial saturation not less than 92%, adequate ventilator rate and sedation to minimize the work of breathing.63 Positive-pressure ventilation and PEEP may produce further hemodynamic compromise if volume status of the patient is not maintained. PEEP may also be desirable in patients with ARDS or pulmonary edema to ensure adequate oxygenation. (b) Acid base Balance The previous standard practice of administering bicarbonate to patients with shock and lactic acidosis has been revised. Recent evidence has demonstrated that metabolic acidosis of the plasma may infact be protective in shock states and that bicarbonate administration may transiently decrease intracellular and cerebrospinal fluid PH.111 The mechanism being production of CO2 as a product of the bicarbonate buffering of hydrogen ion and the rapid diffusion of this non ionized CO2 across cellular membranes. This paradoxical intracellular acidosis hinders brain and cardiac functions. Thus, the optimal approach to the management of lactic acidosis is to improve organ and systemic perfusion so that anaerobic metabolisms is limited and the liver as well as kidney can clear the accumulated lactate. If not effective, it has been suggested to restrict the use of sodium bicarbonate to situations with PH <7.1-7.15. Fluids Common to all etiologies of hemodynamic instability and shock is the need to provide optimal intravascular volume to ensure adequacy of preload. Thus, it is appropriate to begin fluid administration in all shock patients who lack signs of pulmonary edema and left ventricular overload. Substantial controversy exists regarding the appropriate use of crystalloid and colloid fluids for resuscitation.112-114 Several metaanalyses determined that there is no benefit and even perhaps mild increased mortality associated with the use of colloids instead of crystalloids for fluid

resuscitation.115 Thus, given the much higher cost of colloids, resuscitation of shock should generally focus on crystalloid solutions unless speed of resuscitation is paramount (i.e., acute major trauma or massive hemorrhage). What is most important when either type of fluid is used is to determine responses to these fluid challenges. Optimal therapy generally means administering the quantity of fluid that maximizes Do2 while avoiding left ventricular overload and pulmonary edema. Also, sufficient preload should be there before or during institution of pharmacologic therapy for hypoperfusion. (d) Vasopressor agents The term pressor refers to any substance that raises BP. These agents are divided into 3 categories: (i) lonotropes/chronotropes (i.e., drugs that increase cardiac output (CO) by increasing cardiac contractility and heart rate); (ii) vasoconstrictors (i.e., agents that raise BP by increasing systemic vascular resistance); and (iii) mixed pressor agents (i.e., drugs that act through both mechanism). (i) Ionotropic/chronotropic agents Dobutamine hydrochloride, a synthetic b1, b2 receptor agonist is often used for ionotropic support in cardiogenic shock. It increase myocardial contractility and CO, reduces afterload through peripheral vasodilatation and decreases left ventricular filling pressures with improvement in diastolic coronary blood flow. It also prevents increase in infarct size in patients with acute myocardial infarction by improved collateral blood flow and balance between oxygen supply and demand.116,117 Because of b2 mediated vasodilatation caution should be observed if it administered to hypotensive patients, especially with coexistent hypovolemia. Milrinone lactate, a selective phosphodiesterase III inhibitor increases ionotropy and decreases systemic vascular resistance by preventing the degradation of cyclic adenosine monophosphate. The hemodynamic effects are similar to those of dobutamine. Amrinone, is rarely used because of excessive vasodilatation and thrombocytopenia following long term use. It may be useful for synergy in patients already taking a-agonists and for patients receiving b-blocking agents. The most accepted use of these agents in the ICU in the management of congestive heart failure, cardiogenic shock and post-cardiopulmonary by pass myocardial dysfunction.




Dopexamine, a synthetic catecholamine, augments cardiac performance through both b2 mediated afterload reduction and baroreceptor reflex mediated ionotropy. Also, added benefit is its dopaminergic mediated increase in renal blood flow. Isoproterenol hydrochloride, a pure b receptor agonist produces CO augmentation by increasing both HR and contractility. Dysrythmias and increased myocardial oxygen requirement limit the use. Digitatis has limited use in treating acute states of hypoperfusion due to its slow onset of action and lower potency. (ii) Vasoconstrictor agents Phenylephrine is a pure adrenergic agonist. It causes vasoconstriction thereby increasing BP, generally decreasing CO and often reflex slowing of HR. It should be used as a first line agent in neurogenic shock. It can also be useful in patients who, despite maximal fluid and ionotropic support, remain hypotensive with evidence of organ hypo perfusion. Pure vasoconstrictors may compromise flow and perfusion, thus attention to renal function, acid-base balance, serum lactate and Do2 is imperative. Vasopressin is used as an alternative therapy for vasodilator shock especially where a stimulation does not produce a satisfactory vasoconstrictor response.118,119 Most studies have used doses between 0.01 and 0.1U per minute.120,121 Other vasoconstrictors are nor-epinephrine and bitartrate. (iii) Mixed Pressor Agents Dopamine, a precursor of norepinephrine, is commonly used as an initial pressor agent, acting at several receptors in a dose related manner. It can be titrated towards achieving different aims of therapy : dopaminergic effects at less than 4-5 mgkg-1min-1 (e.g., vasodilatation of renal and splanchnic vascular beds), b effect at 5-10 mgkg-1min-1 (e.g., augmentation of cardiac contractility and HR) and a effects at more than 10 mgkg-1min-1 (e.g., vasoconstriction). Debate continues, however, as to whether dopamine truly improves renal function or merely increases urine output through diuretic effect. There has been a decreased enthusiasm for its routine use to protect the kidneys from hypoperfusion insults or as a means to promote urine output in post hypoperfusion oliguria.122 However, at dose of 2-3 mgkg-1min-1 it can reverse vasoconstrictor (f)

induced increases in renal vascular resistance during vasoconstrictor infusion.123,124,125 Norepinephrine exerts both powerful ionotropic (cardiac a and b1 adrenoreceptors) and peripheral vasoconstriction effects (a adrenoceptors). It can be used for persistent hypotension despite high dose dopamine during septic and obstructive shock.126 It may also improve splanchnic oxygen dynamics in patients with sepsis.127 Epinephrine is occasionally used when other ionotropes/vasopressors have failed to support blood pressure and/or cardiac output in circulatory shock.128 It is the first line agent for management of anaphylactic shock. All currently used vasopressors agents ultimately produce their effects by increasing intracellular ionized calcium concentration. Thus normal ionized calcium concentration should be maintained in patients who are on vasopressor support. (e) Vasodilator agents These drugs reduce afterload and improve CO in acute and chronic ventricular failure. For acute vasodilatation and preload reduction, nitroglycerin is the agent of choice; for afterload reduction, sodium nitroprusside, hydralazine hydrochloride, anggiotensin converting enzyme inhibitors and fenoldopam are preferable. Patients with right-sided heart failure may benefit from pulmonary vasodilators i.e., prostacyclin, prostaglandin E1 and inhaled nitric oxide. Steroids Prospective, double-blind, randomized, multicenter studies have demonstrated no benefit of steroid administration in hyperdynamic/septic shock. Thus, the practice of routine administration of high dose steroids was abandoned. Stress doses of glucocorticoids are appropriate for treating shock when it is associated with adrenal insufficiency, hypothyroidism, in patients with impaired adrenal pituitary axis, or in those who require steroids for treatment of an underlying immunologic disease (e.g., vasculitis). Conversely, steroids are relatively contraindicated in patients with cardiogenic shock as they alter the healing process of the myocardium and predispose to myocardial rupture.133 But recent reports also suggest a decrease in the endogenous production of stress steroids in sepsis, causing vasopressor dependence and failure to respond to therapy.131,132 Administration of 100 mg of hydrocortisone 8 hourly indicates benefit. The mechanism for benefit may be



reversal of catecholamine receptor down regulation or prevention of inflammatory mediated induction of nitric oxide synthase. Patients of shock, who require increasing doses of vasopressors or do not respond within 24 hrs of therapy may be administered steroids. However, the topic still remains controversial. Experimental Therapies A number of promising new agents have begun to undergo experimental and clinical study for the treatment of ischemia and circulatory shock. The release of proinflammatory cytokines is one of the pathway to MODS in shock.134 The use of receptor and enzymatic blockers as well as immunotherapy to minize the effect of these agents is of little use.135 Antibodies to endotoxin, platlet activating factor, tumor necrosis factor, receptor blockers to interleukin-1, administration of the anti-inflammatory cytokine interleukin1, and inhibition of nitric oxide synthase have not been effective in randomized studies of patients with SIRS.136-140 Magnesium chloride complexed adenosine triphosphate (ATP-Mgcl2),141 pentoxifylline,142 oxygen free radical scavengers143 (i.e., superoxide dismutase, allopurinol), calcium channel blockers,144,145 haemoglobin based blood substitutes (i.e., diaspirin-linked hemoglobin, bovine hemoglobin) are being assessed in experimental hemorrhagic and septic shock models.146,147 Studies of activated protein (APC) have supported its role as an endogenous anti-inflammatory compound that also blocks thrombin induced microcoagulation.148 APC levels are decreased in 85% of patients with sepsis and SIRS. The recommendation is for the early (within 24 hours of diagnosis) administration to all patients with three of four indices of SIRS, known or suspected infection, and single-organ dysfunction. Other agents that may hold some promise for the management of circulatory shock of varying causes include novel buffers of acidemia (i.e., disodium carbonate/sodium bicarbonate),149 bacteriocidal increasing permeability protein (BPI)150 and chloroquine.151 Recently, terlipressin, a long acting vasopressin analogue has also been studied in cases with septic shock who did not respond to corticosteroids and methylene blue. This agent has been suggested to be an effective rescue therapy and was able to restore blood pressure in patients with catecholamine-resistant septic shock without obvious complications including rebound hypotension as has been reported with vasopressin.152

Summary Produced by multiple interacting mechanisms, shock is a complex, dynamic disorder of tissue and cellular hypoperfusion that may lead to MODS and death. Successful treatment of patients with shock requires prompt recognition of the shock state and a thorough understanding of the pathophysiology of various types of shock. Fluids and pharmacologic agents are the mainstay in the treatment of shock. Response to therapy can be monitored by indicators of both total systemic and individual organ perfusion. Considering the ongoing research and documentation of the advances in relation to the subject of shock, it worthwhile to mention that this brief review shall need revisions repeatedly in the future times. References
1. Rodriguez RM., Rosenthal MH. Etiology & Pathophysiology of shock. In: Murray MJ, Coursin DB, Pearl RG, Prough DS. eds. Critical care medicine - Perioperative management. Lippincott William & Wilkins, London. 2003; 192-205. Le Dran HF: A treatise, or reflections drawn from practice on gun-shot wounds. London. 1737 (Translated and selfpublished by J Clarke. 1743). Morris EA: A practical treatise on shock after operations and injuries. London, 1867. Hardwicke. Blalock A. Acute circulatory failure as exemplified by shock and haemorrhage. Surg Gynecol Obstet. 1934; 58: 551-566. kumar A, Parrillo JE. Shock: Classification, pathophysiology, and approach to management. In: Parrillo JE, Dellinger RP. eds. Critical Care medicine. Principles of Diagnosis and management in the adult. Mosby. London. 2001; 291-339. Hinshaw LB, Cox BG. The fundamental mechanisms of shock, New York, 1972. Plenum Press. Jimenez EJ. Shock. In: Civetta JM, Taylor RW, Kirby RR eds. Critical Care. Lippincott, Raven publishers. Philadelphia. 1997; 359-385. Mela L, Bacalaz OL, Miller L. Defective oxidative metabolism of rat mitochondria in hemorrhage and endotoxin shock. Am J Physiol 1971; 220: 571. Vogt MT, Fraber E. The effects of ethionine treatment on the metabolism of liver mitochondria. Arch Biochem Biophys 1970; 141: 162.


3. 4. 5.

6. 7.



10. Horpacsy G, Schnells G. Metabolism of adenine mucleotides in the kidney during hemorrhagic hypotension and after recovery. J Surg Res 1980; 29: 11. 11. Chaudry IH, Sayeed MM, Baue AE. Alteration in high-energy phosphates in hemorrhagic shock as related to tissue and organ function. Surgery 1976; 79: 666. 12. Chaudry IH, Sayeed MM, Baue AE. Effect of adenosine triphosphate-magnesium chloride administration in shock. Surgery 1974; 75: 220.

SETHI, SHARMA, MOHTA, TYAGI : SHOCK 13. Chaudry IH, Sayeed MM, Baue AE. Effect of hemorrhagic shock on tissue adenine nucleotides in conscious rats. Can J Physiol Pharmacol 1974; 52: 131. 14. Ayala A, Perrin MM. Meldrum DR, et al. Hemorrhage induces an increase in serum TNF which is not associated with elevated levels of endotoxin. Cytokine 1990; 2: 170. 15. Calandra T, Baumgartner J, Grau GE, et al. Prognostic values of tumor necrosis factor/cachectin, interleukin-1, and interferon-g in the serum of patients with septic shock. JID 1990; 151: 982. 16. Giroir BP. Mediators of septic shock: new approaches for interrupting the endogenous inflammatory cascade. Crit Care Med 1993; 21: 780. 17. Levine B, Kalman J, Mayer L, et al. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 1990; 323: 236. 18. Pinsky MR, Vincent JL, Deviere J, et al. Serum cytokine levels in human septic shock: relation to multiple system organ failure and mortality. Chest 1993; 103: 565. 19. Bone RC. The pathogenesis of sepsis. Ann Intern Med 1991; 115: 457. 20. Bone RC. Inflammatory Mediators in Sepsis and Septic Shock. Ann Intern Med 1991; 115: 457. 21. Reilly JM, Cunnion RE, Burch-Whitman C, et al. A circulating myocardial depressant substance is associated with cardiac dysfunction and peripheral hypoperfusion (lactic acidemia) in patients with septic shock. Chest 1989; 95: 1072. 22. Parrillo JE, Burch C, Shelhamer JH, et al. A circulating myocardial depressant substance in humans with septic shock. Septic shock patients with a reduced ejection fraction have a circulating factor that depresses in vitro myocardial cell perormance. J Clin Invest 1985; 76: 1539. 23. Lorente JA, Landin L, Renes E, et al. Role of nitric oxide in the hemodynamic changes of sepsis. Crit Care Med 1993; 21: 759. 24. Nathan C. Nitric oxide as a secretory product of mammalian cells. FASEB J 1992; 6: 3051. 25. Kilbourn RG, Gross SS, Jubran A, et al. N-methyl-L-arginine inhibits tumor necrosis factor-induced hypotension: implications for the involvement of nitric oxide. Proc Natl Acad Sci 1990; 87: 3629. 26. Granger DN, Rutili G, McCord JM. Super-oxide radicals in feline intestinal ischemia. Gastroenterology 1981; 81: 22. 27. McCord JM. Oxygen-derived free radicals. New Horiz 1993; 1: 70. 28. Saugstad OD, Ostrem T. Hypoxanthine and urate levels of plasma during and after hemorrhagic hypotension in dogs. Due Surg Res 1977; 9: 48. 29. Cryer HM, Kaebrick H, Harris PD, Et al. Effect of tissue acidosis on skeletal muscle microcirculatory responses to hemorrhagic shock in unanaesthetized rats. J Surg Res 1985; 39: 59.

355 30. Hollenberg SM, Cunnion RE, Parrillo JE. The effect of tumor necrosis factor on vascular smooth muscle. In vitro studies using rat aortic rings. Chest 1991; 100: 1133. 31. Coleman B, Glaviano VV. Tissue levels of norepinephrine in hemorrhagic shock. Science 1963; 139: 54. 32. Beasley D, Cohen RA, Levinsky NG. Interleukin-1 inhibits contraction of vascular smooth muscle. J Clin Invest 1989; 83: 331. 33. McKenna TM, Reusch DW, Simpkins CO. Macrophage conditioned medium and interleukin-1 suppress vascular contractility. Circ Shock 1988; 25: 187. 34. Chernow B. Roth BL. Pharmacologic manipulation of the peripheral vasculature in shock: clinical and experimental approaches. Circ Shock 1986; 18: 141. 35. Bond RF, Bond CH, Peissner LC, et al. Prostaglandin modulation of adrenergic vascular control during hemorrhagic shock. Am J Physiol 1981; 241: H85. 36. Slotman GJ, Burchard KW, Williams JJ, et al. Interaction of prostaglandins in clinical sepsis and hypotension. Surgery 1986; 99: 744. 37. Thiemermann C, Szab C, Mitchell JA et al. Vascular hyporeactivity to vasoconstrictor agents and hemodynamic decompensation in hemorrhagic shock is mediated by nitric oxide. Proc Natl Acad Sci 1993; 30: 267. 38. Zingarelli B, Squadrito F, Altavilla D, et al. Evidence for a role of nitric oxide in hypovolemic hemorrhagic shock. J Cardiovas Pharmacol 1992; 19: 982. 39. Koyama S, Aibiki M, Kanai K, et al. Role of the central nervous system in renal nerve activity during prolonged hemorrhagic shock in dogs. Am J Physiol 1988; 254. 40. Carden DI, Smith JK. Zimmerman BJ, et al. Reperfusion injury following circulatory collapse: the role of reactive oxygen metabolites. J Crit Care 1989; 4: 294. 41. Shasby DM, Shasby SS, Peach MJ, et al. Granulocytes and phorbolyristate acetate increase permeability to albumin of cultured endothelial monolayers and isolated perfuse lungsrole of oxygen radicals and granulocyte adherence. Am Rev Resp Dis 1983; 127: 72. 42. Thijs LG. Groenveld ABJ. Peripheral circulation in septic shock. Appl Cardiopul Path 1998; 2: 203. 43. Shah DM, Dutton RE, Newell JC, et al. Vascular autoregulatory failure following trauma and shock. Surg Forum 1977; 28: 11. 44. Chien S. Role of the sympathetic nervous system in hemorrhage. Physiol Rev 1967; 47: 214. 45. Bond RF, Green HD. Cardiac output redistribution during bilateral common carotid artery occlusion. Am J Physiol 1969; 216: 393. 46. Haupt MT. The use of crystalloidal and colloidal solution for volume replacement in hypovolemic shock. Crit Rev Clin Lab Sci 1989; 27: 1. 47. Gann DS, Carlson DE, Byrnes GJ, et al. Role of solute in the early restitution of blood volume after hemorrhage. Surgery 1983; 94: 439.

356 48. Davis JO, Freeman RH. Mechanisms regulating rennin release. Physiol Rev 1976; 56: 1. 49. Peach MJ. Renin-angiotensin system: biochemistry and mechanisms of action. Physiol Rev 1977; 57: 313. 50. Klingbeil CK, Keil LC, Chang D, et al. Role of vasopressin in stimulation of ACTH secretion by angiotensin II in conscious dogs. Am J Physiol 1986; 251: E52. 51. Liard JF. Vasopressin in cardiovascular control: role of circulating vaspressin. Clin Sci 1984; 67: 473. 52. Bond RF. Peripheral macro-and microcirculation. In: Schlag G, Redl H. eds: Pathophysiology of shock, sepsis and organ failure, Springer-Verlag Berlin. 1993. 53. Higgins CB, Vatner SF, Franklin D, et al. Pattern of differential vasoconstriction in response to acute and chronic low output states in the conscious dog. Cardiovasc Res 1974; 8: 92. 54. Kaihara S, Rutherford RB, Schwentker EP, et al. Distribution of cardiac output in ex-perimental hemorrhagic shock in dogs. J Appl Physiol 1969; 27: 218. 55. Forsyth RP, Hoffbrand BI, Melmon KL. Redistribution of cardiac output during hemorrhage in the unanesthetized monke. Circ Res 1970; 27: 311. 56. Kalter ES, Henning J, Thijs L, et al. Effects of methylprednisolone on P50, 2, 3-diphosphoglycerate and arteriovenous oxygen difference in acute myocardial infarction, Circulation 1980; 62: 970. 57. du Luz PL, Cavanilles JM, Michaels S, et al. Oxygen delivery, anoxic metabolism and hemoglobin-oxygen affinity in patients with acute myocardial infarction and shock. Am J Cardiol 1975; 36: 148. 58. Autoregulation of cerebral blood flow: Influence of the arterial blood pressure on the blood flow though the cerebral cortex. J Neurol Neurosurg Psychiatry 1966; 29: 398. 59. Lindenberg R. Patterns of CNS vulnerability in acute hypoxemia including anaesthesia accidents. In: Schade JP, McMeney WH. eds: Selective Vulnerability of the brain in hypoxemia: a symposium. Philadelphia, 1963, FA Davis. 60. Sander-Jenson K, Secher NH, Bie P, et al. Vagal slowing of the heart during hemorrhage: observations from twenty consecutive hypotensive patients. Br Med J 1986; 295: 364. 61. Barriot P, Riou B. Hemorrhagic shock with paradoxical bradycardia. Intensive Care Med 1987; 13: 203. 62. Sarnoff SJ, Case RB, Waitag PE, et al. In-sufficient coronary flow and myocardial failure as a complicating factor in late hemorrhagic shock. Am J Physiol 1954; 176: 439. 63. Hallstrom S, Vogl C, Redl H, et al. Net inotropic plasma activity in canine hypovolemic traumatic shock: low molecular weight plasma fraction after prolonged hypotension depresses cardiac muscle performance in vitro. Circ Shock 1990; 30: 129. 64. Douglas ME, Downs JB, Dannemiller FB, et al. Acute respiratory failure and intravascular coagulation. Surg Gynecol Ostet 1976; 143: 555.


65. Roussos C, Macklem PT. The respiratory muscles. N Engl J Med 1982; 307: 786. 66. Johnson G, Henderson D, Bond RF. Morphological differences in cutaneous and skeletal muscle vasculature during compensatory and decompensatory hemorrhagic hypotension. Circ Shock 1985; 15: 111. 67. Myer B, Moran S. Hemodynamically mediated acute renal failure. N Engl J Med 1986; 314: 97. 68. Badr KF, Ichikawa E Prerenal failure. adeleterious shift from renal compensation to decompensation. N Engl J Med 1988; 319: 623. 69. Rose BD. Meaning and application of urine chemistries. In: clinical physiology of acid-base and electrolyte disorders. McGraw-Hill ed 2, New York. 1984,. 70. Astiz ME, Rackow EC, Weil MH. Pathophysiology and treatment of circulatory shock. Crit Care Clin 1993; 9: 183. 71. Bhagwat AG, Hawk WA. Terminal hemorrhagic necrotizing enteropthy. Am J Gastroenteral 1966; 45: 163. 72. Robert A, Kaufman G. Stress ulcers erosions, and gastric mucosal injury. In: Sleisenger M. Fortran J. eds. Gastrointestinal disease. WB Saunders Philadelphia. 1989,. 73. Deitch E, Bridges W, Baker J, et al. Hemorrhagic shockinduced bacterial translocation is reduced by xanthine oxidase inhibition or inactivation. Surgery 1988; 104: 191. 74. Lillehei RC, MacLean LD. The intestinal factor in irreversible endotoxin shock. Ann Surg 1958; 148: 513. 75. Champion HR, Jones RT, Trump BF, et al. A clinicopathologic study of hepatic dysfunction following shock. Surg Gynecol Obster 1976; 142: 657. 76. Bor NM, Alvur M, Erean MT, et al. Liver blood flow rate and glucose metabolism in hemorrhagic hypotension and shock. J Trauma 1982; 22: 753. 77. Counts HB, Haisch C, Simon TL, et al. Hemostasis in massively transfused trauma patients. Ann Surg 1979; 190: 91. 78. Arnold J, Leinhardt D, Little RA. Metabolic response ot trauma. In Schlag G, Redl H. eds: Pathophysiology of shock sepsis and organ failure. Springer-Verlag Berlin. 1993. 79. Naylor JM, Kronfeld DS. In-vivo studies of hypoglycemia and lactic acidosis in endotoxic shock. Am J Physiol 1985; 248. 80. Daniel AM, Pierce CH, Shizgal HM, et al. Protein and fat utilization in shock. Surgery 1978; 84: 588. 81. Bagby GJ, Spitzer JA. Decreased myocardial extracellular and muscle lipoprotein lipase activities in endotoxin-treated rats. Proc Soc Exp Biol Med 1981; 168: 395. 82. Hoyt DB, Junger WG, Ozkan AN. Humoral mechanisms. In: Schlag G, Redl H. eds. Pathophysiology of shock, sepsis and organ failure. Springer-Verlag. Berlin. 1993. 83. Stephan R, Ayala A, Chaudry IH. Monocyte and lymphocyte responses following trauma. In: Schlag G, Redl H. eds. Pathophysiology of shock, sepsis and organ failure. SpringerVerlag Berlin. 1993.

SETHI, SHARMA, MOHTA, TYAGI : SHOCK 84. Milne ENC. Impact of imaging in the intensive care unit. Curr Opin Critical Care 1995; 1: 43. 85. Khoury AF, Afridi I, Quinones MA, et al. Transesophageal echocardiography in critically ill patients: feasibility, safety and impact on management. Am Heart J 1994; 127: 1363. 86. Kinch JW, Ryan TJ. Right ventricular infarction. N Engl J Med 1994; 330: 1211. 87. Cohn J. blood pressure measurement in shock: Mechanisms of inaccuracy in auscultatory and palpatory methods. JAMA, 1967; 199: 118. 88. Packman MI, Rackow EC. Optimum left heart filling pressure during fluid resuscitation of patients with hypovolemic and septic shock. Crit Care Med 1983; 11: 165. 89. Weisul RD, Vito L, Dennis RC, et al. Myocardial depression during sepsis. Am J Surg, 1977; 133: 512. 90. Tuchschmidt J, Fried J, Astiz M, et al. Elevation of cardiac output and oxygen delivery improves outcome in septic shock. Chest 1992; 102: 216. 91. Fleming A, Bishop M, Shoemaker W, et al. Prospective trial of supranormal values as goals of resuscitation in severe trauma. Arch Surg 1992; 127: 1175. 92. Naylor CD, Sibbald WJ, Sprung CL, et al. Pulmonary artery catheterization: can there be an integrated strategy of guideline development and research promotion? JAMA 1993; 269. 93. Abraham E, Smith M, Silver L. Continuous monitoring of critically ill patients with transcutaneous oxygen and carbon dioxide, and conjunctival oxygen sensors. Ann Emerg Med 1984; 13: 1021. 94. Tremper KK, Keenan B, Applebaum R, et al. Clinical and experimental monitoring with transcutaneous PO2 during hypoxia, shock, cardiac arrest, and CPR. J Clin Invest 1981; 6: 149. 95. Abraham E, Smith M, Silver S. Conjunctival and transcutaneous oxygen monitoring during cardiac arrest and cardiopulmonary resuscitation. Crit Care Med 1984; 12: 419. 96. Gutierrez G, Bismar H, Dantzker D, et al. Comparison of gastric intramucosal pH with measures of oxygen transport and consumption in critically ill patients. Crit Care Med 1992; 20: 451. 97. Maynard N, Bihari D, Beal R, et al. Assessment of splanchnic oxygenation by gastric tonometry in patients with acute circulatory failure. JAMA 1993; 270: 1203. 98. Fiddian-Green RG, Haglung U, Gutierrez G, et al. Goals for the resuscitation of shock. Crit Care Med 1993; 21 (suppl): 25. 99. Porembka DT. Transesophageal echocardiography. Crit Care Clin 1996; 12: 875. 100. Shoemaker WC. Invasive and noninvasive cardiopulmonary monitoring of acute circulatory dysfunction and shock. Curr Opin Critical Care 1995; 1: 189. 101. Simonson SG, Piantadosi CA. Near-infrared spectroscopy for monitoring tissue oxygenation in the critical care setting. Curr Opin Critical Care 1995; 1: 197.

357 102. Wo CC, Shoemaker WC, Bishop MH, et al. Noninvasive estimations of cardiac output and circulatory dynamics in critically ill patients. Curr Opin Critical Care 1995; 1: 211. 103. Shoemaker WC, Wo CC, Bishop MH, et al. Multicenter trial of a new thoracic electrical bioimpedance device for cardiac output estimation. Crit Care Med 1994; 22: 1907. 104. Groeneveld AB, Kolkman JJ: Splanchnic tonometry. a review of physiology, methodology, and clinical applications. J Crit Care 1994; 9: 198. 105. Arnold J, Hendriks J, Ince C, et al. Tonometry to assess the adequacy of splanchnic oxygenation in the critically ill patient. Intensive Care med 1994; 20: 452. 106. Hayes MA, Timmins AC, Yau EHS, et al. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med 1994; 330: 1717. 107. Gattinoni L, SVO2 Collaborative Group. A trial of goaloriented hemodynamic therapy in critically ill patients. N Engl J Med 1995; 333: 1025. 108. Durham RM, Neunaber K, Mazuski JE, et al. The use of oxygen consumption and delivery as end points for resuscitation in critically ill patients. J Trauma 1996; 41: 32. 109. Yu M, Takanishi D, Mayers SA, et al: Frequency of mortality and myocardial infarction during maximizing oxygen delivery: a prospective, randomized trial. Crit Care Med 1995; 23: 1025. 110. Johnson TJ, Stothert JC. Respiratory evaluation and support in the ICU. Curr Opin Critical Care 1995; 1: 306. 111. Cooper DJ, Walley KR, Wiggs BR, et al. Bicarbonate does not improve hemodynamics in critically ill patients who have lactic acisosis. A prospective, controlled clinical Study. Ann Intern Med 1990; 112: 492. 112. Haupt MT, Kaufman BS, Carlson RW. Fluid resuscitation in patients with increased vascular permeability. Crit Care Clin 1992; 8: 341. 113. Bissoni RS, Holtgrave DR, Lawler R, et al. Colloids versus crystalloids in fluid resuscitation: an analysis of randomized control trials. J Fam Pract 1991; 32: 387. 114. Velanovich V. Crystalloid versus colloid fluid resuscitation: a meta-analysis of mortality. Surgery 1989; 105: 65. 115. Human albumin administration in critically ill patients: systematic review of randomized controlled trials. Cochrane Injuries Group Albumin Reviewers. Br Med J 1998; 317: 235. 116. Gillespie TA, Ambos HD, Sobel Be, et al. Effects of dobutamine in patients with acute myocardial infarction. Am J Cardiol 1977; 39: 588-594. 117. Leier CA. Acute inotropic support. In: Leier CV, ed. Cardiotonic drugs: a clinical survey. Marcel Dekker. New York: 1986. 118. Rozenfeld V, Cheng JW. The role of vasopressin in the treatment of vasodilation in shock states. Ann Pharmacother 2000; 34: 250-254.

358 119. Landry DW, Levin HR, Gallant EM, et al. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 1997; 95: 1122-1125. 120. Argenziano M, Choudhri AF, Oz MC, et al. Aprospective randomized trial of arginine vasopressin in the treatment of vasodilatory shock after left ventricular assist device placement. Circulation 1997; 96: 286-290. 121. Malay MB, Ashton RC, Landry DW, et al. low-dose vasopressin in the treatment of vasodilatory shock. J Trauma 1999; 47: 699-703. 122. Bellomo R, Chapman M, Finfer S, et al. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomized trial: Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet 2000; 356: 2139-2143. 123. Hoogenberg K, Smit AJ, Girbes ARJ. Effects of low-dose dopamine on renal and systemic hemodynamics during incremental norepinephrine infusion in healthy volunteers. Crit Care Med 1998; 26: 260-265. 124. Duke GJ, Briedis JH, Weaver RA. Renal support in critically ill patients: low-dose dopamine or low-dose dobutamine? Crit Care Med 1994; 22: 1919-1925. 125. Sachaer GL, Fink MP, Parillo JE. Norepinephrine alone versus nor-epinephrine plus low-dose dopamine enhanced renal blood flow with combined pressor therapy. Crit Care Med 1985; 13: 492-496. 126. Martin C, Papzian L, Perrin G, et al. Norepinephrine or dopamine for the treatment of hyperdynamic septic shock? Chest 1993; 103: 1826-1831. 127. Marik PE, Mohedin M. The contrasting effects of dopamine and nor-epinephrine on systemic and splanchnic oxygen utilization in hyperdynamic sepsis. JAMA 1994; 272: 13541357. 128. Harari A, Martin E. Decreased dopamine beta hydroxylase activity in septic shock. Anesthesiology 1979; 51: S155. 129. Bone RC, Fisher CJ, Clemmer TP, et al. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 1987; 317: 653-658. 130. The Vterans Administration systemic Sepsis Cooperative Study Group Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. N Engl J Med 1987; 317: 659-665. 131. Bollaert PE, Charpentier C, Levy B, et al. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med 1998; 26: 645-650. 132. Briegel J, Forst H, Hummel T, et al. Stress doses of hydrocortisone: reverse hyperdynamic septic shock: a prospective randomized, double-blind, single-center study. Crit Care Med 1999; 27: 723-732. 133. Roberto R, DeMillo V, Sobel BE. Deleterious effects of methylprednisolone in patients with myocardial infarction. Circulation 1976; 53: 204.

INDIAN JOURNAL OF ANAESTHESIA, OCTOBER 2003 134. Bone RC. Towards a theory regarding the pathogenesis of systemic inflammatory response syndrome: what we do and do not know about cytokine regulation. Crit Care Med 1996; 24: 163-172. 135. Zeni F, Freeman B, Natanson C. Anti-inflammatory therapies to treat sepsis and septic shock: a reassessment. Crit Care Med 1997; 25: 1095-1100. 136. Angus DC, Birmingham MC, Balk RA, et al. F5 murine monoclonal anti endotoxin antibody in gram-negative sepsis: a randomized controlled trial. JAMA 2000; 283: 1723-1730. 137. Cohen J, Carlet J. INTERSEPT: an international, multicenter, placebo-controlled trail of monoclonal antibody to human tumor necrosis factoralpha in patients with sepsis. International Sepsis Trial Study Group. Crit Care Med 1996; 24: 1431-1440. 138. Opal SM, Fisher CJ, Dhainaut JFA. Confirmatory interleukin-I receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. Crit Care Med 1997; 25: 1115-1124. 139. Remick DG, Garg SJ, Newcomb De, et al. Exogenous interleukin-1 fails to decrease the mortality and morbidity of sepsis. Crit Care Med 1998; 26: 895-904. 140. Avontaur JAM, Nothenius RPT, Bujik SLCE, et al. Effect of L-Name, an inhibitor of nitric oxide synthesis, on cardiopulmonary function in human septic shock. Chest 1998; 113: 1640-1646. 141. Harkema JM, Chaudry IH. Magnesium-adenosine triphosphate in the treatment of shock, ischaemia, and sepsis. Crit Care Med 1992; 20: 263. 142. Ward A, Clissold SP: Pentoxifylline; a review of its pharmacodynamic and pharmcokinetic properties and its therapeutic efficacy. Drugs 1987; 34: 50. 143. Karkema JM, Singh G, Wang P, et al. Pharmacologic agents in the treatment of ischemia, hemorrhagic shock and sepsis. J Crit Care 1992; 7: 189. 144. Maitra SR, Krikhely M, Dulchavsky SA, et al. Beneficial effects of diltizem in hemorrhagic shock. Circ Shock 1991; 33: 121. 145. Sayeed MM, Maitra SR. Effect of diltiazem on altered cellular calcium regulation during endotoxic shock. Am J Physiol 1987; 253: R549. 146. Soltero RG, Hansbrough JF. The effects of diaspirin crosslinked hemoglobin on hemodynamics, metabolic acidosis, and survival in burned rats. J Trauma 1999; 46: 286-291. 147. Manning JE, Katz LM, Brownstein MR, etal: Bovine hemoglobin-based oxygen carrier (HBOC-201) for resuscitation of uncontrolled, exsanguinating liver injury in swine. Carolina Resuscitation Research Group. Shock 2000; 13: 152. 148. Bernard GR, Vincent JL, Laterre PE, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344: 699-709. 149. Rhee KH, Toro LO, McDonald GG, et al. Carbicarb, sodium bicarbonate, and sodium chloride in hypoxic lactic acidosis:

SETHI, SHARMA, MOHTA, TYAGI : SHOCK effect on arterial blood gases, lactate concentrations, hemodynamic variables,and myocardial intracellular PH. Chest 1993; 104: 913. 150. Hansbrough J, Tenenhaus M, Wikstrom T, et al. Effects of recombinant bactericidal/permeability-increasing protein (rBP123) on neutrophil activity in burned rats. J Trauma 1996; 40: 886.

359 151. Ertel W, Morrison MH, Ayala A, et al. Chloroquine attenuates hemorrhagic shock induced immunosuppression and decreases susceptibility to sepsis. Arch Surg 1992; 127: 70. 152. Alastair O’Brien, Lucie Clapp, Mervyn Singer. Terlipressin for noreplnephrine-resistant septic shock. Lancet 2002; 359: 1209-1210.

ISA NEWS : Election - ISA - 2004 - Vaccancies - Notification
Election to the Governing Council ISA-2004 will be held at the Conference venue of ISACON 2003, on 28.12.2003 at Bhuvaneshwar. The vacancies open for the year - 2004 are: (a) (b) (c) (d) President Vice-President Editor Governing Council Members (one post) (one post) (one post) (3 posts)

The rules and regulations regarding the election to the Governing Council of ISA are as per the Constitution of ISA (Article No.VII) published in 2002. Nomination in the proper format may be forwarded to the Secretary ISA, at Society’s office by registered post/courier/in person, on or before 27th November 2003.

Secretary ISA (National)



(For Nomination of Office - Bearers to the Governing Council ISA National) I propose the name of Dr……………..................................................……...............……………………………………….. of …………….................................…………City Branch/Direct Member …………..............…..............…………………………… .....................……as President / Vice President / Editor / Governing Council Member of Indian Society of Anaesthesiologists. Candidate’s Name & Qualification Address ISA No.

Proposer’s Name


ISA No. Signature

Seconder’s Name

I second the above proposal Address

ISA No. Signature

I give my consent to the above proposal Conference Attended: 1998 - Kathmandu 1999 2000 Place: Date: Cochin Nagpur Signature of the candidate …………………………… 2001 - Ahmedabad 2002 Coimbatore

Alan E. Jones Jeffrey A. Kline

In philosophic terms, shock can be viewed as a transition between life and death. Whether shock results from hemorrhage, sepsis, or cardiac failure, mortality rates exceed 20%. [1] [2] In scientific lexicon, shock results from the widespread failure of the circulatory system to oxygenate and nourish the body adequately. In the laboratory, the scientist defines the metabolic effect of shock quantitatively, by examining the mechanisms by which shock alters mitochondrial energy transfer, evokes the production of toxic chemicals, and reduces their removal. At the bedside, the clinician identifies shock by linking the clinical impression, synthesized from the patient's history of present illness, age, underlying health status, and general appearance, to quantitative data, including vital signs, blood chemistry, urine output, and direct measurements of oxygenation. When the clinical impression and the quantitative data suggest widespread inadequate organ perfusion, emergent resuscitation must restore normal tissue oxygenation and substrate delivery to prevent deterioration into systemic inflammation, organ dysfunction, and death.

For years, shock has been classified into four broad categories based on Blalock's 1934 description: hematological, neurologic, vasogenic, and cardiogenic. [3] Although it seems archaic to classify a gunshot wound as “hematologic” shock, this basic organization scheme remains useful today. Box 4-1 outlines five categories of shock that generally have specific mechanisms and treatments. BOX 4-1 Categories of Shock According to Primary Treatment Causes That Require Primarily the Infusion of Volume

Hemorrhagic shock Traumatic Gastrointestinal Body cavity Hypovolemia Gastrointestinal losses Dehydration from insensible losses Third-space sequestration from inflammation

Causes That Require Improvement in Pump Function by Either Infusion of Inotropic Support or Reversal of the Cause of Pump Dysfunction

Myocardial ischemia Coronary artery thrombosis Arterial hypotension with hypoxemia Cardiomyopathy Acute myocarditits Chronic diseases of heart muscle (ischemic, diabetic, infiltrative, endocrinologic, congenital) Cardiac rhythm disturbances

Atrial fibrillation with rapid ventricular response Ventricular techycardia Supraventricular tachycardia Hypodynamic septic shock (late sepsis) Overdose of negative inotropic drug β-blocker Calcium channel antagonist overdose (e.g., verapamil) Structural cardiac damage Traumatic (e.g., flail mitral valve) Ventriculoseptal rupture Papillary muscle rupture

Causes That Require Volume Support and Vasopressor Support

Hyperdynamic sepsis syndrome (early sepsis) Anaphylactic shock Central neurogenic shock Drug overdose (dihydropyridines, α1-antagonists)

Problems That Require Immediate Relief from Obstruction to Cardiac Output

Pulmonary embolism Cardiac tamponade Pneumothorax Valvular dysfunction Acute thrombosis of prosthetic valve Critical aortic stenosis Congenital heart defects in newborn (e.g., closure of patent ductus arteriosus with critical aortic coarctation) Critical idiopathic subaortic stenosis

Cellular Poisons That Require Specific Antidotes

Carbon monoxide Methemoglobinemia Hydrogen sulfide Cyanide


The epidemiology of shock in the emergency department remains speculative because shock rarely is listed as a primary coding diagnosis and usually is hidden within another diagnosis. Patients presenting with traumatic, cardiogenic, or septic shock constitute about 1% of all emergency department visits. This chapter reviews the metabolic, systemic, and inflammatory responses that occur in all types of circulatory shock and discusses specific pathophysiology of the major causes of shock.

At the subcellular level, shock first affects the mitochondria. Mitochondria function at the lowest oxygen tension in the body, but paradoxically, they consume almost all the oxygen used by the body. More than 95% of aerobic chemical energy comes from mitochondrial combustion of fuel substrates (fats, carbohydrates, ketones) plus oxygen into carbon dioxide and water. Mitochondria have been referred to as the “canaries in the coal mine” because they are affected first in conditions of inadequate tissue perfusion. [4] [5] When mitochondria have inadequate oxygen, the cell converts fuels to lactate ( Figure 4-1 ), which accumulates and diffuses into the blood.

Figure 4-1 Energy metabolism with special reference to the development of lactic acidosis in shock. At site A, oxygen availability to the mitochondrial electron transport system decreases. In the tricarboxylic acid (TCA) cycle (site B), intermediary metabolites accumulate, including acetyl coenzyme A (AcCoA), which causes the pyruvate dehydrogenase enzyme complex (site C) to shut down, leading to accumulation in pyruvate. At site D, pyruvate is reduced to lactate, which generates oxidized + nicotinamide adenine dinucleotide (NAD ) to permit anaerobic glycolysis to generate a marginal supply of adenosine triphosphate (ATP). Lactate can diffuse across the cell membrane through a specific monocarboxylase transporter in the cytosolic membrane (dotted horizontal line). ADP, adenosine diphosphate; NADH, reduced nicotinamide adenine dinucleotide.

Most cellular energy transfer derives from combustion of acetyl coenzyme A (CoA) in the tricarboxylic acid (TCA) cycle to form reduced pyridine and flavin nucleotides, which pass electrons along a series of proteins in the inner mitochondrial membrane, culminating in the reduction of molecular oxygen to form water. The mitochondrion harnesses energy from this process in an electromotive (proton) gradient to form adenosine triphosphate (ATP) from adenosine diphosphate plus inorganic phosphate. Acetyl CoA is primarily formed by one of two pathways: β-oxidation or decarboxylation of pyruvate. Either fatty acids or ketones are processed by β-oxidation. Pyruvate derives from either glycolysis or lactate dehydrogenation. In addition, almost every cell in the body possesses its own internal reserve of chemical energy in the form of triacylglycerol (fat) and glucose (glycogen), which it can expend in times of stress and inadequate tissue perfusion to allow continuous supply of acetyl CoA into the mitochondria.

In the early stage of shock, the skeletal muscle and splanchnic organs are affected more by oxygen deprivation than by a lack of delivery of fuel substrate. As a result, shock rapidly stalls transfer of electrons in the mitochondria and “jams” the pathways of acetyl CoA input into the TCA. The main byproduct of this jam in oxidative metabolism is lactic acid, which can exit the cell across the cell membrane by way of a specific protein transporter. In the resuscitated sepsis syndrome[6] and in resuscitated hemorrhagic shock,[7] skeletal muscle may produce lactate not entirely because of low mitochondrial oxygenation, but because the delivery of pyruvate from glycolysis overwhelms the ability of dehydrogenase enzymes in the TCA to dispose of pyruvate, which is converted to lactate. This scenario has been termed aerobic glycolysis.[8] Regardless of etiology, elevated concentrations of lactate in the blood serve as a sentinel marker of widespread inadequate tissue perfusion and disappear when adequate resuscitation has been achieved. At the whole-body level, shock from any etiology initiates a sequence of stress responses that are intended to preserve flow to vital organs and to signal cells to expend internal energy stores ( Figure 4-2 ). Shock initially reduces wall tension in the large intrathoracic arteries, which activates their baroreceptors, which activate adrenergic reflexes that have neural and circulating hormonal components. The two major arms of the neural component include sympathetic fibers from the stellate ganglion, which stimulates the heart, and sympathetic fibers from regional ganglia, which cause peripheral arterial vasoconstriction. Exceptions include certain toxic causes of shock (e.g., septic shock) and many drug overdoses, which can block these reflex sympathetic actions on the heart and vascular smooth muscle. The circulating “stress hormones” derive mainly from the hypothalamic-pituitary-adrenomedullary axis, which leads to secretion of epinephrine and norepinephrine from the adrenal medulla and corticosteroids from the adrenal cortex, renin from the kidney, and glucagon from the pancreas. These hormones signal the liver to break down glycogen to release glucose into the plasma and alert adipose tissue to release fatty acids via lipolysis. As a result, stress hormones increase the input of carbon substrates into the TCA throughout the body, often overwhelming the mitochondrial ability to oxidize them and leading to an increase in lactic acid production and release into the bloodstream.

Figure 4-2 Overview of whole-body hormonal stress response to shock. Upper left, Stress hormones (catecholamines, glucagons) stimulate the liver to increase glucose output, derived from glycogen breakdown and by synthesis from lactate and alanine, which are released from skeletal muscle catabolism (right side). Lower left, Adrenal medulla secretes glucocorticosteroids and catecholamines, which induce glycogenolysis, insulin resistance, hypokalemia, and lipolysis. Juxtaglomerular cells of the kidney release renin, which activates the renin-angiotensin-aldosterone (RAA) system. Upper right, Skeletal muscle becomes more resistant to substrate uptake and continues to release lactate, which becomes the main fuel source for the heart in shock. FFA, free fatty acids.

Although lactic acidosis is a unifying feature of shock, its exact source may depend on the cause of shock. Lactic acidosis from hemorrhagic shock probably arises largely from skeletal muscle during hypotension and after resuscitation,[9] whereas with sepsis the skeletal muscle probably extracts lactate until the late stage. Some evidence suggests that the viscera and the lung are the primary sources of lactic acidosis in septic shock.[10] Initiation of inflammatory events constitutes a third unifying feature of shock. Shock causes neutrophil activation and liberation of adhesion molecules, which promote binding of neutrophils to vascular endothelium. Activated, sticky neutrophils can damage organs directly by liberating toxic reactive oxygen species, N-chloramines, and proteolytic enzymes. Neutrophils also can plug capillaries and cause microischemia.[11] Although much of the knowledge about the inflammatory responses in shock has evolved from the study of septic shock, the consensus is that any low-perfusion state that produces widespread cellular hypoxia can trigger systemic inflammation. Early in sepsis, multiple tissues (e.g., macrophages, endothelial and epithelial cells, muscle cells) are signaled to upregulate transcription of messenger RNA (mRNA) coding for cytokines, including tumor necrosis factors (TNF-α, TNF-β) and interleukins (IL-1, IL-6). Figure 4-3 is a brief overview of some of the inflammatory changes that can occur in shock, using the action of TNF-α on a heart muscle cell as the prototype. Cytokines bind to surface receptors and cause changes that lead to the activation of nuclear factor κ B (NFκB), a protein that travels to the cell nucleus. NFκB upregulates the transcription of mRNA needed to synthesize inflammatory cytokines and leads to production of inducible nitric oxide (NO) synthase, which liberates high concentrations of NO. NO causes vascular smooth muscle relaxation. Under healthy conditions, NO is produced in small amounts by a native enzyme, constitutive NO synthase. Constitutive NO synthase provides enough NO to help balance against naturally produced vasoconstrictors to maintain blood flow to autoregulated organs. When inducible NO synthase becomes upregulated, however, too much NO is produced, leading to pathologic vasodilation and eventually conversion of NO to a highly reactive free radical, peroxynitrite, which can damage cell membranes, DNA, and organelles and contribute to organ failure during shock. [12]

Figure 4-3 Overview of selected inflammatory mechanisms of shock, using the muscle cell as a prototype. Tumor necrosis
factor α (TNF-α) causes upregulation of inducible nitric oxide synthase (iNOS), which overproduces nitric oxide (NO). In conditions of low oxygen tension, NO reacts with superoxide (O 2 ) generated from the mitochondria to form peroxynitrite (ONOO ), which can damage mitochondria and decrease adenosine triphosphate (ATP) production. TNF-α also binds to a surface receptor and causes a shift of nuclear factor κ B (NFκB) protein into the nucleus, which further increases production of TNF-α and other inflammatory cytokines. TNF-α also causes production of sphingosine, which can directly block release of calcium from the sarcoplasmic reticulum (SR) and depress cardiac contraction. cGMP, cyclic guanosine monophosphate; IL, interleukin.

Heart Function

During resuscitation from shock, the heart must transition rapidly from a low-work, low-flow state to a higher workload and maintain adequate cardiac output in the presence of inflammatory injury to the cardiac myocyte. The degree to which the heart is affected by shock depends on the cause of shock, but the pathophysiologic effect of cytokine exposure, arterial hypotension, and acidosis on cardiac function can be generalized. The heart generates its pumping power during systole by interaction of actin and myosin in the myofilament. For this interaction to occur, the contractile apparatus has two basic needs, calcium and chemical energy (ATP or creatine phosphate). Calcium reaches troponin C in the contractile apparatus by the mechanism of excitation-contraction. In this model, intracellular calcium release starts with an external electrical signal on the myocyte surface, which opens voltage-dependent calcium channels on the membrane. These slow, or L-type, channels conduct the current of calcium that causes the plateau phase (II) of the ventricular myocyte action potential. This relatively small influx of calcium triggers a larger release of calcium from the sarcoplasmic reticulum by way of a connection between involutions of the plasma membrane, called the T tubules. This connection is the ryanodine-sensitive pathway; the alkaloid agent ryanodine is used experimentally to evoke calcium release from the sarcoplasmic reticulum. The force of cardiac contraction varies in proportion to the amount of calcium bound to troponin C during systole. To increase strength of cardiac contraction, or cardiac contractility, the clinician either must increase calcium entry through the L channel or must increase calcium release from the sarcoplasmic reticulum. In almost all cases, clinically available inotropic drugs work by the former mechanism, by binding to cardiac membrane β1-receptors (catecholamines), or by inhibition of cyclic adenosine monophosphate (cAMP) breakdown (phosphodiesterase inhibitors), which leads to phosphorylation of the L channel via the stimulatory G protein. Phosphorylation of the L channel increases its probability of opening, increasing calcium entry and myocardial contractility. The other component of cardiac contraction, chemical energy, comes almost entirely from mitochondrial oxidative phosphorylation. Myocardial mitochondria must remain highly active to meet the mechanical energetic needs of the heart. The heart lives on a thin margin of high-energy phosphate supply; it has been estimated that the heart completely turns over its reserve of ATP and creatine phosphate every 5 to 10 beats.[13] Cardiac function may be indirectly depressed in shock conditions by coronary hypotension. In an isolated working heart, the strength of cardiac contraction varies in proportion to the coronary perfusion pressure (the Gregg phenomenon). The cellular basis for the link between contractile strength and coronary perfusion pressure seems to be independent of the L-type calcium current.[14] Although decreased coronary perfusion aggravates cardiac performance in shock,[15] it is more difficult to determine if coronary hypotension causes myocardial ischemia in shock. While myocardial oxygen delivery decreases as coronary flow diminishes in shock, the oxygen requirement for the heart decreases in proportion to coronary flow because the external workload on the heart diminishes. With respect to oxygen, the heart [16] seems to obtain what it needs during hypotensive shock. Whether shock is caused by hemorrhage, [18] [17] sepsis, or drug-induced cardiogenic shock, the heart extracts lactate, indicating the absence of global myocardial hypoxia. A substantial body of evidence now suggests that specific actions of cytokines may decrease cardiac function, especially in hyperinflammatory causes of shock, such as sepsis (see Figure 4-3 ). [12] [19] [20] In addition, intracellular and extracellular acidosis can depress cardiac contraction, but in the whole picture of shock, the contribution of acidosis to depressed heart function is probably minimal.

Specific Causes Hemorrhagic Shock
Hemorrhagic shock results from a rapid reduction in blood volume, which causes baroreceptor activation and leads to vasoconstriction, increased strength of cardiac contraction, and increased heart rate (HR). Cardiovascular response to hemorrhage can vary with underlying cardiopulmonary status, age, and presence of ingested drugs. Responses of HR and blood pressure (BP) are notoriously variable in hemorrhage, so no firm conclusion can be made at the bedside about the presence or absence of hemorrhagic shock simply by evaluating HR and BP.[21] In general, hemorrhage first increases pulse and cardiac contraction, then increases vasoconstriction. The first clinical manifestations of hemorrhage are tachycardia, then a slight increase in the diastolic BP, causing the pulse pressure (difference between systolic and diastolic BP) to narrow. With worsened bleeding, ventricular filling is compromised, and cardiac output decreases, followed by a reduction in systolic BP. Before the total cardiac output begins to

decrease, blood flow to noncritical organs and tissues (e.g., skin, skeletal muscle, viscera) begins to decrease, and these tissues produce lactic acid. Consequently a change in arterial acid-base status often precedes any significant decrease in cardiac output with hemorrhage.[22] The base deficit is defined as the amount of strong base that would have to be added to 1 L of blood to normalize the pH. In the clinical setting, the base deficit is indirectly calculated from the pH and arterial carbon dioxide partial pressure (PaCO2) and is normally more positive than -2 mEq/L. Accordingly the arterial and venous blood base deficit worsens (the numeric measurement becomes more negative) early in hemorrhage even while pH and BP remain in the normal range. It can be scientifically rationalized that the threshold to distinguish simple hemorrhage from hemorrhagic shock occurs when the base deficit worsens (the total body base deficit increases, but the laboratory numeric measurement becomes more negative), indicating widespread tissue hypoperfusion. To maintain a normal arterial pH, the brainstem chemoreceptor responds to acidemia by increasing minute ventilation, leading to reduced PaCO2. After approximately one third of the total blood volume is acutely lost, cardiovascular reflexes no longer can cause adequate filling of the arterial circuit, and frank hypotension supervenes. Arterial hypotension is generally and arbitrarily defined as a systolic arterial BP less than 90 mm Hg, but this threshold should be increased to 100 mm Hg in patients with known systemic hypertension and in patients older than age 60 years. Usually coincident with the development of hypotension, the patient no longer can hyperventilate sufficiently to maintain a normal arterial pH, and acidemia occurs. Hemorrhagic shock causes a large activation of the hypothalamic-pituitaryadrenomedullary axis, with release of stress hormones that cause glycogenolysis, lipolysis, and mild hypokalemia (see Figure 4-2 ). In the emergency department, patients sustaining traumatic hemorrhage generally have an arterial lactate concentration greater than 4 mmol/L, a PaCO2 less than 35 mm Hg, and mild hyperglycemia (150 to 170 mg/dL) and hypokalemia (3.5 to 3.7 mEq/L). Although hemorrhagic hypotension does significantly alter ventilation-perfusion relationships in the lung, hemorrhagic hypotension seldom produces arterial hypoxemia if the airway is clear, the lungs are not injured, and respiratory effort is adequate. The second phase of organ injury from hemorrhagic shock occurs during resuscitation. Many experts assert that the period of hemorrhage “cocks the gun,” and resuscitation “pulls the trigger” to cause organ injury from hemorrhagic shock. During resuscitation, neutrophils become most aggressive, binding to the lung endothelium and initiating capillary leak, which can produce acute respiratory distress syndrome (ARDS). Inflammatory cytokines are liberated during resuscitation, and membrane injury occurs in many cells. In the liver, damage from inflammation and reactive oxygen species from neutrophils is compounded by persistent microischemia. During resuscitation from hemorrhagic shock, the normal balance of vasodilation by NO versus vasoconstriction by endothelins becomes distorted, producing patchy centrilobular ischemic damage in the liver, which may produce an immediate increase in blood transaminase levels. A growing body of evidence suggests that retransfusion from hemorrhage exerts greater injury to the heart than the actual hypotensive insult. [23] [24] Depending on the degree of hypotensive insult, the kidney may manifest acute spasm of the preglomerular arterioles, causing acute tubular necrosis. Systemic metabolic changes can impair fuel delivery to the heart and brain, secondary to depressed hepatic glucose output, impaired hepatic ketone production, and inhibited peripheral lipolysis.[25]

Septic Shock
Septic shock can be produced by infection with any microbe. Previously, gram-negative aerobic bacteria were the primary organisms that caused septic shock; however, more recently the incidence of gram[1] positive infections has increased to a frequency equal to that of gram-negative infections. In one third of cases of septic shock, no organism is identified. One of the chief mediators of sepsis is lipopolysaccharide, which is contained in the cell wall of gram-negative bacteria. Infusion of lipopolysaccharide into humans or animals produces cardiovascular, immunologic, and inflammatory changes identical to the changes observed with microbial infection. In recent years, multicenter trials have suggested the emergence of gram-positive organisms as the chief cause of sepsis in hospitalized patients. Further growth in primarily gram-positive sepsis occurs for two main reasons: 1. More patients are being treated at home for chronic immunocompromising diseases with indwelling catheters, which serve as excellent portals of entry into the vascular space for Staphylococcus aureus and coagulase-negative staphylococci. The frequency of community-acquired infections caused by antibiotic-resistant, gram-positive organisms has increased greatly, including infections caused by S. aureus, Streptococcus


pneumoniae, and Streptococcus pyogenes.

Septic shock causes three major effects that must be addressed during resuscitation: hypovolemia, cardiovascular depression, and induction of systemic inflammation. Septic shock always produces relative hypovolemia from increased venous capacitance, which reduces right ventricular filling. Septic shock often causes absolute hypovolemia from gastrointestinal volume losses, tachypnea, sweating, and decreased ability to drink during development of the illness. Sepsis also induces capillary leak, which leads to relative loss of intravascular volume into third spaces. Evidence has shown that septic shock causes myocardial depression simultaneously with vasodepression and capillary leak. For years it was thought that septic shock depressed the heart only in the later, hypodynamic stages because sepsis induces hyperdynamic heart function, characterized by an increase in cardiac output.[26] More sophisticated and direct measurements of cardiac contractility have shown, however, that cardiac mechanical function becomes impaired early in the course of septic shock, even in the hyperdynamic stages.[27] Evidence for multiple mechanisms may explain depressed heart function in sepsis, including actions of specific cytokines (most notably TNF-α and IL-1β),[20] overproduction of NO by inducible NO synthase,[12] and possibly impairment in mitochondrial oxidative phosphorylation[28] coincident with reduced mechanical efficiency.[29] Evidence indicates that circulating mediators, myocellular injury from inflammation, and deranged metabolism interact synergistically to injure the heart during septic shock. Systemic inflammation causes capillary leak in the lung, which may cause alveolar infiltration characteristic of ARDS early in the treatment of septic shock in 40% of patients.[1] With the potential for early development of ARDS, more profound ventilation-perfusion mismatching, and pneumonia or pulmonary aspiration, hypoxemia is more severe with septic shock than hemorrhagic shock.

Cardiogenic Shock
Cardiogenic shock results when more than 40% of the myocardium becomes necrosed from ischemia, inflammation, toxins, or immune destruction. The primary cause of cardiogenic shock is pump failure. Otherwise, cardiogenic shock essentially produces the same circulatory and metabolic alterations that are observed with hemorrhagic shock. Impaired baseline cardiac function can contribute to the development of circulatory shock state secondary to infection, hemorrhage, or vasodilatory drug overdose. When shock results from a pure cardiac cause, however, severe left ventricular dysfunction is evident on echocardiography early in the course. Patients with severe left ventricular dysfunction are far more likely to have a cardiogenic cause of shock than patients with normal or moderate left ventricular dysfunction.[30] Acute massive pulmonary embolism produces circulatory shock by obstruction of the pulmonary vasculature, which leads to right ventricular overload and impairs left ventricular filling. Echocardiogram and electrocardiogram (ECG) observations suggest that selective right ventricular ischemia occurs with [31] massive pulmonary embolism. A pulmonary embolism large enough to cause shock always results in pulmonary ventilation-perfusion mismatching, so arterial hypoxemia becomes a significant problem. Hypoxemia, together with coronary hypoperfusion from arterial hypotension, and systemic acidosis may produce synergistic effects on cardiac function, resulting in a “stunning” effect on right and left ventricles.[32]

Anaphylactic Shock
Anaphylactic shock results from an IgE-mediated systemic response to an allergen. The mast cell plays a central role in the etiology of anaphylactic shock. IgE causes mast cells to release histamine, which results in vascular smooth muscle relaxation, bronchial smooth muscle constriction, and capillary leak of plasma into interstitial spaces. Platelets also participate in anaphylaxis by secreting platelet-activating factor (PAF), which is derived from membrane phospholipid. PAF causes peripheral vasodilation, bronchial constriction, and pulmonary arterial and coronary vasoconstriction. Antagonists to PAF can [33] reverse the negative inotropy and vasodilation observed with experimental anaphylaxis. As such, PAF may be an important mediator of anaphylaxis that is refractory to antihistamine treatments.

Patients frequently present to the emergency department in shock with no obvious etiology. Rapid recognition of shock requires the integration of information from immediate history and physical

examination. Shock can be strongly supported by the presence of a worsening base deficit or lactic acidosis. In general, patients in shock exhibit a stress response: They are ill appearing, pale, often sweating, usually tachypneic or grunting, and often with a weak and rapid pulse ( Box 4-2 ). HR can be normal or low in shock, especially in cases complicated by prescribed drugs or profound hypoxemia that can depress HR. BP can be normal because of adrenergic reflexes or because of measurement errors from cuff sphygmomanometry.[21] As a result, arterial BP as a sole measurement remains an unreliable marker of circulatory status. The HR-to-systolic BP ratio may provide a better marker of shock than either measurement alone; a normal ratio is less than 0.8.[34] Urine output provides an excellent indicator of organ perfusion and is readily available with insertion of a Foley catheter into the bladder. Measuring urine output requires at least 30 minutes, however, to determine accurately if output is normal (>1 mL/kg/hr), reduced (0.5 to 1 mL/kg/hr), or severely reduced (<0.5 mL/kg/hr). Measurements of the arterial lactate concentration and the base deficit can be performed rapidly and provide accurate assessment of global perfusion status. An arterial lactate concentration greater than 4 mM/L or an arterial base deficit more negative than -4 mEq/L predicts the presence of circulatory insufficiency severe enough to cause subsequent multiple organ failure.[35] BOX 4-2 Empiric Criteria for Diagnosis of Circulatory Shock[*]

▪ ▪ ▪ ▪ ▪ ▪

Ill appearance or altered mental status Heart rate >100 beats/min Respiratory rate >22 breaths/min or PaCO2 <32 mm Hg Arterial base deficit <-5 mEq/L or lactate >4 mM/L Urine output <0.5 mL/kg/hr Arterial hypotension >20 minutes duration

* Regardless of cause. Four criteria should be met.

When the empiric criteria for circulatory shock are discovered, the next step is to classify the cause of shock ( Figure 4-4 ). Although the questions in Figure 4-4 are connected in sequence to allow logical organization, parallel processing of all these questions is required to determine a cause rapidly in practice. The history, vital signs, and physical examination documented by prehospital providers represent a valuable insight into a patient's physiologic status before any medical intervention and can be useful in emergency department management. A study found that nontrauma patients with symptoms consistent with circulatory insufficiency and prehospital hypotension (systolic BP <100 mm Hg) have a threefold increase in in-hospital mortality than patients without hypotension. [36]

Figure 4-4 Flow diagram to classify undifferentiated shock.

The primary survey must ensure presence of a patent airway and sufficient respiratory effort to ensure adequate oxygenation and ventilation. The physical examination should be performed on an undressed patient and should begin with general inspection of the body for visual or tactile evidence of trauma; odor of ethanol or other toxins; presence of any indwelling devices; and evidence of soft tissue or bone infection, rashes, or extremity edema. Dry mucous membranes suggest dehydration, whereas distended jugular veins suggest cardiac failure or obstruction from pulmonary embolism or cardiac tamponade. Muffled heart sounds suggest cardiac tamponade, whereas a loud machine-like systolic murmur indicates acute rupture of a papillary muscle or rupture of the interventricular septum. Bilateral pulmonary rales in a patient with a normal rectal temperature help to define the presence of left ventricular failure. Wheezing suggests bronchospasm from anaphylaxis or, less likely, cardiac failure or pulmonary embolism. Abdominal tenderness may indicate peritoneal inflammation or occult trauma. Rectal and pelvic examinations may disclose occult gastrointestinal hemorrhage or an unexpected adnexal mass or tenderness indicating an ectopic pregnancy. Rectal temperature should be performed on every patient with suspected shock. The initial neurologic examination may be extremely helpful, especially to providers later during hospitalization, and should include notation of speech fluency and content, ability to follow one-step commands, pupillary function and cardinal eye movements, symmetry of extremity movements, and strength. In children, documentation should include level of alertness, response to parents, appropriateness of crying, pupillary function, symmetry of grimace, and symmetry of extremity movements (and motor tone in infants). Laboratory, radiographic, and other ancillary data should be ordered (1) to assess tissue and vital organ perfusion and (2) to diagnose injury from trauma, find the source of infection with sepsis, or identify the

cause of cardiac failure. A chest radiograph can identify significant thoracic trauma, pulmonary infection, pulmonary edema, or tension pneumothorax. In adults, an ECG helps to identify myocardial ischemia, cardiac failure from dysrhythmia, or pulmonary embolus. A finger-stick glucose measurement can identify unsuspected hyperglycemia or hypoglycemia, which might prompt further evaluation for myocardial ischemia or a source of infection. A hemoglobin level less than 8 g/dL strongly suggests the need for blood transfusion if other criteria for shock are present (see Box 4-2 ). Serum electrolytes can help identify a metabolic acidosis indicating lactic acidosis, an elevated blood urea nitrogen-to-creatinine ratio suggests dehydration or chronic gastrointestinal bleeding, and combined electrolyte abnormalities of hyponatremia and hyperkalemia suggest adrenal insufficiency. The complete blood count helps to diagnose anemia or identify neutropenia. Arterial blood gases are ordered for a base deficit calculation; a normal arterial oxygen partial pressure (PaO2) from a patient breathing room air can rule out hypoxemia. Serum lactate measurement should be performed as early as possible in patients with suspected shock. Urinalysis can reveal dehydration (specific gravity >1.025 with ketones present) and can identify urinary infection as a cause of sepsis. Some emergency departments have bedside ultrasound capability, and cardiac and abdominal scanning can be performed rapidly at the bedside to screen for inadequate central venous volume, occult hemoperitoneum, abdominal aortic aneurysm, left ventricular failure, and cardiac tamponade. A systematic ultrasound protocol can improve significantly the physician's ability to diagnose accurately the etiology of undifferentiated shock in emergency department patients.[37] Consensus definitions of shock show the spectra of hypoperfusion for the following three common causes of shock ( Box 4-3 ): Septic shock. The American College of Chest Physicians and Society for Critical Care Medicine[38] developed a consensus to distinguish septic shock from its precursor conditions, systemic inflammatory response syndrome and sepsis syndrome. Although this particular consensus requires persistent hypotension to define septic shock, initiation of treatment for empirically diagnosed septic shock should not await the onset of hypotension. 2. Hemorrhagic shock. The American College of Surgeons has divided hemorrhagic shock into four stages, depending on the severity of blood loss and the physiologic response to this loss, but such arbitrary divisions are of little value. A more useful approach defines hemorrhagic shock as being present when systemic hypoperfusion manifests as lactic acidosis with organ dysfunction. 3. Cardiogenic shock. Many experts reserve the definition of cardiogenic shock for cardiac failure with arterial hypotension that is refractory to inotropic/vasopressor therapy.[39] Cardiogenic shock should be thought to be present, however, whenever cardiac failure (ischemic, toxic, or obstructive) causes systemic hypoperfusion that manifests as lactic acidosis with organ dysfunction. BOX 4-3 Definitions and Criteria for Septic, Hemorrhagic and Cardiogenic Shock 1. Septic Shock

Systemic inflammatory response syndrome (SIRS) Two or more of the following: 1. Temperature >38° C or <36° C 2. Heart rate >90 beats/min 3. Respiratory rate >20 breaths/min or PaCO2 <32 mm Hg 4. While blood cell count >12,000/mm 3, <4000/mm3, or >10% band neutrophilia Sepsis syndrome SIRS associated with organ dysfunction or hypotension; organ dysfunction may include presence of lactic acidosis, oliguria, or altered mental status Septic shock SIRS with hypotension despite adequate fluid resuscitation; septic shock should still be diagnosed if vasopressor therapy has normalized blood pressure

Hemorrhagic Shock

▪ ▪

Simple hemorrhage Suspected bleeding with pulse <100 beats/min, normal respiratory rate, normal blood pressure, and normal base deficit Hemorrhage with hypoperfusion Suspected bleeding with base deficit <-5 mEq/L or persistent pulse >100 beats/min Hemorrhagic shock Suspected bleeding with at least four criteria listed in Box 4-2

Cardiogenic Shock

Cardiac failure Clinical evidence of impaired forward flow of the heart, including presence of dyspnea, tachycardia, pulmonary rales, peripheral edema, or cyanosis Cardiogenic shock Cardiac failure plus four criteria listed in Box 4-2

Monitoring Perfusion Status
In the effort to resuscitate a patient with circulatory shock, the clinician must follow specific indices of systemic perfusion and organ function to know if the resuscitation effort is working. In all patients with shock, circulation must be monitored by continuous ECG and pulse oximetry to follow HR and to maintain arterial oxygenation. BP should be measured by cuff sphygmomanometer every 2 to 5 minutes during resuscitation. Because cuff sphygmomanometer measurement may be inaccurate in severe hypotensive states, the use of an arterial pressure monitoring line should be considered. Clinicians should remember that BP and HR correlate poorly with cardiac index in shock and often underestimate the severity of systemic hypoperfusion.[21] Children with hypovolemic shock frequently have a normal BP until they rapidly deteriorate to a near-arrest hemodynamic state.[40] Urine output should be measured as an index of vital organ perfusion in patients (about 1 mL/kg/hr in persons without renal disease). Normalization of the serum lactate concentration or the base deficit, when observed with improving vital signs and urine [35] output, can gauge reliably the adequacy of resuscitation and prognosis in shock from any etiology. [41] An increasing lactate concentration (or refractory hypotension with worsening base deficit) with ongoing volume resuscitation portends high mortality and mandates more aggressive resuscitation or specific procedural intervention. The method of achieving intravenous access in a patient with suspected shock has been controversial. Most patients with shock can be fully resuscitated and adequately monitored with peripheral venous access established either with two catheters of size 18-gauge or smaller or with one catheter 16-gauge or larger. Patients with cardiac failure or renal failure may require closer measurement of the central venous pressure (CVP) and insertion of a central venous catheter. An 8.5F central venous catheter allows for accurate measurement of the CVP and insertion of a pulmonary artery catheter or other monitoring device if needed. In children, a 3F or 5F bi-lumen catheter can be placed in the femoral vein with few [42] complications. To reduce the potential for limb damage from extravasation from a peripheral intravenous catheter, vasoactive medications optimally are administered through a central venous catheter. If vasoactive medications are administered, additional peripheral intravenous catheters are required for infusion of crystalloid and other treatments. Many patients with renal disease or cancer have indwelling catheters in place. In patients with empiric criteria for shock, this catheter should be used for intravenous access, unless satisfactory access already has been established. In emergency departments, where the standard practice is not to use these ports at the request of other physicians, a specific hospital policy and training session should be developed to make an exception in the case of circulatory shock. If such a policy does not exist, the threat to the patient from failure to administer fluids rapidly and in sufficient quantity outweighs considerations about preservation of the line for future therapy.

Goal-Directed Therapy
Goal-directed therapy refers to the practice of resuscitating patients to a defined physiologic endpoint indicating that systemic perfusion and vital organ function have been restored. [35] For many years in the intensive care unit (ICU), physicians have relied on the use of the pulmonary artery catheter to help optimize left ventricular filling indices. At present, the use of the pulmonary artery catheter is controversial, based on evidence suggesting that its insertion was associated with increased morbidity in ICU populations. One multicenter randomized, controlled trial evaluated using pulmonary artery catheters in ICU patients with shock or ARDS (or both), and there were no differences in the use of vasoactive agents, number of days of organ failure, or mortality.[43] When data from 16 randomized, controlled trials were aggregated in a meta-analysis, however, pulmonary artery catheterization was associated with significantly reduced morbidity in ICU populations.[44] Insufficient data have been published to support the use or avoidance of pulmonary artery catheters in emergency department patients. Several alternative methods to the pulmonary artery catheter have been proposed as endpoints to resuscitation in the emergency department. The lactate clearance index refers to serial measurements of arterial lactate.[41] Lactate clearance involves measuring the blood lactate concentration at two or more times. If the lactate concentration has not decreased by 50% 1 hour after resuscitation has begun, additional steps must be taken to improve systemic perfusion. Resuscitation should continue until the lactate concentration decreases to less than 2 mM/L. Enthusiasm for lactate measurement as an endpoint must be tempered by the relative lack of data from emergency department studies and the lack of availability of the test. Mixed venous oxygen saturation (SvO2) measurements reflect the balance between oxygen delivery and oxygen consumption. Previous studies suggested that the SvO2 can be used as a surrogate to cardiac index when targeting normalization of endpoints (SvO2 70% or cardiac index 2.5 to 3.5 L/min/m2) for therapeutic intervention in critically ill patients.[45] Although SvO2 requires the use of a pulmonary artery catheter, the central venous oxygen saturation (ScvO2) drawn from the central circulation has been shown to parallel the SvO2 closely, especially when tracking changes or trends in the values.[46] Gastric or rectal tonography also has been studied extensively in ICU populations. A buffer-filled balloon consisting of a permeable membrane is inserted into the stomach or rectum. The balloon has an electrode in the buffer solution and can estimate the intramucosal pH. Mucosal pH is used to estimate the perfusion status of the gut. Use of gastric tonography as an endpoint failed to predict organ dysfunction and mortality in one randomized, controlled study of heterogeneous ICU patients admitted from an emergency department.[47] Goal-directed therapy incorporates multiple indices of circulatory status and oxygenation status. One study found that goal-directed therapy significantly reduced mortality and morbidity in emergency department patients with systemic inflammatory response syndrome and several criteria for severe sepsis [48] or septic shock. Patients were resuscitated within the first 6 hours of care to achieve several hemodynamic parameters and to maintain central venous oxygen saturation greater than or equal to 70% ( Figure 4-5 ). This new treatment strategy has not been tested in other causes of shock, but it shows the value of using defined physiologic endpoints to measure systemic perfusion during resuscitation from shock in the emergency department. This approach also further substantiates the view that the real “make-or-break” time to treat shock occurs during the first 6 hours of resuscitation.

Figure 4-5 Flow diagram outlining the protocol for early goal-directed therapy when treating patients with severe sepsis or
septic shock. This protocol outlines specific hemodynamic and physiologic parameters the clinician should seek to achieve within the first 6 hours of care. This protocol is focused on resuscitation and should be used in conjunction with standard clinical care for patients with suspected infection, such as appropriate diagnostic studies to determine the focus of infection and appropriate antimicrobial agents to treat the infection. CVP, central venous pressure; MAP, mean arterial pressure; Scvo2, central venous oxygen saturation. (Redrawn from Rivers E, et al: Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 345:1368, 2001.)

Rapid sequence intubation is the preferred method in most patients with shock (see Chapter 1 ). Anesthetic agents with a high degree of cardiovascular stability, such as ketamine or etomidate, should be used in reduced dosages (half of normal induction dose) with a full dose of succinylcholine to achieve intubation while minimizing cardiovascular depression. Intubation prevents aspiration, increases oxygenation, treats acute respiratory failure, provides initial treatment for metabolic or hypercarbic acidemia, and protects the patient who will be sent to an uncontrolled environment (e.g., for tests). Intubation also reduces the work of breathing, which, in the hypoperfused patient, further exacerbates lactic acidemia. Strenuous use of accessory respiratory muscles can increase oxygen consumption by 50% to 100% and decrease cerebral blood flow by 50%. [49] [50] More importantly, if the patient has increased airway resistance (e.g., bronchospasm with anaphylaxis) or a decrease in lung compliance (e.g., pulmonary edema, ARDS), a more negative intrathoracic pressure must be generated to fill the lungs with each inspiration. The greater suction effect also is exerted on the left ventricle, impeding its ability to eject and increasing functional afterload. Positive-pressure ventilation removes this impedance and can improve ventricular function and cardiac output 30%.[49] All intubated shock patients require at least 5 cm H2O of positive end-expiratory pressure to prevent alveolar consolidation. In acute respiratory failure, ventilation at zero positive end-expiratory pressure can

cause widespread alveolar collapse and lead to severe ventilation-perfusion mismatch and hypoxemia (see Chapter 2 ).

Volume Replacement
The next imperative in shock is to decide when “the tank is full.” The goal in volume replacement is slightly elevated left ventricular end-diastolic volume, which is a difficult measurement to make in the emergency department. The CVP is used most often to estimate right ventricular filling pressure and is used in some goal-directed algorithms. Because both ventricles tend to stiffen during shock, a high CVP (10 to 15 cm H2O) is often needed to produce adequate filling volume. It is a long way, however, from the CVP measurement to actual knowledge of left ventricular end-diastolic volume; a presumed adequate CVP must be substantiated by increases in urine output and BP and decreasing lactate concentrations. [51]

Treating Specific Causes
Box 4-4 summarizes the general treatment approach for the four common causes of shock. BOX 4-4 Clinical Management Guidelines for Four Common Causes of Shock Hemorrhagic Shock

▪ ▪ ▪ ▪ ▪ ▪ ▪

Ensure adequate ventilation/oxygenation Provide immediate control of hemorrhage, when possible (e.g., traction for long bone fractures, direct pressure) Initiate judicious infusion of lactated Ringer's solution (10-20 mL/kg) or 5% hydroxyethyl starch (5 mL/kg) With evidence of poor organ perfusion and 30-minute anticipated delay to hemorrhage control, begin packed red blood cell (PRBC) infusion (5-10 mL/kg) With suspected central nervous system trauma or Glasgow Coma Scale score <9, immediate PRBC transfusion may be preferable as initial resuscitation fluid Treat severe acidosis (pH <6.8) with THAM Treat coincident dysrhythmias (e.g., atrial fibrillation with synchronized cardioversion)

Cardiogenic Shock

▪ ▪ ▪ ▪

Ameliorate increased work of breathing; provide oxygen and positive end-expiratory pressure (PEEP) for pulmonary edema Begin inotropic support; dobutamine (5μg/kg/min) is common empiric agent Seek to reverse the insult (e.g., initiate thrombolysis, arrange percutaneous transluminal angioplasty, or administer charcoal for drug overdose) Consider intra-aortic balloon pump counterpulsation for refractory shock

Septic Shock

Ensure adequate oxygenation; remove work of breathing.

▪ ▪ ▪

Administer 20 mL/kg of crystalloid or 5 mL/kg of colloid, and titrate infusion to adequate urine output Begin antimicrobial therapy; attempt surgical drainage or debridement If volume restoration fails to improve organ perfusion, begin vasopressor support; initial choice includes dopamine, infused at 5-15μg/kg/min, or norepinephrine, infused at 0.1-1μg/kg/min

Anaphylactic Shock

▪ ▪ ▪ ▪

Control airway and ventilation Administer 10-20 mL/kg of crystalloid Test an intravenous bolus of epinephrine (50-100μg), then mix 5 mg of epinephrine in 500 mL of normal saline. Begin infusion at 10 cc/hr, and titrate to arterial blood pressure response Administer 5-10 mg/kg of hydrocortisone or 1-2 mg/kg of methylprednisolone

Hemorrhagic Shock
Standard treatment for hemorrhagic shock consists of rapidly infusing several liters of isotonic crystalloid in adults or three successive 20-mL/kg boluses in children. Colloids, including albumin and hydroxyethyl hetastarch (Hespan), also can be used but at considerable increase in cost and without substantial effect on morbidity or mortality. Colloids offer the theoretical advantage of a high osmotic pressure, which should help to maintain a normal intravascular volume after retransfusion from hemorrhage. If criteria for shock persist despite crystalloid infusion (see Box 4-2 ), packed red blood cells should be infused (5 to 10 mL/kg). Type-specific blood should be used when the clinical scenario permits, but uncrossmatched blood should be used immediately for patients with arterial hypotension and uncontrolled hemorrhage. Onegative blood is used in women of childbearing age, and O-positive blood is used in all other patients (see Chapter 5 ). Substantial evidence supports the use of leukodepleted blood, which has been filtered to remove donor neutrophils.[52] Leukodepleted blood is used in countries outside the United States because it produces less retransfusion-related organ damage.[53] The infusion of hemoglobin-based oxygen carriers as alternatives to packed red blood cells for resuscitation of hemorrhagic shock patients has been studied extensively. In a large randomized, controlled trial, diaspirin cross-linked hemoglobin, a purified and chemically modified human hemoglobin substrate, was compared with crystalloid for initial resuscitation in critically injured patients, and its use [54] resulted in a higher mortality at interim analysis resulting in termination of the trial. Other artificial hemoglobin substitutes may be available in the future but at present show no benefit over packed red blood cells. More recent studies have endorsed the concept of either delayed resuscitation or hypotensive resuscitation for hemorrhagic shock. Bickell and associates[55] showed improved mortality among patients with penetrating torso trauma in whom all resuscitation was withheld until they reached the operating room compared with patients who received standard resuscitation in the prehospital and hospital setting. Other studies have found no mortality difference in patients with hemorrhagic shock who were resuscitated to either standard clinical parameters (systolic BP >100 mm Hg) or hypotensive parameters (systolic BP 70 mm Hg).[56] Although interesting concepts, further prospective controlled studies are needed before the concept of withholding or limiting volume resuscitation in patients with severe bleeding can be endorsed. Controlling hemorrhage remains the cornerstone of treating hemorrhagic shock, and evidence continues to support immediate surgery when direct vascular control cannot otherwise be obtained (see Chapter 34 ). In rare instances, hypodynamic hemorrhagic shock may be treated with a positive inotropic drug. Amrinone and dopamine decrease mortality in crystalloid-resuscitated animals with hemorrhage. [57]

Septic Shock

Septic shock begins as an infectious nidus, which triggers a domino effect of cellular, microvascular, hematologic, and cardiovascular dysfunction. Treatment begins by establishing adequate ventilation to correct hypoxia and pH and to reduce systemic oxygen consumption and left ventricular work. Endotracheal intubation and sedation with or without chemical paralysis are often required. The second goal is to achieve adequate ventricular filling. The choice of fluids in treating septic shock is probably less important than scrupulous monitoring for adequate tissue perfusion. Colloid solutions may decrease the incidence of postresuscitative pulmonary edema and degree of ARDS.[58] Choices for fluid resuscitation involve consideration of availability and the cost-to-benefit ratio. The initial volume replacement should include rapid infusion of 20 to 25 mL/kg of crystalloid, followed by 5- to 10-mL/kg boluses of the least expensive colloid available (usually 6% hydroxyethyl hetastarch) for persistent hypoperfusion. Blood should be transfused in the emergency department to restore hematocrit to at least 30% to 35%. The third directive is to eradicate the infection with antimicrobial therapy and, when necessary, surgical or percutaneous drainage. If an infectious focus is found, the choice of antimicrobial agent can be directed by clinician experience and institutional minimal infective concentration data. When no focus can be found in septic shock, a semisynthetic penicillin with a β-lactamase inhibitor, in combination with an aminoglycoside plus vancomycin, or monotherapy with imipenem-cilastatin is a rational empiric choice. When neutropenia is suspected in a patient with sepsis syndrome, the progression to refractory, fatal septic shock can be cataclysmic. Neutropenia should be suspected in patients who have recently undergone chemotherapy. Chemotherapy patients with sepsis represent a special challenge because the pathophysiology may be complicated by anemia, thrombocytopenia, dehydration from vomiting, and the effect of adjunctive steroid therapy. Chemotherapy patients often have indwelling catheters, which predispose them to more unusual causes of sepsis, including gram-positive bacteria and fungi.[59] Septic shock refractory to volume restoration (urine output or BP remains low; lactate increases) requires vasopressor support. The primary goal of vasopressor support is to increase cardiac output and oxygen delivery to vital organs. Dopamine is a rational first-line therapy in septic shock at 5 to 15 μg/kg/min and titrated to urine output greater than 1 mL/kg/hr and mean arterial BP (two thirds diastolic plus one third systolic) greater than 70 mm Hg. Dopamine primarily stimulates HR and cardiac contractility in doses ranging from 3 to 8 μg/kg/min, then produces peripheral arterial vasoconstriction at doses greater than 10 μg kg/min. Dopamine also may improve splanchnic, renal, and systemic perfusion. If urine output remains low with high doses of dopamine (>10 μg/kg/min), dobutamine should be started at 5 μg/kg/min to increase cardiac output and increased to 20 μg/kg/min to maintain urine output. Multiple agents have been directed against the biologic actions of lipopolysaccharide. Cytokines and autocoids have been investigated in animal studies and human trials of septic shock, but no antichemokine has been adopted for routine clinical use in the emergency department.[1] It seems that no single cytokine or mediator is the sole cause of septic shock, and no single agent treats it. Evidence has emerged to suggest that derangements in the coagulation cascade in addition to a robust inflammatory response contribute substantially to the development of organ dysfunction in the setting of sepsis. Drotrecogin alfa activated (or activated protein C), a recombinant human activated protein with antiinflammatory, antithrombotic, and profibrinolytic properties, has shown promising preliminary results in the [60] treatment of patients with systemic inflammation and organ failure from acute infection. Patients who receive activated protein C have a lower 28-day mortality, but the use of activated protein C is associated with a greater risk of serious bleeding. Certain subgroups may derive additional benefit from the use of activated protein C, including patients older than 50 years, patients with more than one dysfunctional organ system, patients with an Acute Physiologic and Chronic Health Evaluation (APACHE) II score greater than 24, and patients with shock at the time of drug infusion.[61] In general, the institution of activated protein C therapy is not part of the routine emergency department management of sepsis because there is a large window of time for treatment initiation (within 24 hours of meeting criteria). If this therapy is considered, consultation with an ICU physician who would assume care of the patient is recommended because the therapy is continued for 96 hours. The use of corticosteroids in the treatment of sepsis and septic shock has been investigated with mixed results. The results of two large randomized, controlled trials confirm that there is no role for high-dose, short-course corticosteroid therapy in septic shock. [62] [63] Evidence has suggested, however, that some patients with septic shock have relative adrenal insufficiency when the hypothalamic-pituitary axis is tested with a corticotropin stimulation test. One multicenter randomized, controlled trial of patients with septic shock showed a reduction in the mortality rate and number of days on vasoactive medications in nonresponders to a corticotropin stimulation test (defined as an increase of serum cortisol ≤9 μg/dL after

stimulation) who received low-dose hydrocortisone (50 mg every 6 hours for 7 days) versus placebo. [64] More trials are needed to investigate the potential benefit of low-dose hydrocortisone in subgroups of patients with septic shock, and specifically to identify any potential hazards from use of this agent, before any firm recommendations can be made.

Cardiogenic Shock
The immediate treatment of cardiogenic shock focuses on improving myocardial contractility and pump function. Cardiogenic shock traditionally is defined as the combination of systemic signs of hypoperfusion with arterial systolic BP less than 90 mm Hg (or 30% below a known baseline). If work of breathing is tiring the patient, if severe pulmonary edema is causing significant hypoxemia, or if respiratory failure is imminent, intubation and mechanical ventilation should be initiated, followed by emergent treatment of bradydysrhythymia or tachydysrhythmia and inotropic support. For sedation or anxiety, barbiturates, morphine, and benzodiazepines should be avoided in cardiogenic shock; when perfused into a failing heart, their negative inotropism is exaggerated.[65] Cautious doses of fentanyl may be used to manage pain, but the best approach to calm anxiety and restlessness is to improve perfusion. Etomidate has excellent hemodynamic stability and should be used (but in reduced doses) for intubation, accompanied by a full dose of succinylcholine. To improve myocardial contractility, dobutamine and dopamine are the agents of choice begun in order at the same doses used for septic shock. For refractory hypotension and shock, amrinone or milrinone may improve cardiac output. Amrinone and milrinone are biperiden derivatives that increase cAMP by inhibiting phosphodiesterase (complex F-III). These drugs exhibit little tachyphylaxis with no measurable increase in myocardial oxygen consumption.[66] A loading dose of 0.75 mg/kg for amrinone or 50 μg/kg for milrinone is necessary, followed by a titrated constant infusion for either drug (5 to 10 μg/kg/min for amrinone and 0.5 μg/kg/min for milrinone). When pharmacologic support fails to improve indices of perfusion, the next step is to initiate intra-aortic balloon pump counterpulsation (IABPC). IABPC requires the facilities and personnel of a high-level ICU or critical care unit. IABPC can augment diastolic coronary perfusion by 30% and may interrupt the vicious cycle of hypotension-induced myocardial hypoperfusion.[67] Controlled trials have shown IABPC to improve short-term survival, improve post-thrombolytic patency rates, and reduce stroke morbidity. IABPC increases cardiac output by a mean of 30% in refractory cardiogenic shock and can prolong survival until interventional procedures can be performed. IABPC may be contraindicated in patients with aortic insufficiency or severe peripheral vascular disease. The dismal outcome of cardiogenic shock complicating acute myocardial infarction has been improved in recent years. Evidence from a randomized trial suggests that emergent revascularization is not superior to medical management in reducing short-term mortality; however, significant improvements in mortality are seen at 6 months and 1 year (see Chapter 77 ). [68] [69] At present, the management of acute myocardial infarction with cardiogenic shock proceeds as follows and constitutes optimal therapy: (1) ensure adequate ventilation and oxygenation, (2) treat emergent dysrhythmias, (3) initiate inotropic support, (4) administer aspirin if the patient is not allergic, and (5) begin heparin anticoagulation (in absence of contraindications) and arrange for emergent percutaneous transluminal coronary angioplasty.

Anaphylactic Shock
Therapy for anaphylactic shock is aimed at reversing the effect of its mediators. Aggressive volume resuscitation with isotonic fluid should be initiated rapidly in any patient with suspected anaphylactic shock. Epinephrine effectively counteracts the vasodepression, bronchoconstriction, fluid transudation, and reduced cardiac function in anaphylaxis. Epinephrine should be administered intravenously in patients with hypotension, even in the presence of coronary artery disease. Initially, 1 mL of 1:10,000 epinephrine (100 μg) can be injected slowly and the response monitored. Afterward, 5 mg of epinephrine can be diluted in 500 mL of saline, with a starting infusion rate of 10 mL/hr (about 0.02 μg/kg/min) and titrated to maintain perfusion. Corticosteroids are integral to arresting synthesis and release of anaphylaxis mediators. Corticosteroids inhibit phospholipase A2 and decrease prostanoid, leukotriene, and PAF synthesis. Corticosteroids also quench T-cell and mast cell triggering and reduce late-phase bronchial inflammation. Hydrocortisone (5 to 10 mg/kg intravenously) or methylprednisolone (1.5 to 2 mg/kg intravenously) are good choices in anaphylaxis. Histamine receptor antagonists (H1 and H2) prevent urticaria, aid in reducing bronchoconstriction, reduce fluid transudation, and may improve myocardial function. Diphenhydramine (0.5 mg/kg intravenously) and cimetidine (2 to 5 mg/kg intravenously) may be used. Nebulized β2-agonists can be used to help reduce bronchospasm. For patients with profound bronchospasm, obvious increased work of breathing, and hypotension, mechanical

ventilation is indicated. Ketamine is a logical agent to use for sedation during rapid sequence intubation with succinylcholine (see Chapter 1 ).


▪ ▪ ▪ ▪ ▪

Circulatory shock often occurs with normal arterial BP, and not all patients with arterial hypotension have circulatory shock. A base deficit more negative than -4 mEq/L or a serum lactate greater than 4 mmol/L indicates the presence of widespread circulatory insufficiency in suspected shock. Urine output is a reliable index of vital organ perfusion in patients with suspected shock. Ill patients with tachycardia, a worsening base deficit, and low urine output should be diagnosed with circulatory shock. Use of defined physiologic endpoints to measure systemic perfusion during resuscitation (goaldirected therapy) is a valuable approach to optimal resuscitation in emergency department patients with shock.

Munish Goyal, MD David F. Gaieski, MD

Early Goal-Directed Therapy Program Department of Emergency Medicine University of Pennsylvania

• • • • • • Definition of Shock Oxygen Delivery Initial Examination of Patients in Shock Classification of Shock Septic Shock Early Goal-Directed Therapy for Severe Sepsis and Septic Shock


“I’m all congested up here”
• 53 y/o African American Male • HPI
– 1 week chest congestion, cough, f/c

– Seizures, thrombocytopenia

• SH
– Heavy EtOH, 1 ppd tobacco

Triage Vital Signs
Temp: BP: HR: SpO2: RR: 101.6° F 97/65 135 86% on RA 32


Physical Exam
Gen: HEENT: Lungs: CVS: ABD: EXT: Skin: Neuro: WDWN male in respiratory distress Sclerae icteric; MM dry Decreased BS at left base, dullness to percussion; rhonchi R mid lung field Tachy nl. S1, S2; - obvious murmur NT, ND, + BS - C, C, E No rash, hot to touch Alert, but fatigued

Initial Management
IV access Fluid resuscitation Supplemental oxygen Cardiac monitor Labs, cultures, CXR Antibiotics

Is this patient in shock?


What is Shock?
• A physiologic state characterized by
– Decrease in tissue perfusion – Inadequate oxygen delivery

• Delivery isn’t keeping up with demand

What is Shock?
• First clinical definition in 1800s by John Collins Warren
– “A momentary pause in the act of death”
» Warren JC. Surgical pathology and therapeutics. Philadelphia: 1895.

• 1872 - Samuel Gross
– “A rude unhinging of the machinery of life”
» Gross SG. System of surgery: Pathological diagnostic, therapeutique, and operative. Philadelphia: Lea & Febiger; 1872


States of Shock
• Compensated Shock (Warm/Early)
– Organ function maintained – BP remains normal

• Uncompensated Shock (Cold/Late)
– Microvascular perfusion decreases – Organ and cellular function deteriorate – Hypotension develops

Compensatory Mechanisms
• Baroreceptors
– In aortic arch and carotid sinus – Hypotension stimulates vasoconstriction, increased HR, BP and CO

• Chemoreceptors
– Respond to cellular acidosis with vasoconstriction and respiratory stimulation


Compensatory Mechanisms
• Renin-angiotensin system
kidney perfusion leads to renin secretion – Renin Anigiotensin II leading to vasoconstriction and aldosterone release – Aldosterone leads to sodium and water reabsorption

• Humoral Response
– Catecholamine release leading to increased contractility and vasoconstriction

Organ Dysfunction
• Uncompensated Shock Organ Dysfunction
– Decreased urine output ARF – Restlessness agitation obtundation coma – Tachypnea Respiratory muscle hypoxia worsening acidosis respiratory failure – Tachycardia increased myocardial oxygen demand increased catecholamines tachycardia myocardial ischemia

• Initially reversible, becomes irreversible


Irreversible Changes
Cell membrane ion pump dysfunction Intracellular edema Leakage of intracellular contents into the extracellular space This triggers inflammatory cascade

Cascade of Damage
Cell Death End-Organ Damage Failure of Multiple Organ Systems Death Early interventions prevent progression of Shock


Oxygen Delivery
The amount of O2 delivered to tissue (DO2) DO2 = CaO2 x CO CaO2 = Content of O2 in arterial blood
CaO2 = (Hgb x SaO2 x 1.34) + (PaO2 x 0.0031)

CaO2 = Hgb x SaO2


Influenced By


A-a gradient DPG Acid-Base Balance Blockers Competitors Temperature

Influenced By

Drugs Conduction System



EDV Ventricular Compliance

CVP Venous Volume Venous Tone

Influenced By



Influenced By

Afterload Temperature Drugs



Oxygen Delivery



Delivery vs. Consumption

Supply independant

Supply dependant



• A patient can be in shock with
– High or low SVR – High or low CO – High, low or normal blood pressure

Shock is inadequate oxygen delivery to meet metabolic needs

Determinants of BP
Myocardial Contractility Stroke Volume Cardiac Output Blood Pressure Systemic Vascular Resistance
Textbook of Pediatric Advanced Life Support, 1988

Preload Afterload

Heart Rate


Hemodynamic Response to Hemorrhage
% of Control Vasc Resistance

100 Blood Pressure Cardiac Output
25% 50% % Plasma Loss

Common Features of Shock
• Hypoxia acts at cellular level • S/S - manifestations of cellular response
– Fever – Tachycardia – Oliguria – Change in mental status – Metabolic acidosis – Hypotension

Oxygen Delivery is always inadequate


Common Features of Shock
• Hypotension: SBP < 90 or MAP < 65
– Cryptic shock
• normal SBP despite profound tissue hypoxia

– Baseline Hypertension
• drop of > 40mmHg in SBP is highly suggestive of shock

– Baseline Hypotension
• Some patients live in 80s/50s

Initial Examination
• History and Physical often limited by patient’s condition • Exam
– quick – high yield for finding source of shock

• Often in conjunction with treatment


Physical Exam (cont’d)
• • • • Gen: Distress?, mentating?, LETHARGIC HEENT: Sclera; mucous membranes; pupils NECK: JVD; meningeal signs LUNGS: Tachypnea; accessory muscle use; Kussmaul respirations; abnormal or absent breath sounds • CVS: Tachycardia; dysrhythmias; murmurs; muffled heart sounds; strength of pulses • Abdomen: Scars; bowel sounds; guarding; rebound; peritoneal signs; ascites

Physical Exam (cont’d)
• Rectal: Decreased tone, blood • Extremities: Swollen calf; palpable cord; pulse differentials • Neuro: Agitation; confusion; delirium; coma; focal deficits; seizure activity • Skin: Temperature; hyperemic; rashes; petechiae; urticaria; cellulitis; embolic stigmata


Limb hypoperfusion

Classification of Shock
1. 2. 3. 4. Hypovolemic Shock Cardiogenic Shock Distributive Shock Neurogenic Shock

Oxygen Delivery is always inadequate


Cardiovascular Changes
Type Hypovolemic Cardiogenic Distributive Neurogenic -- / Preload Afterload Contractility -- /

Hypovolemic Shock
• Problem: Decreased Preload preload SV CO DO2 • Initial response is to increase HR in attempt to maintain CO • Result of:
– Hemorrhage – Dehydration – Fluid loss


Cardiogenic Shock
• • • Problem: Contractility Pump failure alters Frank-Starling curve; results in SV and CO Multiple causes:
1. Myopathies: ischemia; dilated cardiomyopathy; myocardial depression of sepsis 2. Arrhythmias: atrial or ventricular 3. Mechanical: acute MR; acute AI; critical AS 4. Obstructive: Extracardiac causes including tamponade, tension pneumothorax, massive PE

Distributive Shock
• Essential derangement: hypovolemia • Multiple causes: SVR, functional

– SIRS Inflammatory cascade: pancreatitis; burns; trauma; infection – TSS – Anaphylaxis – Addisonian Crisis – Myxedema Coma


Neurogenic Shock
• Problem: Functional hypovolemia with lack of compensation • Paralysis of the sympathetic chain which controls vascular tone from injury to thoracic or cervical level spinal cord injury • Produces SVR from loss of vascular tone and bradycardia from unopposed parasympathetic input to SA node

Septic Shock
• Combination
– Distributive – Cardiogenic – Hypovolemic

• Most common form of Shock • On a continuum from SIRS to Septic Shock


The Continuum of Sepsis
SIRS Sepsis Severe Sepsis Septic Shock

Systemic Inflammatory Response Syndrome SIRS criteria • • • • Temp < 96.8° or > 100.4° F HR > 90 RR > 20 or PCO2 < 32 WBC < 4 or > 12 or bands > 10%
Bone et al. Chest 1992;101:1644

The Continuum of Sepsis
SIRS Sepsis Severe Sepsis Septic Shock

Systemic Inflammatory Response to Infection • Suspected or confirmed infection • 2 or more SIRS criteria

Bone et al. Chest 1992;101:1644; Balk, RA


The Continuum of Sepsis
SIRS Sepsis Severe Sepsis Septic Shock

Sepsis plus Organ Dysfunction • Elevated Creatinine • Elevated INR • Altered Mental Status • Elevated Lactate • Hypotension that responds to fluid
Bone et al. Chest 1992;101:1644

The Continuum of Sepsis
SIRS Sepsis Severe Sepsis Septic Shock

Severe Sepsis and Hypotension • Hypotension that does NOT respond to fluid (30 cc/kg bolus)

Bone et al. Chest 1992;101:1644


Why is this so Important?
• • • • 750,000 cases/yr of severe sepsis in US 215,000 deaths/yr directly related to sepsis Tenth leading cause of death in USA Rate of sepsis cases is increasing faster than the population • 37% of severe sepsis patients come through the ED

Why so Important? (cont’d)
Mortality of Severe Sepsis

200,000 150,000 100,000 50,000 0
AIDS* Breast AMI† Severe Cancer§ Sepsis‡

†National Center for Health Statistics, 2001. §American Cancer Society, 2001. *American Heart Association. 2000. ‡Angus DC et al. Crit Care Med. 2001 (In Press).


• AMI – “Time is Muscle”

Early Interventions in Medicine

– ACC/AHA guidelines for STEMI
• Door-to-needle time for initiation of fibrinolytic therapy should be achieved within 30 minutes • Door-to-balloon (or medical contact–to-balloon) time for PCI can be kept under 90 minutes.

• Stroke – “Time is Brain”
• IV rtPA is strongly recommended within 3 hours of onset of ischemic stroke (grade A).

• Trauma
– Golden Hour – …the lives of severely injured people could be saved if treated by trauma specialists

Early Goal-Directed Therapy (EGDT)


• Design
– Randomized, Blinded, Controlled trial

• Patients
– 263 adults with severe sepsis and lactate > 4 or septic shock

• Intervention
– 6 hours of algorithmic care which optimized
• CVP 8-12 • MAP > 65 • ScvO2 > 70%

• Outcome
– Mortality in house, 28 day, and 60 day

Rivers, E. et al. N Engl J Med 2001;345:1368-1377


Rivers, E. et al. N Engl J Med 2001;345:1368-1377

EGDT Results
28-day Mortality
60 50 40 30 20 10 0 49.2%

P = 0.01*

Standard Therapy n=133

EGDT n=130

*Key difference was in sudden CV collapse, not MODS
Rivers E. N Engl J Med 2001;345:1368-77.


Insert CVC in IJV or SCV Send ScvO2 if not Presep® catheter Notify Super SAR about need for MICU Bed, measure Apache II score





Bolus 500 ml NS q15-20
MAP 65




1. Start/Titrate norepi 2 mcg/min or dopamine 5 mcg/kg/min* 2. Dexamethasone 4 mg IV Q6 for refractory hypotension 3. Place arterial line if time permits
ScvO2 70%



*If patient requires vasopressor: Serum cortisol just prior to giving ACTH Give 250 mcg ACTH IV Serum cortisol 1 hour after ACTH given

Transfuse PRBC’s until HgB

10 Consider activated protein C if Apache II > 25




No Start/Titrate Dobutamine 2.5 mcg/kg/min (increase by 2.5 mcg/kg increments; hold for hr > 120, map < 65)





CVP, MAP, ScvO2 goals achieved.

Re-evaluate to achieve goals.

What is Central Venous Pressure (CVP)?
Pressure in the thoracic vena cava Estimates right atrial pressure Estimates right ventricular pressure Estimates right ventricular volume

Estimates preload


CVP Values
• Normal in a healthy human
– 0-8 mmHg

• Goal if spontaneously breathing
– 8-12 mmHg

• Goal with positive pressure ventilation
– Increases 3-5 mmHg (11-16mmHg)

CVP Values
• Low CVP (<8)
– Volume depleted – Negative pressure inspiration

• High CVP (>12)
– Heart failure – Volume overload – Obstructed flow (pulmonary htn, TS) – Increased intrathoracic pressure


CVP Monitoring
• CVP is first physiologic parameter in EGDT
– CVP < 8 = volume resuscitation – CVP normal or elevated, proceed to MAP

Mean Arterial Pressure
• MAP = [(2 x diastolic)+systolic] / 3 • Goal MAP - 65 • Measured directly or indirectly
– Arterial Catheters
• • • • Direct measurements Most accurate technique in shock states Continuous hemodynamic information Facilitates ABG measurement
Hollenberg SM. Crit Care Med 1999; 27:639-660. Bellomo R. Lancet 2000; 356: 2139-2143. Kellum J. Crti Care Med 2001; 29: 1526-1531.


Mean Arterial Pressure
• If MAP < 65 after fluid challenge start Vasopressors
• Should be used transiently in the face of life-threatening hypotension, while fluid challenge is in progress

• Norepinephrine or dopamine in septic shock
• Norepinephrine may be more effective at reversing hypotension in septic shock patients • Dopamine may be useful in patients with compromised systolic function but causes more tachycardia and arrhythmias

LeDoux D. Crit Care Med 2000;28:2729-2732. Martin C. Chest 1993;103:1826-1831. DeBacker D. Crit Care Med 2003;31:1659-1667. Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

Regnier B. Intensive Care Med 1977;3:47-53. Martin C. Crit Care Med 2000;28:2758-2765. Hollenberg SM. Crit Care Med 1999; 27: 639-660.

• Oxygen Saturation of Venous hemoglobin • Amount of oxygen left over after the body removes what it needs • Represents the balance between oxygen delivery and consumption



Rivers et al, 2001

Continuous ScvO2 Catheter


SvO2 v. ScvO2

75% 75%




Rivers et al, 2001


Return to our Patient
Temp: BP: HR: SpO2: RR: 101.6° F 97/65 135 86% on RA 32

Physical Exam
Gen: HEENT: Lungs: CVS: ABD: EXT: Skin: Neuro: WDWN male in respiratory distress Sclerae icteric; MM dry Decreased BS at left base, dullness to percussion; rhonchi R mid lung field Tachy nl. S1, S2; - obvious murmur NT, ND, + BS - C, C, E. No rash, hot to touch Alert, but fatigued


How’s Our Patient Doing?
• SpO2 91%, RR 36, HR 130, BP 138/74 • Notable labs: – WBC: 5.3 – Hgb: 15 (Hct - 43) – Platelet: 19 – BMP 131/3.5/94/16/23/2.0/116 – INR – 1.8, PTT – 46.2 – Tbili=6.6; direct=5.3 – Lactate 8.4 Cryptic Shock • CXR: Left Lower Lobe pneumonia


ED Course
• • • • • Cefepime 1 gm IV Intubated for hypoxemia, AMS, ScvO2 catheter placed Arterial line placed Initial ABG – on 100% FiO2
– 7.27/42/126/-6.6 P/F ratio = 126


ED Course
• CVP – 8 (intubated)
– 500 cc NS bolus q 30 min until CVP – 12 – Total intake – 9L

– Initially 70s, dropped to 60 – Norepinephrine started at 1 mcg/min – Maintained MAP >65 with norepi @ 2

• ScvO2
– Remained 70-80%


ED Course
• Repeat Labs
– Creatinine – 1.1 (2.0) – Lactate – 5.8 (8.4) – Base Deficit – 1.0 (6.6) – pH – 7.38 (7.27)

• Transferred to MICU
– Continued Goal-Directed Therapy

Case Conclusion
• Blood and Sputum Cx
– Streptococcus pneumoniae

• Weaned off vasopressors HD # 5 • Self-extubated at HD # 5 • D/c’ed home on hospital day # 14


Topics Covered
• • • • • • Definition of Shock Oxygen Delivery Initial Examination of Patients in Shock Classification of Shock Septic Shock Early Goal-Directed Therapy for Severe Sepsis and Septic Shock


Sign up to vote on this title
UsefulNot useful