EMCrit.org

Shock and Vasoactive Agents

vasoactive handout

Best Circulatory Review (Chest 2002;121:877)

Best article on VR and CVP physiology (Anesthes 2008;108(4):735)

Starling Curves

Poiseuille’s law representing the relationships among flow (Qflow), pressure, and resistance.

Figure 3 illustrates a three-compartment circulatory model that conceptualizes the circulatory system as a hydraulic pump composed of a right heart pump linked in series to a left heart pump. As a consequence of this serial hydraulic alignment, CO cannot exceed venous return (VR) and vice versa. In other words, left heart output cannot exceed right heart output, which allows for the conceptualization of both pumps as a single hydraulic unit. The hydraulic pump is primed with volume from the venous capacitance bed [ie, the volume reservoir] and empties into the arterial impedance bed (ie, the resistive element). Guyton et al⁴⁹ recognized that the pressure gradient for VR is the ratio of pressure in the venous capacitance bed (PVC) to the RAP (VR = PVC - RAP), thus establishing the integral role of the right atrium (RA) as a coupler of the venous system and cardiac hydraulic circulation. The graphic solution of this observation is depicted in Figure 3 . PVC is a function of venous volume and vascular tone, which must exceed the RAP to maintain VR. The RAP provides not only an assessment of the pressure in the right heart but an indirect gauge of the pressure in the venous capacitance system. Thus, the circulatory system can be defined as a three-compartment model; a capacitance bed that provides volume to a hydraulic pump that generates flow into an impedance bed. Any hemodynamic abnormality can be characterized by disturbances of one or more of these three variables. The surrogates for venous capacitance pressure, hydraulic pump function, and impedance are RAP, CO, and systemic vascular resistance (SVR), respectively. Invasive monitoring is frequently not in place on initial presentation, and, given the controversies surrounding its risks and benefits,⁵⁰ it is prudent to utilize readily available physical examination surrogates to define the model variables. Estimation of the RAP from the internal jugular vein approximates the pressure in the venous capacitance system, and the pulse character and temperature of the extremities approximate impedance (resistance). Warm flushed extremities with a wide pulse pressure indicate low impedance (ie, resistance), whereas cool constricted extremities with a narrow thready pulse suggest high impedance (ie, resistance). The latter is a consequence of the catecholamine-mediated vasoconstriction that is initiated to create perfusion pressure gradients to redistribute and optimize the low-flow state. In shock patients, flow and resistance are almost uniformly reciprocal (Qflow x resistance = pressure or CO x SVR = BP). Therefore, the initial assessment of impedance (ie, resistance) allows for the inferential derivation of hydraulic flow (ie, CO). Obviously, invasive monitoring will be needed if the physical examination findings cannot be well-characterized. Representative examples are illustrated in Figure 3 .

Pathophysiology
Mechanism of Cardiac Failure
Cardiac failure from MPE results from a combination of the increased wall stress and cardiac ischemia that comprise RV function and impair left ventricular (LV) output. Research from animal models and evidence from clinical investigations clearly demonstrate that the impact of embolic material on the pulmonary vascular outflow tract precipitates an increase in RV impedance. This initiates the vicious pathophysiologic cycle depicted in Figure 4 . The degree of increase in RV impedance is predominantly related to the interaction of the mechanical obstruction with the underlying cardiopulmonary status.^{51 52 53} Additional factors reported to contribute to increased RV impedance include pulmonary vasoconstriction induced by neural reflexes,⁵⁴ the release of humoral factors⁵⁵ from platelets (ie, serotonin and platelet activating factor), plasma (ie, thrombin and vasoactive peptides C3a, C5a), tissue (ie, histamine), and systemic arterial hypoxia.⁵⁶ The acute development of this increased RV impedance constitutes a pressure afterload on the RV and has multiple effects on RV and LV function.

Given the reciprocal relationship between RV stroke volume and vascular load, RV stroke volume will diminish with increasing load.⁵⁷ Initially, the compensatory maintenance of CO is achieved by a combination of catecholamine-driven tachycardia and the utilization of the Frank-Starling preload reserve (the latter being responsible for RV dilatation). This increase in RV cavitary pressure and radius serves to significantly increase RV wall stress (wall stress = pressure x radius). This is the primary determinant of RV oxygen uptake, thus creating the potential for RV ischemia. With increasing RV load and wall stress, RV systolic function becomes depressed and CO begins to decrease. Interestingly, systemic BP may be adequately maintained by systemic vasoconstriction at this point.⁵⁸ From the point of initial CO depression, it has been reported⁵⁹ that increases in load sufficient to further decrease CO by 20% will result in a disproportionate increase in end-systolic volume compared to end-diastolic volume. Afterload mismatch has been used to describe the phenomenon of RV pressure work exceeding RV volume work in this setting.⁶⁰ As a consequence of this mismatch, LV preload will decrease, given the ventricular alignment in series. LV preload is additionally impaired by decreased LV distensibility as a consequence of a leftward shift of the interventricular septum and of pericardial restraint, both of which are related to the degree of RV dilatation.^{61 62 63} It also has been suggested that MPE may impair LV function independently of preload mechanisms.⁶⁴ In the presence of declining LV forward flow, MAP can be maintained only by catecholamine-induced vasoconstriction. A further decrease in LV flow results in systemic hypotension. RV coronary perfusion pressure (CPP) depends on the gradient between the MAP and the RV subendocardial pressure. Decreases in MAP associated with increases in RV end-diastolic pressure (RVEDP) impair the subendocardial perfusion and oxygen supply. Elevated right-sided pressures can further impair coronary perfusion and LV distensibility by increasing coronary venous pressure.⁶⁵ Increased oxygen demands associated with elevated wall stress coupled with decreased oxygen supply have been shown to precipitate RV ischemia, which is thought to be the cause of RV failure.⁶⁶ Clinical evidence of RV infarction as a consequence of the preceding condition has been demonstrated in patients with and without obstructive coronary disease.^{67 68 69} A reversal of PE-induced RV ischemia and RV failure can be accomplished by the infusion of vasoconstrictors to raise aortic pressure and to increase the coronary perfusion gradient.^{66 70}

Translation of the pathophysiology of MPE into the previously discussed three-compartment hydraulic model of the circulation is shown in Figure 5 . Catecholamine-induced venoconstriction increases the PVC to maintain a pressure gradient for VR in response to the PE-induced RAP elevation. The impairment of RV hydraulic pump function compromises LV hydraulic output, which is manifested as systemic arterial hypotension. Thus, the model variables would reveal an increased RAP, a decreased CO, and an increased SVR. The clinical correlates would be jugular venous distention, a thready pulse, and cool extremities, respectively.

1st Question: Is this patient in shock; is the shock adequately resuscitated

2nd Question: Does the patient need fluid

Markers of regional perfusion are really the answer to the first question

Neligan Notes

CV system consists of a pump (cardiogenic), tubing (distributive), and fluid (hypovolemic)

Shock is malfunction of at least one of the above. It is hypotension with signs of end organ failure

Another way to think about it is a failure of one of the following: stroke volume, heart, or peripheral vascular resistance and a failure of compensation of the other two.

Dysoxia-when the production of ATP is limited by oxygen supply

Low Stroke Volume

Inadequate Venous Return

Signs= a lingering tachycardia, cold peripheries or a pulse oximeter that is not reading, oliguria, low CVP, a large base excess on blood gas analysis, a lactic acidosis. In this state, patient can become hypotensive from medications such as sedatives.

Diastolic Dysfunction = stiff heart, requiring higher filling pressure to achieve normal volume.

2) Diastolic Dysfunction: loss of left ventricular compliance impairs it’s ability to receive blood. This disorder most commonly results from systolic dysfunction, and as a consequence of myocardial fibrosis – for example due to ischemia or hypertension. Diastolic dysfunction is characterized by the requirement of higher filling pressures to achieve normal filling volumes, while the heart is less compliant and receptive to blood. Aggressive volume loading of patients with diastolic dysfunction frequently results in backward heart failure, causing acute pulmonary edema.

Cardiac inflow obstruction is caused by a pericardial (tamponade) or intrathoracic process (PEEP), or a lesion within the heart itself (mitral stenosis).

3) Cardiac inflow obstruction: occurs either due to a constriction around the heart, a pericardial or intrathoracic process, or a lesion within the heart itself. Pericardial injuries include pericardial effusion or hematoma constrictive pericarditis – an acute crisis associated with a pericardial injury is called tamponade. Tamponade is diagnosed as a tetrad of shock, clear lung fields, inaudible or muffled heart sounds, and an increase in the jugular venous pulse waveform on inspiration.

An often forgotten but extremely common cause of hypotension is excessive intrathoracic pressure. This can be transmitted from within the alveolar space – as with positive end expiratory pressure (PEEP) and gas trapping in airway obstruction (auto-PEEP), or within the pleural space – Pneumothorax, hemothorax or, if the patient is in extremis, tension Pneumothorax. Intracardiac lesions may also cause inflow obstruction; these include mitral and tricuspid stenosis or thrombosis, and atrial myxoma.
 

Systolic dysfunction is pump failure from ischemia or overload

Cardiac outflow obstruction is caused by pulmonary embolism, aortic stenosis, aortic crossclamps

2. Outflow obstruction: there are two major sites that cardiac outflow may be blocked: at the level of the aortic valve (aortic stenosis) or within the low pressure (at thus easily occluded) pulmonary circulation – pulmonary embolism. The former can be diagnosed on the basis of history, ECG and classic murmur. The latter may be more difficult to diagnose. Useful information includes risk (cancer, immobility, deep venous thrombosis, lack of prophylaxis,

pelvic and hip surgery), ECG changes (right sided – RVH, sinus tachycardia, atrial fibrillation, right bundle branch block), occasional chest x-ray findings, and definitive diagnosis on ventilation-perfusion scanning, spiral CT or pulmonary angiography.
 

Peripheral Resistance is caused by sepsis, anaphylaxis, or spinal shock

In sepsis, there are three fundamental physiologic upsets: increased synthesis of nitric oxide, activation of ATP-sensitive potassium channels in vascular smooth muscle, and deficiency of vasopressin.

The plasma concentration of nitric oxide is markedly increased in septic shock. The production of this endogenous vasodilator appears to occur due to the expression of inducible nitric oxide synthetase by cytokines. This agent appears to be responsible for the end organ resistance to catecholamines and endothelin in sepsis.
 

If patient is awake, talking, and urinating, then hypotension is probably not shock

Look at lactate and base deficit

Shoot for MAP of 80 in normal folks, 90 in hypotensives

First look at the heart rate

Second look at volume status

Complete heart block, atrial fibrillation, tricuspid stenosis and regurgitation will lead to an inaccurate reading: although the diagnosis of these disorders can be made from the CVP waveform

The central venous pressure should be regarded as a trend. It is conventional to volume load an under-resuscitated patient to a target CVP: I use 8 – 10 mmHg if the non-ventilated patient, and 12 – 16 mmHg, if the patient is on positive pressure ventilation. If there is a question of cardiac disease, cardiac hypertrophy or dilatation or if the patient is middle aged or older, I aim higher – 16 mmHg plus. In many young patients, it is often not possible to raise the CVP above 10 mmHg, such is the efficiency of the cardiovascular system.

Right atrial pressures are more representative of systemic vascular volume. Indeed with pulmonary hypertension, the use of left sided pressures may seriously overestimate the systemic blood volume. The purpose of PACs is to construct Starling (pressure-volume) curves of the left ventricle, to determine the end diastolic volume pressure relationship that optimizes stroke volume. The left ventricular end diastolic pressure is not measured directly, but through a surrogate – the pulmonary capillary wedge pressure (PCWP).

• There is no “normal” CVP or wedge pressures: you must follow a trend and look at responses to therapy, principally fluid boluses.
  
  Abnormal hearts – those with acutely ischemic ventricles, fibrotic or contused myocardiums, are less compliant, and require higher filling pressures to project a “normal” stroke volume. They progressively dilate until there is sufficient muscle stretch to eject this volume. This is why the ejection fraction progressively falls.
  
  It is preferable to use stroke volume rather than cardiac output as the measured response to therapy, as the latter is influence by heart rate, which may be fast for a variety of reasons, and mask a poorly performing ventricle (in sepsis the cardiac output is characteristically high and the stroke volume low).
  
  A low mixed venous oxygen saturation (SvO2) is usually an indication of under-resuscitation, and volume loading is required. It is worthwhile to match this process with lactic acid concentration. An increased SvO2 is difficult to interpret: it may indicate inability to extract oxygen, it may indicate a hyperdynamic circulation.
  
  Normal hearts have huge physiologic reserve, and can cope very well with high filling volumes, consequently, you should never go wrong with aggressively volume loading shocked patients: you will adequately fill abnormal hearts without injuring normal hearts. Always aim your CVP and PCWP targets high!
  
  The first treatment for all kinds of shock, including cardiogenic, is volume, volume and more volume.
  
  A little extravascular lung water is probably less harmful than vasoactive drugs: do not skimp on the fluids for fear of flooding the lungs.
  
  There is no magic mathematical formula which allows you to figure out the influence of PEEP on PCWP and CVP: if transalveolar pressure is kept constant, the trend should be consistent.
  
  The pulmonary artery catheter is a monitor not a therapy: it is not a surrogate for resuscitative therapy or source control.
  
  During the resuscitative process, it should rapidly become apparent to you the CVP and PCWP that the patient’s heart “likes” (in terms of stroke volume and CVP). This is important with regard to fluid mobilization (“deresuscitation”) and redistribution.
  
  If the patient’s blood pressure or stroke volume begins to fall and the filling pressures are higher than those at which optimal stroke volume/cardiac output was obtained, then the patient has likely mobilized fluid, and is now “overloaded”: preload reducing agents such as nitrates and diuretics are required.
  
  An evolving increase in the stroke volume likewise represents hypervolemia: the patient will autodiurese if the kidneys are functioning normally.
  
  Be cautious with the use of derived variables from pulmonary artery catheters. I speak in particular of the “systemic vascular resistance” (SVR). There is, unquestionably, and abnormality in peripheral resistance (PR) in all forms of distributive shock, and appropriate vasoconstriction (and thus high PR) in hypovolemic and cardiogenic shock. Unfortunately, there is no easy method for measuring PR. The SVR is calculated from the equation for change in pressure/flow, which is MAP-CVP/CO. The problem with this equation is the pulsatility of cardiac output flow – it is determined by the heart rate. A fast heart rate for the same stroke volume will lead to the measurement of a lower SVR than before. The PR may not have changed.
   

CO = SV * PR.

The stroke volume of the left ventricle is ultimately determined by the interaction between its preload, the contractile state of the myocardium and the afterload that the ventricle faces. Unfortunately, there is no simple measure of the 'contractile state' and as a result, there is no single equation which describes the relationship between these three parameters.

Preload.
That the 'preload' or stretch on myocardial fibres at the end of diastole had a significant effect on the subsequent force of contraction was recognised by the physiologist Otto Frank at the end of the nineteenth century ¹ (Figure 1).

This fundamental relationship has since been analysed in great detail and the adjustment of preload by blood volume transfusion or depletion remains one of the most important therapeutic manoeuvres in acute cardiovascular medicine.

In practice, such volume adjustments can be made by various means:

1. Circulating blood volume can be increased by the administration of fluid, or reduced by the use of diuretics and / or fluid restriction.

2. Venous return can be varied by the adoption of a head-down or head-up posture.

3. Venous capacitance can be altered by the use of vasoconstrictor or vasodilator therapy.

Contractile State.
In its strictest sense, the term 'contractility' refers to the inotropic state of the myocardium - that is, the force and velocity with which the myocardial fibres contract. This can be easily measured in an isolated muscle preparation under specified loading conditions, but is notoriously difficult to measure in the intact human.

In clinical practice, various contraction-phase indices such as velocity of fibre shortening, peak rate of ventricular pressure rise and end-systolic pressure:volume relationship (Figure 2) are used, but they are all affected by loading conditions to a greater or lesser degree.

The 'chronotropic' or 'rate' state of the intact heart should also be incorporated into any clinical definition of 'contractility' - because variations in the pulse rate can have obvious, important effects on the cardiac output and manipulation of pulse rate by the use of positive or negative chronotropes can be an important therapeutic manoeuvre in sick patients.

It is not possible to make any precise measurements of contractility with a PAC, although it is possible to make reasonable inferences about the contractile state by the use of ventricular function curves (Figure 1). This concept has been developed by Barash et al who have described the use of a 'Hemodynamic Tracking System' which defines the relationship between LVSWI and PAOP in patients with normal, slightly depressed and severely depressed ventricular function ².

Adjustment of both the inotropic and chronotropic state of the heart by the use of inotropic drugs is commonly practised in cardiovascular medicine.

Afterload.
In physiological terms, afterload can be defined as 'The sum of all those forces which oppose ventricular muscle shortening during systole' - although in a clinical sense it is probably more useful to consider systemic vascular resistance as the appropriate measure.

In isolated cardiac muscle, there is an inverse relationship between afterload and the initial velocity of shortening of the muscle (Figure 3). This would suggest a potential dependance of cardiac output on afterload. In fact, in the intact human, the output of the normal heart is relatively unaffected by changes in vascular resistance until afterload becomes quite extreme (Figure 4). This is probably because an increase in afterload leads to an almost immediate, secondary increase in preload by a 'damming up' of the blood within the left ventricle. This, in turn, increases end-diastolic volume which enhances contractility through the Frank-Starling mechanism. In contrast, if myocardial function is severely depressed, cardiac output may become crucially afterload-dependent as illustrated in Figure 4.

Thus, 'sick' hearts can be considered to be relatively preload independent but afterload dependent while the reverse is true for 'healthy' hearts. As a result, 'afterload reduction' (reduction of systemic vascular resistance by the use of appropriate vasoactive drugs) is of the greatest benefit in those in whom myocardial function is most depressed.

The role of blood viscosity and, indirectly, haemoglobin concentration in determining SVR is often overlooked. Although haemodilution is not commonly used as a therapeutic manoeuvre for afterload reduction, inadvertent haemodilution is often a concomitant of serious illness. Haematocrit and fibrinogen are the most important determinants of blood viscosity and, in turn, contribute significantly to vascular resistance. These relationships are illustrated graphically in Figure 5. Because blood is a non-Newtonian fluid, there is no simple expression to relate SVR to haematocrit and fibrinogen levels, however, it is easy to demonstrate the completely passive increase in venous return ³ and cardiac output which occur during haemodilution ⁴.

Finally, it should not be forgotten that there is a degree of ventricular interdependence which can determine ventricular performance ⁶. - The position of the interventricular septum (IVS) can alter the compliance of each ventricle under altered loading conditions with secondary effects on contractility. This effect is not usually important, but can become so in conditions such as tension pneumothorax, tamponade, right ventricular infarction etc.

1. Frank O: Zur Dynamik des herzmuskels. Ztschr fur Biol 32:370, 1895

2. Barash PG, Chen Y, Kitahata LM et al The Hemodynamic Tracking System. Anesth. Analg. 59:169 (1980)

3. Guyton AC, Richardson TQ Effect of hematocrit on venous return. Circ Res 9:157-163, 1961

4. LeVeen HH, Ip M, Ahmed N et al Lowering blood viscosity to overcome vascular resistance. Surg Gynecol Obstet 150:139-149, 1980

5. Eckmann DM, Bowers S, Stecker M, Cheung AT Hematocrit, volume expander, temperature, and shear rate effects on blood viscosity. Anesth Analg 2000 Sep;91(3):539-45

6. Taylor RR, Covell JW, Sonnenblick EH et al: Dependence of ventricular distensibility effect on filling of the opposite ventricle. Am J Physiol 218:711, 1967

Last edited on: 14/11/2000

Ventricular function curves describe the fundamental Frank-Starling relationship. - As the amount of 'stretch' (preload) on the ventricular fibres is increased in diastole, so the resulting force of contraction of the next beat is increased. Note that in the failing heart (shown in red), the curve is relatively 'flat'. Under these circumstances, increasing preload will not enhance ventricular performance. In fact, the reverse may occur because wall tension will increase with a concomitant increase in oxygen requirements of the heart.

The green curve represents a heart in which contractility is increased.

In this example, the cardiac output is used as an index of the force of contraction and the PAOP as a measure of sarcomere length.

Repeated measurements of PAOP and output can be made after therapeutic interventions such as volume loading or the use of inotropes. The results can be plotted onto a diagram of the form shown here and a notion of the 'contractile state' of the individual patient developed.

Endpoints of resuscitation

CVP=15

PAWP=20-22

CI>3

VO2>100cc/min/m2

Lactate<4

Base Deficit=-3 to 3

Pathophysiology

Insult causes decreased O2 delivery to cells (DO2).  DO2 is the product of CO and PaO2.  The body compensates by releasing epi and norepi which raise the CO.  In addition, dopamine, cortisol, glucagon, growth hormone, and anti-diuretic hormone (ADH) are also released.  Cells will increase the amount of Oxygen withdrawn from the blood causing decreases from the normal venous sat of 70-75%.  When despite this increased extraction there is not enough oxygen, the cells begin anaerobic metabolism and release lactate.  Eventually the acidosis surrounding the cells causes membrane disruption and cell death.  Eventually, hypoxic cells of the vascular endothelium activate tissue macrophages and leukocytes, leading to the production of numerous harmful inflammatory mediators.7 Mediators that have been implicated in shock include tumor necrosis factor, interleukins 1 and 2, eicosanoids, interferon gamma, and platelet activating factor. With resuscitation, the hypoxic vascular beds are reperfused, resulting in the delivery of these mediators to the systemic circulation. It is this washout of inflammatory mediators that leads to the development of the systemic inflammatory response syndrome (SIRS). Due to compensatory mechanisms, the effects of age, or the use of certain medications, a large percentage of patients in shock will present with a normal blood pressure and heart rate. Thus, normal vital signs cannot be used to exclude the presence of shock. In fact, waiting for hypotension and tachycardia to develop to make the diagnosis invariably will increase patient mortality(EM Reports)

Base Deficit-amount of base that must be added to 1 liter of blood to normalize pH

MUST have peep on during all ventilations including BVM

In fact, strenuous accessory muscle use can increase consumption anywhere from 50% to 100%, leading to a decrease in cerebral blood flow by as much as 50%.³ Thus, the tachypneic patient in shock ultimately may require mechanical ventilation as respiratory muscles fatigue, hypercapnia increases, and acidosis worsens. Advantages to mechanical ventilation include improved oxygen delivery to the alveoli, correction of hypercapnia, and, most importantly, a decrease in oxygen consumption by the respiratory muscles.

Monitoring

CVP

• Low: < 6 cmH₂O;

• Normal: 6-12 cmH₂O;

• High: > 12 cmH₂O

JVD

In addition to noting simple engorgement, determine whether the veins remain distended or enlarge with inspiration. Normally, neck veins should collapse during inspiration, because of decreased intrathoracic pressure. In the presence of impaired venous return or elevated right heart pressures, neck veins will paradoxically swell (Kussmaul’s sign). This phenomenon occurs with tension pneumothorax, right ventricular infarction, pericardial tamponade, and massive pulmonary embolism.

Monitor by BP (Need mean of 60-65), Mental Status, Urine Output, and Base Deficit/Lactate

Dobutamine 5-20 ug/kg/min

Dopamine 5-20 ug/kg/min

Epinephrine 5-20 ug/min

Norepinephrine: 5-30 ug/min (0.2-1.3 mcg/kg/min)

Stability of norepinephrine infusions prepared in dextrose and normal saline solutions Conclusion: Norepinephrine solutions, in concentrations commonly used in the clinical setting, are chemically stable for seven days, at room temperature and under ambient light, when diluted either in D5W or NS.

Phenylephrine 2-200 ug/min

Auscultatory blood pressure measurement underestimates true arterial pressure in shock by an average of 15 mmHg, particularly when peripheral vascular resistance is high.^21,22 However, Doppler measurements of blood pressure in hypotensive patients correlate well with direct arterial systolic blood pressure measurements

We are not good at detecting hypovolemia by physical exam. Postural tachycardia and dizziness are fairly good, rest are crap (Ann Emerg Med 2005;45(3):327)

Dobutamine

dobutamine is a racemic mixture. In a normal person with a low adrenergic state, the partial agonist and antagonist effects of the two enantiomers more or less balance out. In a high-adrenergic state, it is highly likely that *both* enantiomers will antagonise the effects of alpha agonists at the alpha receptor. My understanding is that the *affinity* of dobutamine for the alpha receptor is about 20 times that of noradrenaline (norepinephrine).

Norepinephrine

 Conclusion: Norepinephrine solutions, in concentrations commonly used in the clinical setting, are chemically stable for seven days, at room temperature and under ambient light, when diluted either in D5W or NS.

Epinephrine

Lancet. 2007 Aug 25;370(9588):676-84.Click here to read Links
Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial.
Annane D, Vignon P, Renault A, Bollaert PE, Charpentier C, Martin C, Troché G, Ricard JD, Nitenberg G, Papazian L, Azoulay E, Bellissant E; CATS Study Group.

Raymond Poincaré Hospital (AP-HP), University of Versailles Saint Quentin, PRES UniverSud, Paris, France. djillali.annane@rpc.aphp.fr

BACKGROUND: International guidelines for management of septic shock recommend that dopamine or norepinephrine are preferable to epinephrine. However, no large comparative trial has yet been done. We aimed to compare the efficacy and safety of norepinephrine plus dobutamine (whenever needed) with those of epinephrine alone in septic shock. METHODS: This prospective, multicentre, randomised, double-blind study was done in 330 patients with septic shock admitted to one of 19 participating intensive care units in France. Participants were assigned to receive epinephrine (n=161) or norepinephrine plus dobutamine (n=169), which were titrated to maintain mean blood pressure at 70 mm Hg or more. The primary outcome was 28-day all-cause mortality. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00148278. FINDINGS: There were no patients lost to follow-up; one patient withdrew consent after 3 days. At day 28, there were 64 (40%) deaths in the epinephrine group and 58 (34%) deaths in the norepinephrine plus dobutamine group (p=0.31; relative risk 0.86, 95% CI 0.65-1.14). There was no significant difference between the two groups in mortality rates at discharge from intensive care (75 [47%] deaths vs 75 [44%] deaths, p=0.69), at hospital discharge (84 [52%] vs 82 [49%], p=0.51), and by day 90 (84 [52%] vs 85 [50%], p=0.73), time to haemodynamic success (log-rank p=0.67), time to vasopressor withdrawal (log-rank p=0.09), and time course of SOFA score. Rates of serious adverse events were also similar. INTERPRETATION: There is no evidence for a difference in efficacy and safety between epinephrine alone and norepinephrine plus dobutamine for the management of septic shock.

Dopamine

Greet van den Berghe's work shows neuroendocrine dysfunction as well as immunological modulation secondary to prolactin

(Anesth & Analg, 2004, 98,461-468)

Reasons Dopamine is Bad

Does not benefit the renal system

Induces Natriuresis and Diuresis

Shunts blood away from outer medulla, which is the region most prone to ischemic damage

Possible induction of decreased splanchnic perfusion

Decreases GI Motility

Impairs ventilatory response to hypoxemia and hypercapnia

Effects on anterior pituitary--decreases prolactin secretion

and (Holmes CL and Walley KR, Bad medicine: low-dose dopamine in the ICU, Chest, 2003, 123: 1266-1275)

Meta-Analysis: Low-Dose Dopamine Increases Urine Output but Does Not Prevent Renal Dysfunction or Death
Jan O. Friedrich, MD, DPhil; Neill Adhikari, MD, CM; Margaret S. Herridge, MD, MPH; and Joseph Beyene, PhD
Ann Intern Med 5 April 2005 | Volume 142 Issue 7 | Pages 510-524

Renal dose also causes a. fib in post op pts (Crit Care Med 2005;33:1327)

Assoc c higher mortaility in Sepsis patients in the SOAP study:

Conclusions: This observational study suggests that dopamine administration may be associated with increased mortality rates in shock. There is a need for a prospective study comparing dopamine with other catecholamines in the management of circulatory shock. (Crit Care Med 2006;34(3):589)

Gastric tonometry

measures pH of cells lining gut; based on hypothesis that CO2 in lumen of stomach or intestine in rapid equilibrium with CO2 in cells lining them; during ischemia, cells switch to anaerobic metabolism, and PCO 2 increases; splanchnic circulation believed to be first to develop ischemia; basing management on restoring gastric intramucosal pH more effective in lowering mortality than management based on hemodynamic parameters; difficult to perform; more practical new development may be noninvasive sublingual tonometry

Trendelenberg

No evidence that it works, may make things worse (Canadian JEM Vol. 6, No. 1, January  2004)
 

Three systems respond to hypotension:

sympathetic

vasopressin

renin/angiotensin

If two are blocked then difficult to control hypotension

may need Vasopressin 3-5 unit IV bolus if other two systems are blocked

Bolus Dose Pressors

Phenylephrine

Comes in 1% 1cc vials this means 10 mg/cc

Dilute in 10 cc syringe and you get 1 mg/cc

Dilute again 1 cc in 10 cc and you get 100 mcg/cc

give 50-100 mcg (.5-1 cc at a time) at a time

max 1 mg/dose)

then 40-60 mcg/min

potent, rapid onset, short duration

Ephedrine

Comes in 50 mg 1 cc vial; dilute into 10 cc of NS to get 5 mg/cc

5-25 mg IV q 5-10 min

primarily direct beta, with some indirect alpha

large doses required

slow onset, long duration

Calcium

100 mg then 1-5 mg/hr

synergistic with vasopressors, increased MAP, increased SVR, increased inotropy
 

Obstructive Shock

Decreased Diastolic Filling

Tamponade

Pneumothorax

Increased Ventricular Afterload

Pulmonary embolism

use norepi (amrinone promising, but not enough studies (Emedhome.com article.)

Cardiogenic

Cardiogenic Shock

For SBP > 80 mmHg, dobutamine is recommended as the initial agent of choice. It has been shown to cause less tachycardia, vasoconstriction, and arrhythmia than other agents (38,39,40). Additionally, dobutamine increases coronary blood flow and collateral blood flow to ischemic areas while raising myocardial contractility and cardiac output, but lowering left ventricular filling pressures (ref 39,41).

For Moderate Hypotension (e.g. SBP < 80 mmHg), dopamine is recommended as the agent of choice since vasoconstriction of peripheral vessels is needed to maintain vital organ perfusion.

For Profound Hypotension (e.g. SBP < 70 mmHg) or refractory hypotension, norepinephrine is recommended. Hemodynamic studies of acute myocardial infarction in cardiogenic shock treated with norepinephrine have shown a rise in mean arterial pressure and systemic vascular resistance. These studies also revealed improved myocardial perfusion and oxygenation, however there was no change in cardiac output. This failure to augment cardiac output is thought to represent the magnitude of the ischemic zone and lack of inotropic reserve (ref 42). The phosphodiesterase inhibitors, amrinone and milrinone, are known to increase contractility. They do not stimulate adrenergic receptors and play a reserve role when other catecholamines are ineffective, or when beta receptors are blocked.

Thrombolytics, due to poor reperfusion rates, have shown no mortality benefit in cardiogenic shock in large, randomized studies (ref 43,44). Intra-aortic balloon pumps decrease systemic afterload and increase diastolic perfusion pressure without increasing oxygen demands. While balloon pump use is considered standard of care, no improvement in outcome has been associated solely with its use. However, IABP does seem to function as a bridging device to revascularization. The ongoing TACTICS (thrombolysis and counterpulsation to improve cardiogenic shock survival) will address the role of IABP as an adjunct to thrombolysis (ref 45).

Vasodilating agents will increase CO, decrease PCWP; with little change in art pressure

at moderate and high doses there will be a decreased ABP

The increase in CO is seen in patients with high LV filling pressures, in normal patients the loss of filling will decrease CO b/c of decreased starling. (Circulation 1973;48:1183)

Cardiogenic Shock needs early revascularization (JAMA 2006;295(21):2511)

Review Article (Curr Opin Crit Care 2006;12:431)

SHOCK trial (NEJM 1999;341:625)

cardiac power important prognostically: product of CO and MAP

Effect of Vasopressin in card shock from MI (Am J Cardiol 2005;96:1617)

vasopressin, in studies of septic shock, has been shown to increase MAP without affecting PCWP or CO

norepi increased cardiac power; vasopressin did not

retrospective and most patients on multiple pressors

Review of Inodilators (Am J Cardiol 2005;96(supp):47G)

Milrinone and dobutamine seem to have similar outcomes and side effects

In advanced vasodilatory shock, disease oriented outcomes may be better with norepi+vaso when compared to norepi alone (Circ 2003;107:2313)

horrible case series of inadequate pressor doses, then pts had vasopressin added. In 2 of the 3 cases CI then decreased. (Crit Care Med 2000;28(1):249)

review article (Med Clin N Am 2007;91:713)

Study of vaso vs. norepi for hyptension after milrinone showed vaso had less effects on PVR, but the MAPs were driven higher with norepi confounding the study (Eur J Cardio-Thor Surg 2006;29:952)

Editorial Letter pointing out problems with this study (Eur J CT surg 2006;30:686)

Tachycardia-related Hypotension

TCA overdose

Norepinephrine

new class includes calcium sensitizer levosimendan (Simdax), opens potassium channels in vascular smooth muscle for vasodilator effect, long-term use not associated with increased mortality, in contrast to other inotropic agents; significantly improves cardiac function, ejection fraction, and functional status

Hypovolemic

Sources Of Occult Hemorrhage.

Trauma

• Solid organ injury
• Pulmonary parenchymal injury
• Myocardial laceration/rupture
• Vascular injury
• Retroperitoneal hemorrhage

• Pelvic fracture
• Ruptured duodenum
• Ruptured kidney

• Fractures, especially bones and pelvis
• Lacerations, especially scalp
• Epistaxis

Gastrointestinal tract

• Mallory-Weiss tear
• Esophageal varices
• Peptic ulceration
• Gastritis/esophagitis
• Meckel’s diverticulum
• Malignancies
• Vascular lesions (arteriovenous malformations, rare congenital anomalies)
• Inflammatory bowel disease
• Ischemic bowel disease
• Diverticular disease

Reproductive tract

• Vaginal bleeding

• Malignancies
• Miscarriage
• Metrorrhagia
• Retained products of conception
• Placenta previa
• Vaginal or uterine laceration

• Ectopic pregnancy
• Ruptured ovarian cyst

Vascular

• Aneurysms
• Dissections
• Arteriovenous malformations
• Vasculitis (e.g., Henoch-Schönlein purpura)

Others

• Tumor
• Infection (e.g., Mycobacterium tuberculosis [Rasmussen’s aneurysm])
• Spontaneous splenic rupture
• Bleeding dyscrasias

One final controversy in the treatment of patients in hemorrhagic shock is the addition of antioxidants and/or free radical scavengers to resuscitative fluids. Hemorrhagic shock impairs antioxidant defense mechanisms and increases free radical production.²² As discussed in detail above, free radical formation plays a key role in the pathogenesis of shock and subsequent MODS. To date, the results of studies involving superoxide dismutase, N-acetylcysteine, ascorbic acid, vitamin E, and even deferoxamine have been published.²³ Preliminary data imply that the inflammatory response to shock is somewhat mitigated by the addition of an antioxidant to the resuscitation fluid

Bradycardia may be present very often in hypovolemic/hemorrhagic shock.  There is a biphasic response, the first and the one we commonly think of is catecholamine surge with resulting tachycardia and increased card output.  Later on, there is actually a cardiac vagal response resulting in bradycardia.  This may be present in up to 1/3 of hypovolemic patients (BMJ 2004;328:451-453 (21 February))

Distributive

Neurogenic Shock

Dopamine or (ephedrine and atropine)

Anaphylaxis

EPI, final dilution of 1:100,000 infused over 5 to 10 minutes by mixing 0.1 mg (0.1 ml) of 1:1000 with 10 ml of normal saline. This is equivalent to a 100 mcg bolus given at 10 mcg/min. Once therapy has begun, a continuous infusion could be delivered with 0.5 to 5 mcg/min titrated to clinical response

Septic Shock

Start c Norepi until MAP>65 then add dobutamine. (EMEDHOME.com Article  JB18)

Septic Shock
Systemic inflammatory response syndrome (SIRS): by original definition, almost everyone in ICU has SIRS; new definitions may stage SIRS by genetic abnormalities predisposing patient to sepsis, degree of infection, response to infection based on mediators and markers, and presence of organ dysfunction
Antibiotic therapy: choice depends on—organism and site of infection; community-acquired vs hospital-acquired infection; host factors, eg, immunosuppression; severity of infection; local patterns of antibiotic susceptibility and resistance; begin with broad-spectrum antibiotic, then narrow choices based on culture and sensitivity; follow published guidelines for treatment of community-acquired and ventilator-associated pneumonia
Hemodynamic therapy: preload, afterload, and contractility different in sepsis; pressure (eg, wedge pressure) and volume (left ventricular end diastolic volume) related by ventricular compliance; in sepsis ventricular compliance increased, ventricle more relaxed and has higher filling volume than expected at given wedge pressure or central venous pressure; goal is optimized ventricular filling; whereas in other conditions, optimal cardiac output occurs at wedge pressures of 15 to 18 mm Hg, in sepsis, it occurs at lower pressures, eg, 5 to 15 mm Hg, that cannot be predicted; give fluid boluses until hemodynamic improvement ceases, regardless of wedge pressure, which may be only 5 mm Hg; contractility—may be markedly decreased in spite of high cardiac output caused by tachycardia; due to optimized preload, end diastolic volume increased; stroke volume normal, so ejection fraction decreased; afterload also decreased, indicating marked decrease in contractility; not due to development of myocardial ischemia; down-regulation of beta- adrenergic receptors may play role but, main mechanism thought to be production of myocardial depressant factors, eg, tumor necrosis factor and interleukin-1
Inotropic therapy: dobutamine—5 to 20 µg/kg per min; has beta-adrenergic effect, ie, increases cardiac output, heart rate, and stroke volume; decreases SVR from vasodilation, has variable effect on BP; if BP declines, give fluid challenges; dopamine—2 to 20 µg/kg per min; increases cardiac output by increasing stroke volume rather than heart rate; does not appear to increase SVR; has variable effect on splanchnic circulation; no evidence for “renal dose” dopamine that would improve renal blood flow; epinephrine—20 to 300 ng/kg per min; has beta-adrenergic effects at lower, doses with resulting increase in BP due to increased cardiac output; alpha-adrenergic effects at higher doses cause BP increase due to increased SVR; worsens lactic acidosis and decreases splanchnic blood flow, particularly in combination with norepinephrine; norepinephrine—used as afterload agent; raises BP and maintains tissue perfusion in septic shock with optimized hemodynamic circulation and elevated cardiac output, as opposed to effects in hypo-volemic and cardiogenic shock (decreased cardiac output, renal failure, bowel ischemia); increase in BP in septic shock due mainly to SVR (heart rate and cardiac output do not change); glomerular filtration rate and urine output improve when vasoconstrictors used in high-output septic shock, renal blood flow maintained; norepinephrine used alone tends to improve splanchnic blood flow, but response variable; definitely improves splanchnic blood flow in combination with dopamine or dobutamine; phenylephrine—data suggest benefits similar to norepinephrine in septic shock; vasopressin—does not constrict renal vasculature; dilates cerebral, coronary, and pulmonary vasculature; small studies suggest vasopressin stabilizes or improves BP, improves urine output and creatinine clearance; used as second-line therapy in septic shock when standard drugs cannot maintain BP without risking adverse renal effects
Steroid therapy: low-dose steroids postulated to address adrenal insufficiency in septic shock; study data—randomized patients to receive placebo or 100 mg hydrocortisone q8h for at least 5 days; greater reversal of shock at 7 days and trend toward reduced mortality among steroid-treated patients; study of similar regimen with dosages individualized by weight showed earlier discontinuation of vasopressor therapy with hydrocortisone (2 days vs 7 days); third study enrolled 310 patients on mechanical ventilation; all received corticotropin-stimulation test, then were randomized to receive 50 mg hydrocortisone q6h or placebo; response to corticotropin-stimulation test defined as increase >9 µg/dL; steroid-treated patients had increased reversal of shock, trend toward improved 28-day survival; benefit limited to patients unresponsive to corticotropin-stimulation test (responders do not have adrenal insufficiency)
Activated protein C: complex anticoagulant, anti-inflammatory compound; levels decreased in sepsis and decrease correlates with outcome; Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial—randomized 840 patients to receive placebo or 96-hr infusion of 24 µg/kg per hr recombinant human activated protein C (drotrecogin alfa, Xigris); mortality reduced to 25% with Xigris compared to approximately 31% with placebo; effect seen primarily in patients with APACHE II scores <25; significant improvement in mortality among sickest 50% of patients; bleeding complications increased from 2% in placebo group to 3.5% in Xigris-treated patients (primarily patients who developed thrombocytopenia or those undergoing invasive procedures without discontinuation of Xigris)
Trends in mortality from septic shock: mortality approximately 65% prior to modern critical care; now approximately 40%, with many studies showing mortality in 30% range; further decline expected over next 5 yr (Audiodigest Anesthesiology)
 

Vasopressin

indicated for catecholamine resistant septic shock. Dose should be no greater than 0.04 U/min to avoid side effects on heart and splanchnic vasculature.

(0.01–0.04 units/min)

Best review article (Volume 30 Number 7 of Intensive Care Medicine)

Review (Inten Care Med 2004;30:1276)

Vasopressin levels are high in early shock and then at 24 hrs begin to become deficient (Crit Care Med 2003;31(6):1752)

Decreased gut perfusion c vaso (Systemic Effects of Vasopressin Administration Oral Presentation 14th Annual Congress S138)

CI impaired with terlipressin compared to norepi (Crit Care Med 2005;33(9):1897)

Review (Chest 2001;120:989)

Review of vaso and terli (Crit Care 2005;9(2):212)

Vaso and Norepi vs. Norepi in under-resused pts showed slightly better creat clearance in vaso group (Anesthesiology 2002;96:576)

another review that states vasopressin does not vasoconstrict the pulmonary vasculature, while norepi may. Also potentially better effects on the kidney. (Can J Anesth 2006;53(9):934)

RCT of norepi vs. vasopressin, aso was ineffective in patients eve at doses beyond the safe limit (Inten Care Med 2006;32:1782)

Vasopressin does not cause as much pulmonary vasoconstriction (Br J Anaesth 2007;99(4):552)

Vasst (NEJM Volume 358:877-887 February 28, 2008 Number 9 Next Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock)

Addisonian Shock

Steroid Insufficiency

Shock in Trauma

Hemorrhagic

External
Chest
Abdomen
Pelvis
Long bone
 

Blood volume = 7% of weight in kg (70 cc/kg)

Non-Hemorrhagic

Tension Pneumothorax
Pericardial Tamponade
Myocardial Contusion
Spinal Shock
 

In head injury patients, norepinephrine is probably better than dopamine (CCM 2004 32:4)

Title
Effects of acidosis and hypoxia on the response of isolated ferret cardiac muscle to inotropic agents.

Source
Cardiovascular Research. 28(8):1209-17, 1994 Aug.

Local Messages
1990-1996

Abstract
OBJECTIVE: The aim was to study the effects of acidosis and hypoxia on the response of cardiac muscle to inotropic agents which (a) act predominantly by increasing intracellular [Ca2+] (raising extracellular [Ca2+], noradrenaline, isoprenaline) and (b) act partly (phenylephrine) or predominantly (EMD 57033) by increasing myofilament calcium sensitivity. METHODS: The experiments were performed on isometrically contracting, isolated ferret papillary muscles (n = 45). For each intervention dose-response curves were performed in control solution (pH 7.35), in hypercapnic acidosis (pH 6.85), and in hypoxia (produced by replacing O2 with N2 in the superfusing solution). In some experiments, the photoprotein aequorin was microinjected into superficial cells of the preparation in order to measure intracellular [Ca2+] as well as force. RESULTS: The results were broadly similar for both classes of inotropic agent. Acidosis caused a shift of the pCa-tension curve to the right (desensitisation of the myofilaments to calcium), but had no significant effect on maximum force. A sufficient inotropic stimulus supplied by either class of inotropic agent could completely reverse the negative inotropic effects of acidosis. The main difference between the two inotropic mechanisms was that the enhanced force produced by calcium sensitisers was associated with a reduction in calcium transient amplitude, while the other inotropes increased the amplitude. The main effect of hypoxia was to decrease maximum force. All the inotropes tested were relatively ineffective in reversing the force depression due to hypoxia. CONCLUSIONS: The negative inotropic effects of acidosis can be reversed by a sufficiently large inotropic stimulus. Since calcium transient amplitude is already increased in acidosis, the results suggest that calcium sensitisers are likely to be less arrhythmogenic in this situation. The relative ineffectiveness of the inotropes in hypoxia indicates that the main mechanisms causing reduced force in this situation lie downstream of the mechanisms of action of the inotropic agents tested.
 

MA of hemodynamic optimization optimization of tissue perfusion showed decreased mortality (Crit Care Med 2002;30(8):1688)

Persistent microcirc abnormailities assoc c death nd organ faiure. used subingual co2 (crit care med 2004;32(9):1825)

Review of targeted resus after trauma (Curr Opin Crit Care 2004;10:529)
critical o2 delivery is the key
steal figure
talks about rvedv swan, pcco, esoph doppler

Low-Tech Management of Shock

Unified theory of shock

It all comes down to end-organ perfusion

Is intravascular volume (preload) adequate?

Is blood flow adequate?

Is vascular resistance appropriate?

Is oxygen transport balance adequate?

Using PAOP assumes that ventricular compliance is unchanging and pressure reflects end diastolic volume

Preload~LVEDV (unless ventricular geometry is changed)

LVEDV~LVEDP (unless ventricular compliance is changed)

LVEDP~LAP (unless there is mitral disease, or intrathoracic or intrabdominal pressure changes)

LAP~PAOP (unless catheter is malpositioned or intrabdominal/intrathoracic pressures are elevated

Coronary Perfusion Pressure=DBP-PAOP

Must maintain over 50 mmHg

Abdominal Perfusion Pressure=MAP-IAP

Should maintain over 50

CO=SVI x HR

Vascular resistance

SVRI (dynes*sec*cm -5)=(MAP-CVP)80 / CI

PVRI=MPAP –PAOP 80/CI

Causes of increased pvri

Pulmonary htn, ards, intra-abd htn, mitral stenosis, aortic stenosis, left heart failure

Ventricular stroke work indices

Work=force x distance or change in pressure x change in volume

LVSWI=(MAP-PAOP) (SVI) (0.0136) (g m/m2)

RVSWI=(MPAP-CVP) (SVI) (0.0136) (g m/m2)

Decreased by inadequate volume, increased resistance, or decreased contractility

Increased by ventricular hypertrophy or physiologic conditioning

CCO

 

Need volumetric data

RVEF=right ventricular ejection fraction

RVEDI=right ventricular end-diastolic volume index

Independent of zero-pressure references and changing compliance

Proof: Cheathem et al. 2000

RVEDI=CI / (HR RVEF) or = SVI/RVEF

Incorrect placement, mitral valve disease, or irregular heart rate can still screw up the measurements

RVEDI reflects preload status

RVEF reflects contractility and afterload

Oxygen Transport

Is tissue oxygen delivery sufficient to meet cellular oxygen demand?

DO2=Delivery-oxygen pumped to the tissues by the heart

VO2=Consumption-amount of oxygen consumed by the tissues

Oxygen Demand=the amount of oxygen required by the tissues to function aerobically. May exceed consumption and delivery in critical illness

Four new Questions:

Does oxygen delivery meet the patient’s needs?

Is cardiac output adequate for consumption?

Is oxygen consumption adequate for demand?

Is patients hypoxemia due to a pulmonary problem or to a low flow state?

Supply and extraction must meet demand

If demand exceeds supply then shock is present

When consumption just meets demand patient is on the brink of decompensation

You need physiologic oxygen reserve

Oxygen content=oxygen bound + oxygen dissolved

C*O2=(1.34x Hb x S*O2)+(P*O2x0.0031)

Where * signifies the location

Each g of hemoglobin can carry 1.34 ml of O2

The solubility of oxygen is 0.0031 cc/dL

The saturation of Hb varies depending on the FiO2 and th