Circulation and circulatory support in the critically ill - technical - for doctors
- Principles of cardiovascular homeostasis
- Pathophysiology of shock
- Circulatory support of the haemodynamically unstable patient
Cardiovascular dysfunction is common in the critically ill patient and is the primary cause of death in a vast array of illnesses. The prompt identification and diagnosis of its probable cause, coupled to appropriate resuscitation and (when possible) specific treatments, are cornerstones of intensive care medicine.
Cardiovascular monitoring and diagnosis—cardiovascular performance can be assessed clinically at the bedside and through haemodynamic monitoring, and with therapeutic or other proactive interventions. Diagnostic approaches or therapies based on data derived from invasive haemodynamic monitoring in the critically ill patient assume that specific patterns of derangement reflect specific disease processes, which will respond to appropriate intervention.
Interpretation of haemodynamic variables—the various adaptive cardiovascular controls and varying metabolic demands make rules about specific haemodynamic variables of limited clinical utility. It is simply not possible to say that, when looking after a critically ill patient, the central venous pressure, or any other single measurable variable, must be kept at x or y. Key points in this context are: (1) tachycardia is never a good thing; (2) hypotension is always pathological; (3) there is no such thing as a normal cardiac output; (4) central venous pressure is only elevated in disease; and (5) peripheral oedema is of cosmetic concern.
Oxygen delivery—while there is no level of cardiac output which is ‘normal’, there are oxygen delivery thresholds below which normal metabolism can no longer occur. One cardinal sign of increased circulatory stress is an increased O2 extraction ratio, which manifests itself as a decreasing mixed venous O2 saturation (SvO 2): a value of less than 70% connotes circulatory stress, less than 60% identifies significant metabolic limitation, and less than 50% frank tissue ischaemia.
Pathophysiology of shock
Circulatory shock can be defined as a decreased effectiveness of circulatory blood flow to meet the metabolic demands of the body. Four basic functional aetiologies are recognized.
- Hypovolaemic shock (e.g. haemorrhage, dehydration)—effective circulating blood volume is inadequate to sustain a level of cardiac output necessary for normal function without supplemental sympathetic tone or postural changes to ensure adequate amounts of venous return.
- Cardiogenic shock (e.g. myocardial infarction)—pump dysfunction can be due to either left ventricular (LV) or right ventricular (RV) failure, or both. LV failure is usually manifest by an increased LV end-diastolic pressure, left atrial pressure and (by extension) pulmonary artery occlusion (‘wedge’) pressure, which must exist to sustain an adequate LV stroke volume.
- Obstructive shock—mechanical obstruction of blood flow (e.g. pulmonary embolism) or of ventricular filling (cardiac tamponade). In the acute setting, neither pulmonary vascular resistance nor mean pulmonary artery pressure need be grossly elevated for RV failure to occur. In cardiac tamponade, the cardinal sign is diastolic equalization of all pressures, central venous pressure, pulmonary arterial diastolic pressure, and pulmonary artery occlusion (‘wedge’) pressure.
- Distributive shock—loss of blood flow regulation occurs as the endstage of all forms of circulatory shock, but as the initial presenting process it is common in sepsis, neurogenic shock, and adrenal insufficiency. The haemodynamic profile of sepsis is one of increased cardiac index, normal pulmonary artery occlusion (‘wedge’) pressure, elevated SvO 2, and a low to normal arterial pressure, consistent with loss of peripheral vasomotor tone.
Circulatory support of the haemodynamically unstable patient
If the cause of hypotension is intravascular volume loss, either absolute or relative, then cerebral and coronary perfusion pressures must be maintained while fluid resuscitation is begun, otherwise cardiac pump failure may develop and limit the effectiveness of fluid resuscitation.
Pharmacotherapies for cardiovascular insufficiency—these are directed at the pathophysiological processes that either induce or compound the problem. They can be loosely grouped into one of three types:
- vasopressor therapy—agents that increase vascular smooth muscle tone include noradrenaline (norepinephrine), adrenaline (epinephrine), dopamine, and phenylephrine;
- inotropic support—agents that that increase cardiac contractility include dobutamine, dopexamine, and phosphodiesterase inhibitors;
- vasodilator therapy—agents that decrease smooth muscle tone include sodium nitroprusside and glyceryl trinitrate (nitroglycerine).
It is important to recognize that most inotropes and vasopressors in clinical use are sympathomimetics that have direct effects on the adrenoreceptor system, and there is a quantitatively unpredictable variation in adrenoreceptor density and function in many pathophysiological states, hence agents acting upon them need to be titrated to effect rather than being given at a defined infusion rate.
Resuscitation strategies—the only prospective clinical trials documenting benefit from particular interventions were applied early in the course of sepsis or in high-risk surgical patients. However, it makes physiological sense to prevent organ ischaemia by maintaining blood flow, hence the following strategies seem warranted.
- Loss of vasomotor tone requires both fluid resuscitation to achieve the increased vascular volume needed to restore an effective pressure gradient for venous return, and increased α-adrenergic tone via sympathomimetic agents to restore arterial and venous vasomotor tone. Targets for resuscitation are an SvO 2 less than 70% with a MAP greater than 60 mmHg.
- Impaired contractility requires afterload reduction, as tolerated, up to a decrease in MAP to approximately 70 mmHg, targeting pulmonary artery occlusion (‘wedge’) pressure less than 18 mmHg and SvO 2 greater than 70%. In sepsis, SvO 2 is usually elevated following fluid resuscitation, hence resuscitation targets usually focus on reaching elevated levels of oxygen delivery (e.g. >450 ml/min per m2).
- In RV failure, maintaining a MAP greater than pulmonary arterial pressure is essential to minimize RV myocardial ischaemia.
Cardiovascular dysfunction is common in the critically ill patient and is the primary cause of death in a vast array of illnesses including sepsis, pulmonary embolism, and acute respiratory failure, as well as in those with cardiac disease. The prompt identification of cardiovascular dysfunction, the diagnosis of its probable cause, and appropriate specific treatments (when possible) coupled to appropriate resuscitation and restorative management are cornerstones of intensive care medicine.
Cardiovascular performance can be assessed at the bedside and through haemodynamic monitoring and therapeutic or other proactive interventions. Diagnostic approaches or therapies based on data derived from invasive haemodynamic monitoring in the critically ill patient assume that specific patterns of derangement reflect specific disease processes, which will respond to appropriate intervention. Why such constellations of measured abnormalities occur is due to the underlying cardiovascular interactions that define normal and pathological states, hence it is essential that the practising clinician be well versed in the underlying principles of cardiovascular physiology and pathophysiology in order to appropriately diagnose and then treat the critically ill.
Principles of cardiovascular homeostasis
Physicians often consider disease states as involving only one organ, such as the heart, during acute coronary ischaemia or the circulation during haemorrhage. However, no organ system operates in the body without numerous and redundant feedback processes which both amplify and inhibit the specific response of the organ and the rest of the body to stress, disease, and treatment. These interactions form the basis of haemodynamic profile pattern recognition. Specific combinations of changing cardiovascular and metabolic variables better reflect specific disease processes than do individual values for specific variables. Furthermore, the change in these variables in response to time and treatment define the progression or resolution of disease, its severity, and subsequent responsiveness to therapy.
Although specific combinations of haemodynamic variables often reflect certain disease states, there may be considerable overlap of haemodynamic data sets among markedly different pathological states, which may require different therapies. These vagaries reflect individual patient differences, complex cardiovascular interactions not considered in the original logic, and also inaccuracies in the measures themselves and incorrect assumptions as to what the primary force is, and what is its response. This confusion can be minimized, however, by performing an experiment at the bedside to force the cardiovascular system into doing one thing or another. This is the essence of a ‘clinical trial’ of positive pressure breathing, passive leg raising, fluid therapy, diuresis, or increased inotropy. Thus, by examining the specific haemodynamic response of the individual to a specific therapy, the clinician at the bedside can gain essential insight into the process that is dysfunctional and also tailor therapy to the individual. Let us first consider normal cardiovascular physiology, then pathophysiology, and finally how to diagnose and treat.
Ventricular pump function
Our understanding of cardiac pump function has evolved greatly since the initial studies of Frank and Starling in the 1890s. Frank, a German physiologist, noted that when cardiac muscle strips were stretched they (unlike skeletal muscle strips) increased their force of contraction. Starling used these data to reason that since the left ventricular (LV) cavity approximated a sphere, increases in LV end-diastolic volume (EDV) should proportionally increase LV myocardial fibre stretch. Thus, he explained the observation that the force of LV contraction was related to left ventricular end-diastolic volume (LVEDV). Based on this construct, increasing LVEDV when LV function is normal will increase LV stroke volume and—for a constant heart rate—cardiac output as well. However, if LV pump function is impaired, then for the same increase in LVEDV stroke volume will not increase as much, if at all. Most studies of ventricular function revolve around LV function, assuming that the right ventricle follows suit.
The Frank–Starling relationship is central to most diagnostic and therapeutic protocols used to assess cardiac function. In fact, clinically, the immediate treatment of acute cardiovascular insufficiency and arterial hypotension is to increase intravascular volume. If arterial pressure increases, then the subject is said to be ‘preload responsive’ and the presumptive diagnosis of hypovolaemia is made. However, this common therapeutic response of fluid resuscitation will only increase cardiac output in half the patients who are haemodynamically unstable, hence understanding better the determinants of cardiovascular insufficiency and how to assess them are important goals in the training of critical care physicians.
When modelling LV pump function, one assesses both stroke volume and pressure work, or stroke work, needed to cause that flow. LV stroke volume varies inversely with outflow pressure (arterial pressure) for a constant LVEDV and LV contractility, whereas stroke work will remain constant. Thus, LV stroke work, rather than stroke volume, is often used to assess LV functional status because it is relatively pressure (afterload) independent. If stroke work is less for the same LVEDV, then LV contractility is also said to be less under this condition (Fig. 1).
Figure 1: Relationship between LV end-diastolic volume (preload) and LV ejection phase indices, including ejection fraction, stroke volume, stroke work, rate of change of LV pressure (dP/dt), and velocity of circumferential fibre shortening (VCF). Shown in the example are three curves of varying performance referred to as hypereffective, normal, and hypoeffective performance. Each ejection phase index is affected to a greater or lesser extent by changes in afterload and contractility.
The measure of LV function best used to assess cardiovascular status is highly dependent on the question being asked. If the question is the adequacy of LV output to meet the metabolic demands of the body, then stroke volume and cardiac output are the relevant measures. However, if the question is ‘what is the functional status of the heart, and can it be counted on to sustain blood flow as ejection pressures rise?’, which in essence is asking ‘what is the level of myocardial contractile reserve, independent of the level of blood flow?’, then the change in LV stroke work relative to the change in LVEDV is a better index.
LV pressure–volume loop
LV pump behaviour is best described using the LV pressure–volume relation, wherein a single cardiac cycle is described as a loop with LV volume on the x-axis and pressure on the y-axis (Fig. 2). In this construct no time units are used. Filling occurs during diastole when LV chamber pressure decreases to less than left atrial pressure. The slope of the passive LV distention is diastolic compliance. At end-diastole, defined by the electromechanical coupling of contraction, the pressure/volume ratio is at its minimum. This point is often used to assess diastolic compliance, but is influenced by external forces independent of the LV, such as the pericardium, lungs, and right ventricle. LVEDV is synonymous with LV preload as applied to the Frank–Starling relationship.
Figure 2: The LV pressure-volume relationship describing all aspects of the cardiac cycle.
With mechanical contraction, the LV intracavitary pressure rises, forcing mitral valve closure and changing the shape of the LV from an elongated ellipsoid into more of a sphere. As contraction progresses, intracavitary pressure rises as the end-diastolic blood volume is trapped in the LV. Once intracavitary pressure exceeds aortic pressure the aortic valve passively opens and ejection begins. In a subject with a normal heart, the point where ejection occurs represents the maximal LV wall stress, itself the product of radius of curvature and developed pressure. Thus, diastolic arterial pressure is a major determinant of LV wall stress, and this LV wall stress is the LV afterload. Any therapy which selectively decreases diastolic arterial pressure will then reduce LV afterload more than therapies which selectively decrease systolic arterial pressure. Similarly, if an inovasodilator, such as dopexamine, were given that decreased LVEDV but increased LV stroke volume and ejection pressure, one may erroneously conclude that LV afterload increased, when in fact it decreased.
Ejection occurs as LV volume decreases and both LV pressure and aortic pressure rise. Due to the filling characteristics of the aorta, aortic pressure increases most towards the end of ejection as the distensible volume of the aorta is finally reached. Thus, most of the increase in arterial pressure occurs when the LV volume is already small. As a result, the maximal LV wall stress usually occurs at the start of ejection and the LV unloads itself during ejection. That the left ventricle unloads itself during ejection has important clinical implications. First, systolic hypertension is better tolerated without much increase in myocardial oxygen demand (MVo2) than is diastolic hypertension. However, if LVEDV is increased such that LV volumes do not decrease much during ejection, as is the case in congestive heart failure, then systolic pressure will be a major contributor to both LV wall stress and MVO2. Accordingly, in dilated heart failure states the LV performance is sensitive to changes in systolic arterial pressure, and end-systolic volume (ESV) then is a function of both afterload and contractility. As such, increases in afterload will increase ESV whereas increases in contractility will decrease ESV.
LV relaxation occurs once ejection has finished. Diastolic relaxation or lusitropy is an energy-dependent process, causes LV intracavitary pressure to decrease faster than would be predicted by passive relaxation alone, and is impaired by myocardial ischaemia. Impaired active diastolic relaxation is the earliest manifestation of myocardial ischaemia and can be readily identified by echocardiography and as an S3 gallop on cardiac auscultation. Since coronary artery blood flow occurs primarily in diastole, when LV wall stress is low and perfusion pressure is high, any process which impairs diastolic relaxation will decrease coronary blood flow.
The entire LV contractile process can be understood better from the perspective, not of a single pressure–volume loop, but of the pressure–volume domain of contraction. In this context, as time progresses from the start of contraction to end ejection, the left ventricle becomes progressively more stiff (e.g. more elastic), such that the pressure may increase and the volume may decrease independent of preload and afterload characteristics, but where on the pressure–volume domain this point lies is a function of the stiffness or elastance of the ventricle. Time-varying elastance (E(t)) describes the progressive stiffening through systole and then its relaxation in diastole in the pressure–volume domain. It can be calculated as a plot of the slopes of the isochronic (similar point in time) pressure–volume relations during ejection as end-diastolic volume is rapidly varied (Fig. 3) by either rapid volume loading or occlusion of venous drainage. The slopes of these sequential pressure–volume lines reflect the obligatory LV pressure–volume domain that must be followed during systole.
Figure 3: Multiple LV pressure-volume relations over time with isochronic pressure-volume domains (time-varying elastance) drawn for all ventricles ending at the end-systolic pressure-volume relationship (ESPVR). Isochronic lines at 20-ms intervals. Note that LV time-varying elastance increases progressively from end diastole to end systole
The end-systolic elastance (Ees) is usually calculated from the regression line of the end-systolic pressure–volume data pairs of repetitive LV pressure–volume loops as either preload or afterload are rapidly varied. Ees is also referred to as the LV end-systolic pressure–volume relationship (ESPVR). Maximal elastance (Emax) is the maximal LV pressure–volume ratio and usually occurs just after end-systole due to the inertial and impedance hydrodynamic characteristics of the arterial tree. Increased contractility results in both a more rapid rise of (E(t)) to Ees and a higher Ees value. Using this construct, it becomes clear that the Frank–Starling relationship is the unidimensional description of the mechanical quality of ventricular ejection as described by time-varying elastance.
Applied cardiac physiology at the bedside
The preload-dependent nature of LV performance is central to the understanding of applied cardiac physiology. In fact, documenting that LVEDV is above some minimal value, despite cardiac output and stroke work both being depressed, is essential for the diagnosis of cardiac pump dysfunction. Similarly, demonstrating that LVEDV is reduced in the setting of haemodynamic instability presumes the diagnosis of inadequate circulating blood volume as the most likely cause of the haemodynamic instability, even though other aetiologies, such as tamponade, cor pulmonale, and restrictive cardiomyopathies can coexist and require different treatments.
However, knowing LVEDV does not predict if LV stroke volume will increase in response to volume loading. Since a fundamental aspect of haemodynamic monitoring is to predict which patients will be preload-responsive, meaning that their cardiac output will increase in response to a fluid challenge, this lack of concordance between right atrial pressure, pulmonary artery occlusion pressure (‘wedge’ pressure), and even ventricular volumes, and subsequent changes in cardiac output in response to volume challenge can be disquieting. Still, it is a reality. However, there are three techniques of proven utility in defining preload responsiveness: the classic volume challenge, noting the magnitude of (1) the arterial pulse pressure or (2) left ventricular stroke volume variation during fixed tidal volume positive pressure ventilation, and (3) noting the change in mean cardiac output in response to a passive leg raising manoeuvre. For either pulse pressure variation (PPV, the ratio of maximal minus minimal pulse pressure to mean pulse pressure over five or more breaths) or stroke volume variation (SVV, the ratio of maximal minus minimal stroke volume to mean stroke volume over five or more breaths) to reflect preload responsiveness, the tidal volume must be fixed during unassisted positive pressure breathing and the sequential R-R intervals must be constant (i.e. no arrhythmias). In patients who are breathing spontaneously, and those with arrhythmias, the mean increase in flow 20 s after a passive leg raising to 30° gives a similar predictive value. In all cases, having a PPV greater than 13% or a SVV or mean increase in flow of more than 10% accurately predicts preload responsiveness as validated by many independent studies. PPV can be measured from the arterial pressure waveform and SVV calculated using numerous devices that assess beat-to-beat stroke volume using the arterial pressure waveform.
Arterial pressure and the vascular circuit
Organ perfusion is dependent on organ perfusion pressure and local vasomotor tone. Local vasomotor tone varies inversely with local tissue metabolic demand. For most organs, except the kidneys and heart, independent changes in arterial pressure above some minimal value are associated with increased vasomotor tone to maintain organ perfusion constant, hence this is essentially independent of cardiac function and cardiac output. In this circumstance, cardiac output is only important to allow parallel circuits to maintain flow without inducing hypotension, and cardiac function is only important in sustaining cardiac output and a given output pressure without causing too high a back pressure in the venous circuits.
Operationally, mean arterial pressure (MAP) is the input pressure to all organs other than the heart. Diastolic aortic pressure is the input pressure for coronary blood flow. Usually, MAP is equal to the diastolic pressure plus one-third the pressure pulse between diastole and systole. If, in a previously nonhypertensive subject, MAP decreases below 65 mmHg, then tissue perfusion will decrease independent of metabolic demand. Hypotension directly reduces organ blood flow and is synonymous with cardiovascular instability and is the essence of circulatory shock.
However, the assumption is often false that because MAP is the major central determinant of organ perfusion pressure, then organ perfusion must be adequate if MAP exceeds some minimal value. Intraorgan vascular resistance and venous outflow pressure are the two other determinants of organ blood flow. Furthermore, in severe stress situations, such as shock states, normal homeostatic mechanisms functioning through carotid body baroreceptors vary arterial vascular tone to maintain MAP relatively constant despite varying cardiac output, this vasoconstriction being done to maintain cerebral and coronary blood flow at the expense of the remainder of the body. In subjects with normal renal function, immediate oliguria is the manifestation of this adaptive response, reflecting marked reduction in renal blood flow and solute clearance by the kidneys despite persisting normal arterial blood pressure, hence normotension does not insure haemodynamic sufficiency. Indirect measures of sympathetic tone, such as heart rate, respiratory rate, and peripheral capillary filling and peripheral cyanosis are better estimates of cardiovascular status than is MAP.
Despite the lack of sensitivity of MAP to reflect haemodynamic sufficiency, measures of MAP are essential in the assessment and management of haemodynamically unstable subjects for several reasons. Measures that increase MAP will also increase organperfusion pressure. Hypotension causes coronary hypoperfusion, impairing cardiac function and cardiac output. Vasoconstrictor therapies will increase vasomotor tone in nonvital peripheral organs, but will maintain flow to the cerebral and coronary beds. It is also important to remember that the normal mechanism allowing autoregulation of blood flow distribution is local changes in organ inflow resistance, such that organs with increased metabolic demand vasodilate to increase their blood flow. If there is hypotension, then local vasodilation will not result in increased blood flow because the pressure gradient for that flow will also be reduced. Thus, hypotension impairs autoregulation of blood flow distribution. Vasopressor therapy can reverse systemic hypotension, but at a price: the only way that it can increase MAP is by reducing blood flow through vasoconstriction. Importantly, cerebral and coronary vascular circuits have minimal α-adrenergic receptors so their beds will not constrict. Regrettably, in hypovolaemic states vasopressor support may improve transiently both global blood flow and MAP, but at the expense of worsening local nonvital blood flow and hastening tissue ischaemia. Initial resuscitative efforts should therefore always include an initial volume expansion component and fluid challenge or other diagnostic approaches that identify preload-responsive shock states, before relying on vasopressors alone to support the unstable patient.
Cardiac output, oxygen delivery, and oxygen consumption
To support cellular metabolism, the circulation must deliver adequate amounts of oxygen (D O 2) and blood flow (cardiac output) to support oxidative phosphorylation. D O 2 is the product of cardiac output and arterial O2 content. Within this construct, cardiac output and D O 2 are often used interchangeably, primarily because the greatest gain in D O 2 comes from varying cardiac output, not arterial O2 content. However, like all simplification constructs, this one is also limited. Nonmetabolic blood flow, such as renal and splanchnic and skin blood flow, are essential to normal homeostasis. All of these processes need to be maintained under normal conditions and cannot be excluded for long in stress states without inducing marked end organ dysfunction.
Since the primary goal of the cardiorespiratory system is to continuously maintain adequate D O 2 to meet the metabolic demands of the tissues, how can one assess its adequacy? As described above, neither LV preload nor MAP are sensitive or specific measures of adequacy of cardiovascular function. Although the best measure of circulatory sufficiency is the maintenance of normal bodily functions, this analysis is often difficult to assess accurately at the bedside during states of stress. Furthermore, since metabolic demand can vary widely, there is no value of cardiac output or D O 2 that ensures circulatory sufficiency. Under normal conditions, D O 2 and metabolic demand vary in parallel. However, as metabolic demands start to exceed D O 2 limits, either because of increased metabolic demand (e.g. seizures, fever, fighting the ventilator) or decreased delivery (e.g. circulatory shock and respiratory failure), the ability of the cardiovascular system to sustain O2 consumption is stressed.
One cardinal sign of increased circulatory stress is an increased O2 extraction ratio, which manifests itself as a decreasing mixed venous O2 saturation (SvO 2). However, even this concept is useful only in limited conditions. Muscular activity effectively extracts O2 from the blood because of the set-up of the microcirculatory flow patterns and the large concentration of mitochondria in these tissues. Thus, normal vigorous muscular activity can be associated with a marked decrease in SvO 2 despite a normal circulatory system. Muscular activities, such as moving in bed or being turned, ‘fighting the ventilator’, and breathing spontaneously increase O2 consumption. In the patient with an intact and functioning cardiopulmonary apparatus, this will translate into an increase in both D O 2 and O2 consumption and a decrease in SvO 2. However, in the sedated and ventilated patient, SvO 2 is a very sensitive marker of circulatory stress. There is no level of cardiac output which is ‘normal’, but there are D O 2 thresholds below which normal metabolism can no longer occur. Using SvO 2 as a sensitive but nonspecific marker of circulatory stress, values less than 70% connote circulatory stress, less than 60% identify significant metabolic limitation, and values less than 50% frank tissue ischaemia.
The various adaptive cardiovascular controls and varying metabolic demands make rules about specific haemodynamic variables of limited clinical utility. It is simply not possible to say that, when looking after a critically ill patient, the central venous pressure, or any other single measurable variable, must be kept at x or y. Table 17.4.1 lists some haemodynamic monitoring key points relevant to the critically ill patient.
Pathophysiology of shock
The heart, vascular integrity, vasomotor tone, and autonomiccontrol all interact to sustain circulatory sufficiency. Circulatory shock reflects a failure of this system and results in an inadequate perfusion of the tissues to meet their metabolic demand, which can lead to cellular dysfunction and death. Numerous disease processes can result in circulatory shock, displaying surprisingly similar gross phenotypic expressions despite being caused by divergent processes whose treatments are equally different.
Weil and Shubin defined circulatory shock in 1968 as a decreased effectiveness of circulatory blood flow to meet the metabolic demands of the body. Four basic functional aetiologies of circulatory shock can be defined: (1) hypovolaemic, due to inadequate venous return (haemorrhage, dehydration), (2) cardiogenic, due to inadequate ventricular pump function (myocardial infarction), (3) obstructive, due to vascular obliteration (pulmonary embolism or tamponade), and (4) distributive, due to loss of vasoregulatory control (sepsis).
|Table 1 The critically ill patient: haemodynamic monitoring key points|
|Tachycardia is never a good thing||Tachycardia defines stress or an adaptation to stress. It may be necessary to sustain adequate blood flow, as in heart failure, but it still reflects heart failure.|
|Hypotension is always pathological||Hypotension impairs blood flow distribution and thus any patient with a MAP <65 mmHg is impaired. They may have hepatic cirrhosis with adequate tissue blood flow at rest, but they have a markedly limited ability to adapt to increased metabolic demand.|
|There is no such thing as a normal cardiac output||Since blood flow is regulated to meet the metabolic demand of the body, and that metabolic demand can vary widely and rapidly, there is no value of total cardiac output that guarantees adequate tissue perfusion. Blood flow is either adequate or inadequate, no matter what the absolute value is.|
|Central venous pressure is only elevated in disease||Under most conditions, the central venous pressure is very close to zero as the heart pumps all venous return immediately back to the body. The CVP will rise if either right or left sided heart failure develops, or fluid overload (due to renal failure and/or iatrogenic). The presence of an elevated CVP before medical intervention connotes disease of some sort.|
|Peripheral oedema is of cosmetic concern||Tissue perfusion is independent of interstitial fluid accumulation. Since the primary concern is maintenance of organ perfusion, which requires an adequate venous return and MAP, restricting fluid resuscitation in an unstable patient because of peripheral oedema is illogical and should be avoided.|
CVP, central venous pressure; MAP, mean arterial pressure.
Tissue hypoperfusion is common in all forms of shock, with the possible exception of hyperdynamic septic shock. This results in tissue hypoxia and a switch from aerobic to anaerobic metabolism, inducing hyperlactacidaemia and metabolic acidosis. However, hyperlactacidaemia, per se, is not a marker of ongoing tissue hypoperfusion because lactate clearance is often delayed or impaired in shock states, and processes such as exercise (seizure activity) can induce hyperlactacidaemia without cardiovascular insufficiency. Sustained circulatory shock results in cellular damage, not from anaerobic metabolism alone, but also from an inability to sustain intermediary metabolism and enzyme production necessary to drive normal mitochondrial performance. Metabolic failure due to sustained tissue hypoxia may explain why preoptimization and early goal-directed therapy improve outcome, whereas aggressive resuscitation after injury is not effective at reducing mortality from a variety of insults.
As stated above, measures of cardiac output, MAP and their changes in response to both shock and its treatment poorly reflect both regional blood flow and microcirculatory blood flow. Since most forms of haemodynamic monitoring measure global parameters like arterial pressure, heart rate, other vascular pressures, and cardiac output, it is clear that assessment of severity of shock and its initial response to therapy is often limited if monitoring is limited to these variables alone. Potentially, measuring SvO 2 or the difference between tissue P CO 2 and arterial P CO 2, referred to as the P CO 2 gap, would allow one to assess effective tissue blood flow since decreases in capillary blood flow initially causes CO2 from aerobic metabolism to accumulate. Gastric tonometry describing P CO 2 gaps identifies gastric ischaemia and may be useful in guiding resuscitation in critically ill patients: sublingual P CO 2 gaps are much easier to measure and offer a readily simple bedside monitoring approach. However, gastric tonometry is confounded by CO2 production from nonoxidative phosphorylation, and sublingual P CO 2 is not yet validated as a routine measure. Thus, at the present time, we are forced to use global measures of circulatory function, and determine which of the four shock categories is the most likely cause of organ dysfunction by noting their characteristic groupings of abnormalities, referred to as haemodynamic profile analysis.
Hypovolaemia is the cardiovascular state in which the effective circulating blood volume is inadequate to sustain a level of cardiac output necessary for normal function without supplemental sympathetic tone or postural changes to ensure adequate amounts of venous return. It is a relative process and can occur through absolute blood loss, as with haemorrhage and trauma, or fluid and electrolyte loss, as with massive diuresis, diarrhoea, vomiting, or evaporation from large burn surfaces. The normal reflex response to hypovolaemia is increased sympathetic tone, vasoconstriction, and tachycardia. Cardiac output is often sustained by these mechanisms such that heart rate is increased and stroke volume decreased, whereas blood flow distribution is diverted away from the skin, resting muscles, and gut. With tissue hypoperfusion, lactic acidosis develops as a marker of tissue anaerobic metabolism. Thus, hypovolaemia initiates as tachycardia, reduced arterial pulse pressure, and (often) hypertension with a near normal resting cardiac output, followed by signs of organ hypoperfusion (oliguria, confusion) as cardiac output decreases. Systemic hypotension is the final presentation of hypovolaemic shock and—if the clinician waits for this before acting—ischaemic tissue injury is almost always present.
Cardiac pump dysfunction can be due to either LV or RV failure, or both. LV failure, as described above, is usually manifest by an increased LV end-diastolic pressure, left atrial pressure, and (by extension) pulmonary artery occlusion (‘wedge’) pressure, which must exist to sustain an adequate LV stroke volume. Tachycardia is universal in the patient who is not β-blocked.
The most common cause of isolated LV failure in the critically ill patient is acute myocardial infarction. Usually, LV stroke work is reduced and heart rate increased. In chronic heart failure both cardiac output and systemic vasomotor tone may be normal, whereas in acute LV failure states both may be reduced. These combined haemodynamic interactions lead Forrester and colleagues to use a pulmonary artery occlusion (‘wedge’) pressure of 18 mmHg and a cardiac index of 2.2 as the cut-off to define heart failure states following acute myocardial infarction. However, neither cardiac output nor systemic vascular resistance is a sensitive marker of LV failure until cardiogenic shock develops. Since pulmonary artery occlusion (‘wedge’) pressure is the back pressure to pulmonary blood flow, increases associated with LV failure may lead to pulmonary oedema and hypoxaemia, and secondary pulmonary hypertension may subsequently impair RV ejection, inducing biventricular failure, peripheral venous hypertension, and peripheral oedema formation, the so-called ‘backward failure’.
The normal adaptive response of the host to impaired LV contractile function is to increase sympathetic tone, induce tachycardia, activate the renin-angiotensin system, retain sodium by the kidneys, and thus increase the circulating blood volume. Fluid retention takes time, whereas acute impairments of LV contractility can occur over seconds in response to myocardial ischaemia. Thus, the haemodynamic profile of acute and chronic LV failure can be different. Acute LV failure is manifest by increased sympathetic tone (tachycardia, hypertension), impaired LV function (increased filling pressure and reduced stroke volume), with minimal RV effects (normal central venous pressure), and increased O2 extraction manifest by a low SvO 2. Cardiac output need not be reduced and may in fact be elevated, owing to the release of catecholamines as part of the acute stress response; vascular resistance is increased. By contrast, in chronic heart failure, although sympathetic tone is elevated, the heart rate is rarely over 105/min, and filling pressures are elevated in both ventricles consistent with combined LV failure and fluid retention. Again, cardiac output is not reduced except in severe heart failure states, but a cardinal finding is the inability of the heart to increase output in response to a volume load or metabolic stress (exercise). Furthermore, owing to the increased sympathetic tone, splanchnic and renal blood flows are reduced and can lead to splanchnic or renal ischaemia.
Obstruction in this context means mechanical obstruction of blood flow or ventricular filling. The most common cause of obstructive shock is pulmonary embolism leading to acute RV failure, but isolated RV dysfunction can occur in the setting of an acute inferior wall myocardial infarction, also as a consequence of pulmonary vascular disease (chronic obstructive pulmonary disease, primary pulmonary hypertension). When RV dysfunction predominates and is induced by pulmonary parenchymal disease, it is referred to as cor pulmonale, which is associated with signs of backward failure, elevated RV volume and pressures, systemic venous hypertension, low cardiac output, as well as reduced renal and hepatic blood flow. LV diastolic compliance decreases as the right ventricle dilates due to ventricular interdependence, either from intraventricular septal shift or absolute limitation of biventricular volume due to pericardial restraint. Thus, pulmonary artery occlusion (‘wedge’) pressure is often elevated for a specific LV stroke work, giving the erroneous appearance of impaired LV contractility, but if LVEDV were measured it is possible that no change in LV function would be seen if this were plotted against LV stroke work.
Neither pulmonary vascular resistance nor mean pulmonary artery pressure need be grossly elevated for RV failure to be present. Indeed, and importantly, if pulmonary arterial pressures are greater than 30 to 35 mmHg, then pulmonary hypertension is probably chronic in nature because acute elevations of pulmonary arterial pressures above this level are not consistent with life. Elevations in central venous pressure of more than 12 mmHg also reflect fluid retention, suggesting further that there is a state of compensated RV failure.
Cardiac tamponade can occur from either (1) ventricular dilation limiting biventricular filling due to pericardial volume limitation, (2) acute pericardial effusion due to either fluid (inflammation) or blood (haemorrhage), which needs not be great in quantity, and (3) hyperinflation, which can act like pericardial tamponade to limit biventricular filling. The first two aetiologies are rarely seen, whereas the third commonly occurs. The cardinal sign of tamponade is diastolic equalization of all pressures, central venous pressure, pulmonary arterial diastolic pressure, and pulmonary artery occlusion (‘wedge’) pressure. Since RV compliance is greater than LV compliance, early on in tamponade there may be selective reduction in RV filling.
Loss of blood flow regulation occurs as the endstage of all forms of circulatory shock, but as the initial presenting process it is common in sepsis, neurogenic shock, and adrenal insufficiency. Sepsis is a systemic process characterized by activation of the intravascular inflammatory mediators and generalized endothelial injury, but it is not clear that tissue ischaemia is an early aspect of this process. Acute septicaemia is associated with increased sympathetic activity (tachycardia, diaphoresis) and increased capillary leak with loss of intravascular volume. Before fluid resuscitation this combination of processes resembles simple hypovolaemia, with decreased cardiac output, normal to increased peripheral vasomotor tone, and very low SvO 2, reflecting systemic hypoperfusion. LV function is often depressed, but only in parallel with depression of other organs, and this effect of sepsis is usually masked by the associated hypotension that maintains low LV afterload. However, most patients with such a clinical presentation receive initial volume expansion therapy such that the clinical picture of sepsis reflects a hyperdynamic state rather than hypovolaemia, which has been referred to as ‘warm shock’ in contrast to all other forms of shock. The haemodynamic profile of sepsis is one of increased cardiac index, normal pulmonary artery occlusion (‘wedge’) pressure, elevated SvO 2, and a low to normal arterial pressure, consistent with loss of peripheral vasomotor tone.
Acute spinal injury, spinal anaesthesia, general anaesthesia, and central nervous system catastrophe all induce a loss of sympathetic tone. The resulting hypotension is often not associated with compensatory tachycardia, hence systemic hypotension can be profound and precipitate cerebral vascular insufficiency and myocardial ischaemia. Since neurogenic shock reduces sympathetic tone, biventricular filling pressures, arterial pressure, and cardiac output all decrease. Treatment consists of reversing the primary process and supporting the circulation with infusion of an α-adrenergic agonist, such as phenylephrine, dopamine, or noradrenaline.
Acute adrenal insufficiency can present with hyperpyrexia and circulatory collapse. This is more common than might be guessed, based on the epidemiology of adrenal cortical disease, because many patients are receiving chronic corticocosteroid therapy for the management of systemic and localized inflammatory states, such as asthma or rheumatoid arthritis, and in such cases the added stress of trauma, surgery, or infection can precipitate secondary adrenal insufficiency, as can the (unwise) discontinuation of long-term steroid treatment. Presentation is with nausea and vomiting, diarrhoea, confusion, hypotension, and tachycardia. Cardiovascular collapse is similar to that seen in neurogenic shock, except that the vasculature is not as responsive to sympathomimetic support. Accordingly, failure to respond to vasoactive pharmacological support in a patient who is hypotensive should suggest the diagnosis of adrenal insufficiency, when giving stress doses of corticosteroids usually reverses the unresponsive nature of the shock process.
Circulatory support of the haemodynamically unstable patient
If the cause of hypotension is intravascular volume loss, either absolute, as would occur with haemorrhage or massive diarrhoea, or relative, as would occur with loss of vasomotor tone or increased capillary endothelial permeability, then cerebral and coronary perfusion pressures must be maintained while fluid resuscitation is begun, otherwise cardiac pump failure may develop and limit the effectiveness of fluid resuscitation. Infusions of vasoactive agents will increase both cardiac output and MAP at the expense of the remaining vascular beds, hence fluid resuscitation to achieve an adequate intravascular blood volume is essential for sustaining isolated vasopressor therapy in the setting of systemic hypotension. Many pathological states and acute stress conditions are associated with either adrenergic exhaustion or blunted responsiveness to otherwise adequate circulating levels of catecholamines, e.g. diabetes, adrenal insufficiency, hypothermia, hypoglycaemia, and hypothyroidism. Furthermore, acute sepsis and systemic inflammation are associated with reduced adrenergic responsiveness. Thus, even if the host makes an otherwise adequate sympathetic response, the vasomotor and inotropic response may be inadequate, requiring transient use of potent sympathomimetic agents to sustain cardiovascular homeostasis.
Pharmacotherapy for cardiovascular insufficiency is directed at the pathophysiological processes that either induce or compound it. These therapies can be loosely grouped into one of three processes: (1) those that increase vascular smooth muscle tone (vasopressor therapy), (2) those that increase cardiac contractility (inotropic support), and (3) those that decrease smooth muscle tone (vasodilator therapy). Infusion of vasopressor agents are indicated to sustain a MAP greater than 60 mmHg to prevent coronary or cerebral ischaemia, while other resuscitative measures, like volume resuscitation, and specific treatment of the underlying condition are ongoing. This level of MAP is clearly arbitrary since some patients maintain adequate coronary and cerebral blood flow at lower MAP levels, whereas others—notably those with either pre-existent systemic hypertension or atherosclerotic cerebrovascular disease—may not tolerate MAP decreasing more than 30 mmHg from their baseline values. Once an adequate MAP has been achieved and intravascular volume losses corrected, care shifts toward maintaining adequate blood flow to metabolically active tissues to sustain organ performance.
Adrenergic receptor physiology
Most inotropes and vasopressors in clinical use are sympathomimetics that have direct effects on the adrenoreceptor system. Adrenoreceptors are complex membrane glycoproteins whose intracellular signal transduction is commonly, although not exclusively, mediated through G proteins and adenylate cyclase in an amplification type system. Adrenoreceptors are classically subtyped into six functional classes: myocardial β1 and smooth muscular β2, postsynaptic α1 and dopamine1 (DA1), and presynaptic α2 and DA2. Despite several recent reports indicating that there are more classes of adrenoreceptors, conceptually the six subtypes serve clinicians well, with most functional issues relating only to α and β adrenergic receptor modulation. Importantly, there is a quantitatively unpredictable variation in adrenoreceptor density and function in many pathophysiological states, hence agents acting upon them need to be titrated to effect rather than being given at a defined infusion rate.
The only noncatecholamine sympathomimetic used, phenylephrine differs chemically from other sympathomimetics by the absence of a hydroxyl group on position 4 of the benzene ring. This deletion reduces its potency relative to other sympathomimetics. It acts as a moderately potent α1-agonist and is used in those patients in whom hypotension is due to decreased arterial elastance (it only activates β-adrenoreceptors at high doses). A modest direct coronary vasoconstrictor effect appears to be offset by autoregulatory mechanisms in the absence of flow-limiting coronary disease. It is not metabolized by catecholamine O-methyltransferase (COMT), which metabolizes catecholamines, and therefore its absolute half-life is considerably longer than catecholamine sympathomimetics.
Noradrenaline has significant activity at α and β1-adrenoreceptors, resulting in a positive vasoconstrictor and inotropic effect. Its β1 activity makes it the α1-agonist of choice in the patient with hypotension and known LV dysfunction. Its positive vasopressor effect may enhance renal perfusion and indices of renal function in haemodynamically stable patients, and this effect may also be seen at higher doses when noradrenaline is used as a vasopressor in those with sepsis. Both observations are likely related to elevation of MAP, the input pressure for organ perfusion. However, concerns regarding renovascular vasoconstriction have led some practitioners to supplement high-dose noradrenaline infusions with a low-dose dopamine infusion to blunt potential ischaemic nephrotoxicity, with support for this practice coming from an animal investigation.
Adrenaline is a very potent catecholamine sympathomimetic that has markedly increased β2-adrenoreceptor activity compared with its molecular substrate, noradrenaline. Adrenaline has potent chronotropic, inotropic, β2-vasodilatory, and α1-vasoconstrictor properties. Its net vasopressor effect is the end result of the balance between adrenaline-mediated β2 and α1 adrenoreceptor stimulation. At low doses this balance may result in no net pressor effect, with a fall in the diastolic blood pressure. Adrenaline, like noradrenaline, is known to have potent renovascular and splanchnic vasoconstrictor properties. Clearance rates are variable and mediated by both the COMT and monoamine oxidase systems.
Dopamine is the most controversial of the clinically utilized catecholamine sympathomimetics. This stems largely from claims for selective, dose-dependent, splanchnic and renovascular vasodilatory properties. Its dopaminergic properties do not reduce the incidence of renal failure in patients with shock when compared to noradrenaline. Dopamine stimulates the release of noradrenaline from sympathetic nerve terminals in a dose-dependent manner, with this indirect noradrenaline effect accounting for up to half of dopamine’s clinically observed physiological activity. Cardiomyocyte noradrenaline stores are finite, accounting for tachyphylaxis to the positive inotropic effects of dopamine observed after approximately 24 h in patients with acute myocardial infarction.
Dobutamine is a synthetic analogue of dopamine. It is utilized by continuous infusion as a positive inotrope, with the improvement in cardiac output noted to potentially increase renal blood flow, creatinine clearance, and urine output. As a β1-agonist it will increase myocardial oxygen consumption, although autoregulatory increases in coronary blood flow usually fully compensate in the absence of flow-limiting coronary artery disease. A noted problem with dobutamine is the development of tachyphylaxis with prolonged (as little as 72 h) infusions, suggested to be due to the down-regulation of β1-adrenoreceptors.
Dopexamine is a synthetic dopamine analogue with significant β2-adrenoreceptor agonist activity. Its splanchnic blood flow effects and positive inotropic activity have lead to enthusiasm for potential utility outside its primary indication, acute heart failure syndromes with hypertension and oliguria. Randomized controlled clinical investigations have demonstrated improvement in morbidity and mortality outcomes when dopexamine was utilized as the pharmaceutical of choice in achieving goal-oriented oxygen delivery values in perioperative critically ill patients.
These agents are not widely used in the management of circulatory shock, but the two most commonly employed agents in this class are amrinone and milrinone. Both are bipyridines, and the class of drugs is otherwise known as ‘inodilators’ with reference to the two predominant dose-dependent modes of action identified. Conventional wisdom is that these agents are much more potent vasodilators than inotropes, with the difference in potency approaching 10 to 100-fold. Milrinone has a shorter half-life and is a more potent (10–15-fold) inotropic agent than amrinone, but from all other aspects they are similar agents. Both are eliminated by conjugation, with amrinone’s biological half-life known to be extended in the presence of congestive heart failure. Their mechanism of action is not precisely known, but at least part of their activity is related to inhibition of phosphodiesterase type 3, found in high concentrations in cardiomyocytes and smooth muscle cells, and they may activate a sodium-dependent calcium channel. The end result is an increase in intracellular cAMP and calcium, with the physiological effect being an improvement in diastolic myocardial function, and for this reason these agents are felt to be positive lusiotropes. Clinically, they are used as positive inotropes, given by continuous intravenous infusion following a loading dose, with their catecholamine-independent mechanism of action making them theoretically attractive as inotropic support of choice in patients with potential β1-adrenoreceptor down-regulation.
Afterload reducing vasodilators act via vascular smooth muscle relaxation. Vascular dilatation is mediated by both nitric oxide (NO) and non-NO-based mechanisms, NO being a powerful, locally acting vascular smooth muscle relaxant. Among commonly used vasodilators in haemodynamically unstable patients, both sodium nitroprusside and glyceryl trinitrate (nitroglycerine) function as NO donors. Numerous other non-NO donor vasodilating agents are available, with hydralazine, clonidine, and inhibitors of the renin-angiotensin system being the most commonly employed non-NO-based vasodilators in patients with cardiovascular instability.
A simple approach to the pharmacotherapy of circulatory shock
Loss of vasomotor tone requires both fluid resuscitation to achieve the increased vascular volume needed to restore an effective pressure gradient for venous return, and increased α-adrenergic tone via sympathomimetic agents to restore arterial and venous vasomotor tone. Targets for resuscitation are an SvO 2 greater than 70% with a MAP greater than 60 mmHg. Impaired contractility requires afterload reduction, as tolerated, up to a decrease in MAP to approximately 70 mmHg, targeting pulmonary artery occlusion (‘wedge’) pressure less than 18 mmHg, and SvO 2 greater than 70%. In sepsis, SvO 2 is usually elevated following fluid resuscitation, hence resuscitation targets usually focus on reaching elevated levels of D O 2 (e.g. >450 ml/min per m2). In states of RV failure, maintaining a MAP greater than pulmonary arterial pressure is essential to minimize RV myocardial ischaemia. Regrettably, the only prospective clinical trials documenting benefit from such resuscitation strategies were applied early in the course of sepsis or in high-risk surgical patients. However, it makes physiological sense to prevent organ ischaemia by maintaining blood flow, hence strategies such as those described above seem warranted in the absence of clinical trial evidence.