Shock is a common life-threatening condition in emergency and critical care, resulting from many heterogeneous disease processes.[1,2] Early management prevents the progression of reversible organ dysfunction to an irreversible state of multiorgan failure. Management of shock can broadly be summarized into four components – (1) prompt recognition of shock; (2) assessment of the type of shock; (3) resuscitation with ventilation, intravenous fluids, and pressor therapy; and (4) diagnosis and treatment of the underlying etiology.
Shock is a clinical manifestation of circulatory failure causing tissue hypoperfusion and inadequate cellular oxygen supply. Tissue hypoperfusion is central to the definition of shock, which is clinically apparent through the three “windows” of the body – skin, kidney, and brain and biochemically with hyperlactatemia indicating impaired oxidative phosphorylation [Box 1].[1–5] Hypotension is typically present with accompanying tachycardia. Systolic blood pressure (SBP) <90 mmHg or the mean arterial pressure (MAP) <70 mmHg usually defines hypotension, which, however, may not be applied to persons with long-standing hypertension, where the magnitude of reduction in the blood pressure is more important.[1,2,5]
Pathophysiology and Classification of Shock
The major determinants of tissue oxygen supply are cardiac output (CO), which is a product of stroke volume (SV) and heart rate (HR) (i.e., CO = SV x HR), and arterial oxygen content. The SV mainly depends on three parameters – (1) Contractility of cardiac muscles; (2) Afterload, i.e., the force against which ventricles must contract (the systemic vascular resistance); and (3) Preload, i.e., length of the myocardial muscle at the onset of contraction (the ventricular end-diastolic volume) (can be remembered as an acronym SV-CAP). Thus, derangement of one or more of these parameters determining tissue oxygen supply can cause shock and also categorize shock into four major types [Figure 1].[1,2]
Early resuscitation aiming for adequate hemodynamic stabilization is essential to prevent the progression of tissue hypoperfusion and multiorgan failure. Resuscitation consists of three main components – Ventilation, Intravenous fluids (IVFs), and Pressor therapy, which can be easily remembered as “VIP resuscitation.”[1,2,6] Ventilation (mask, high-flow nasal cannula, or endotracheal intubation) provides adequate oxygen delivery to the organs, IVF therapy maintains adequate intravascular volume, and pressor support (vasopressors and/or inotropes) increases MAP to improve tissue perfusion.
MAP is the primary driver of CO and remains the essential determinant of mean systemic filling pressure.[2,4] Thus, an increase in MAP usually results in increased tissue perfusion. The measurement using a noninvasive cuff tends to be inaccurate and unreliable. Therefore, invasive arterial blood pressure monitoring with an intra-arterial catheter should be done unless the shock is rapidly reversed.[1,5] The arterial catheter can also facilitate sampling for ABG or lactate. Serial lactate measurement may help in predicting the adequacy of resuscitation.[4,7–9] A central venous catheter (CVC) is frequently required to administer large amounts of IVF, vasoactive drugs, and other medications (e.g., antimicrobial agents in septic shock). The CVC can also monitor central venous pressure (CVP) (to guide fluid therapy) and obtain central venous oxygen saturation (ScvO2). The ScvO2 is a surrogate of mixed venous oxygen saturation; thus, serial monitoring can provide adequacy of oxygen delivery.[2,9] For example, targeting ScvO2 >70% has improved survival in septic shock, but recent data question its compulsory use.[9–13]
Because tissue oxygen supply depends on arterial oxygen content, oxygen supplementation is required in patients with hypoxemia to maintain an arterial saturation of 94-96%.[1,2,5,14–16] Hypoxemia may be related to the cause of shock (e.g., pneumonia, heart failure, pulmonary embolism, or pneumothorax) or the effect of shock (e.g., development of acute respiratory distress syndrome in all types of shock). Endotracheal intubation with mechanical ventilation is required in patients with persistence or worsening of hypoxemia, dyspnea, or metabolic acidosis.[1,2,5] Additionally, invasive ventilation decreases tissue oxygen demand of respiratory muscles and decreases afterload by increasing intrathoracic pressure. The sedative and neuromuscular blocking agents in mechanically ventilated patients should be minimum and intermittent (rather than continuous) to avoid worsening of hypotension.[1,5]
All types of shock require IVF to restore blood flow in the microvascular bed and intravascular volume.[1,2] Even cardiogenic shock should receive initial IVF to optimize cardiac filling pressures and maintain effective intravascular volume status.[17–19] However, overzealous fluid therapy results in pulmonary and peripheral edema and abdominal and other compartment syndromes and impairs oxygen diffusion.[20,21] Although fluid resuscitation is an essential component of early shock management, there is a lack of universal consensus on the type and dose of IVF and pragmatic endpoints.[20,22] However, these factors may affect patient outcomes.
Fluid resuscitation should begin with a crystalloid solution in most patients with shock.[5,23] Although colloids (e.g., albumin) are theoretically more likely to be physiological (e.g., maintaining oncotic pressure) than crystalloids, they do not offer a substantial hemodynamic benefit, and their routine use is not recommended.[5,20,23–25] Moreover, crystalloids are widely available and inexpensive. The most widely used crystalloid is 0.9% sodium chloride (normal saline). It is slightly hyperosmolar, containing higher sodium and chloride concentrations (both, 154 mEq/L) compared with normal human plasma (sodium, 135-145 mEq/L, and chloride, 94-111 mEq/L). Therefore, a large amount of administration may result in hyperchloremic metabolic acidosis, renal vasoconstriction, and acute kidney injury.[26–31] Balanced crystalloids (e.g., Ringer lactate or Hartmann solution, PlasmaLyte®) have a lower chloride content and better match human plasma. Compared to normal saline, balanced crystalloids have shown better outcomes in patients with distributive shock (septic shock and acute pancreatitis) and hypovolemic shock (gastrointestinal losses and diabetic ketoacidosis).[5,21,32–37] When larger amounts of crystalloids are required, administration of albumin (natural colloid) is suggested to achieve the MAP target early with lower net fluid balance.[5,38] Synthetic colloid (e.g., hydroxyethyl starch and gelatin) use for fluid resuscitation has been associated with increased adverse effects and no conclusive survival benefits in patients with shock.[5,39–43]Box 2 shows current recommendations on initial resuscitation with aggressive fluid therapy in common medical conditions associated with distributive and hypovolemic shock in adults.[5,35–37,43–47]
Following the initial bolus doses, it is important to identify which patients will benefit from further IVF. Dynamic measures are more useful to guide fluid resuscitation than a physical examination or static parameters alone.[5,48–50] Dynamic parameters include response after increasing preload by a passive leg raise (PLR) or an IVF bolus on CO or related parameters or point-of-care ultrasound (POCUS) measurement of inferior vena cava (IVC) diameter variation with respiratory phases. While the patient is resting in semi-recumbent (at 45° angle rather than flat), PLR is performed by placing the bed in Trendelenburg position with the legs inclined to 45° angle and the upper section flat.[51–53] An immediate (within 60 s) assessment of an increase in CO (e.g., >10%) identifies fluid responders.[48,49,51–53] Transpulmonary thermodilution or transthoracic echocardiography is commonly used for CO or SV measurement in PLR. In resource constraint settings, an increase in pulse pressure (e.g., >15%) could be used to predict an increase in CO after PLR.[53,54] In mechanically ventilated patients, measuring changes in SV (or pulse pressure) variation during the respiratory cycle may also be considered.[48,49,51–53]
POCUS has been used to assess intravascular volume with IVC diameter and its variation with respiratory phases. During inspiration, the IVC collapses in spontaneously breathing patients and distends in patients on invasive ventilation without spontaneous respiration. During inspiration, a >42% reduction in the IVC diameter (collapsibility index) in spontaneously breathing patients, and in mechanically ventilated patients, a >15% increase in the diameter compared to expiration (distensibility index) may help predict fluid responsiveness.[48,55,56] However, the usefulness of the respiratory variation of IVC has been questioned by recent studies.[48,57–60] Alternatively, while the IVF is being administered, a cardiac scan can assess ventricle contractility with ejection fraction, and a lung ultrasound can look for the development of B lines suggesting hemodynamic pulmonary edema.[1,2]
CVC and pulmonary artery catheter (PAC, Swan-Ganz catheter) have traditionally been used for invasive hemodynamic assessment in shock. Although CVC placement with a low CVP (usually <8 mmHg) is frequently used for fluid responsiveness, recent evidence finds it a poor predictor.[48,61–63] Its accuracy is further compromised by ventilator settings and lung compliance. A PAC allows direct measurement of CVP, pulmonary artery, and pulmonary capillary wedge pressure (a measure of left atrial pressure). Despite the absence of benefits from its routine use, PAC may be required in selected patients with cardiogenic shock or mixed distributive and cardiogenic shock.[64–67] Static measures such as CVP, SBP, or HR alone are poor indicators of volume status. Similarly, besides capillary refill time as an adjunctive measure for septic shock, physical examination findings are not predictive of fluid responsiveness.[5,48] A shock index, the HR to SBP ratio of > 0.9 (normal range 0.5-0.7), may predict a transfusion requirement in hemorrhagic shock.[2,68] The shock index may also indicate a decrease in BP after the initiation of invasive mechanical ventilation.[69,70] Postintubation hypotension usually reflects hypovolemia and a reduction in preload.
Vasopressor or inotropic support is indicated if shock persists despite initial fluid resuscitation or is profound at presentation. Vasoactive drugs are used to increase MAP. An initial target MAP of 65 mmHg is recommended in shock requiring vasoactive medications.[1,2,5,19] A higher target is associated with no survival benefits and increased adverse effects. A CVC is usually indicated to administer vasoactive drugs as peripheral administration may cause extravasation or local tissue injury. However, the initiation of vasoactive agents should not be delayed while waiting for a CVC placement.[5,73]Table 1 shows the usual recommended dose of commonly used vasoactive agents in circulatory shock.
Catecholamines or adrenergic agonists are the first-line pressor agents, given their rapid onset and short duration of action. Because stimulation of each adrenergic receptor causes both therapeutic and adverse effects, pressor therapy should be targeted to the primary pathophysiologic mechanism.[74,75] Norepinephrine remains the first-choice vasopressor in septic shock because of its predominant α-effects (increases systemic vascular resistance) and modest β1-adrenergic activity (maintains CO).[1,5,74,76] Epinephrine has potent β-effects at low doses and with higher doses, causes α-effects (similar to norepinephrine), but also increases the risk of arrhythmia, reduced splanchnic circulation, and metabolic acidosis.[77–80] Dopamine has β-effects at low doses and additional α-effects at high doses; however, these effects are weaker than norepinephrine and epinephrine. Studies have found that dopamine use increases the risk of arrhythmia and overall mortality in patients with cardiogenic and septic shock.[76,81,82] Septic shock may cause a “relative vasopressin deficiency” state.[83,84] Vasopressin acts on the vasopressin (V1) receptors on vascular smooth muscle, and it reverses vasodilation and increases splanchnic blood flow. Vasopressin is recommended as a second agent for septic shock requiring a norepinephrine dose above 0.25-0.5 μg/kg/min [Figure 2].[5,84–86] Vasopressin is usually administered at a fixed dose of 0.03 units/min without titrating to the response. Doses above 0.04 units/min increase the risk of cardiac, splanchnic, and digital ischemia. Other selective V1 agonists, e.g., selepressin and terlipressin, are associated with increased adverse effects and thus not indicated.[88,89] Epinephrine has been suggested as a second- or third-line vasopressor for septic shock.[5,90,91] Angiotensin II, a natural hormone, exerts marked vasoconstrictor effects by stimulating the renin–angiotensin–aldosterone system. Recent trials find an adjunctive role of angiotensin II in managing distributive shock, but strong evidence for its routine clinical use is lacking.[5,92–94]
Dobutamine, a synthetic catecholamine, is considered the inotropic agent of choice due to its predominant β1-adrenergic effects. However, its β2-adrenergic effects may worsen hypotension. Therefore, dobutamine is usually considered a first-line agent for mild cardiogenic shock without severe tissue hypoperfusion (e.g., in patients with chronic cardiomyopathy).[1,19,95,96] A vasopressor remains the first-line agent for profound cardiogenic shock (e.g., after myocardial infarction) [Figure 2].[1,19,67,95] Norepinephrine is preferred over epinephrine in cardiogenic shock.[1,96–98] Dobutamine may improve tissue perfusion and splanchnic blood flow in septic shock, but these effects may not be predictable.[99–101] In patients with septic shock and cardiac dysfunction with persistent hypoperfusion, the addition of dobutamine to norepinephrine or the use of epinephrine alone is suggested by recent guidelines. Thus, it is a phosphodiesterase-3 inhibitor that increases inotropy without significant chronotropic effects and also causes vasodilation in pulmonary and systemic circulations. It has a slow-onset action and long-half life, and the doses require renal modifications. It may increase the risk of arrhythmia and hypotension. Milrinone is primarily used to increase CO in patients who are not critically unstable and without profound hypotension.[19,103] Levosimendan is a calcium-sensitizing drug with both inotropic and vasodilatory properties which has been recently used in septic shock. However, it did not improve outcomes and had a risk of tachyarrhythmia.
Specific Treatment of the Underlying Etiology
Specific forms of shock require therapy directed to the underlying cause. The diagnostic evaluation must begin in all patients while “VIP” resuscitation is ongoing. An initial practical approach is to make a rapid evaluation with limited clinical history, physical examination, and basic laboratory investigations directed to determine the cause and severity of shock. Basic laboratory testing may include complete blood count (with differential), biochemistry with renal and liver functions, arterial blood gas, lactate, electrocardiography, chest radiograph, and coagulation profile.[1,2] POCUS has a diagnostic value in undifferentiated shock (i.e., when the shock is recognized but the cause is not apparent) with a rapid assessment of myocardial function, intravascular volume status, and fluid collections in serous cavities.[2,105] The Rapid Ultrasound in SHock examination is an easy and widely used three-step shock ultrasound protocol [Table 2]. However, a recent trial did not find to improve outcomes using POCUS in patients with undifferentiated shock. The potential diagnostic clues, based on the initial evaluation, should tailor further comprehensive diagnostic testing after an early clinical stabilization.
Distributive shock secondary to sepsis remains the most common cause of shock. Recent guidelines recommend initiating broad-spectrum antimicrobials immediately, preferably within 1 h, in all patients with potential septic shock. Empirical antimicrobial agents should be directed against the likely causative organism (e.g., based on the specific risks for multidrug-resistant Gram-negative bacilli, methicillin-resistant Staphylococcus aureus, or fungal infections) and ideally be administered after obtaining appropriate cultures. The dosing of antibiotics should be optimized based on pharmacokinetic/pharmacodynamic principles.[5,108]Table 3 shows the usual dosing of commonly used antibiotics in adult patients with septic shock. Adjunctive steroids have been widely used in septic shock with persisting hypoperfusion; however, many large trials and meta-analyses have divergent mortality results.[109–111] The recent sepsis guidelines suggest initiating intravenous hydrocortisone at a dose of 200 mg/day if the shock requires norepinephrine or epinephrine at a dose ≥0.25 µg/kg/min for at least 4 h (weak recommendation; moderate quality of evidence).
Distributive shock secondary to anaphylaxis requires removing the inciting allergen, administering epinephrine, and IVF resuscitation. Intramuscular epinephrine (0.3-0.5 mg q 5 min in the outer middle third of thigh or deltoid) is recommended as the first-line treatment. However, if the shock is refractory to 1-2 doses of intramuscular epinephrine and fluid boluses, epinephrine infusion remains the mainstay of treatment [Figure 2].[112,113] Intravenous bolus of epinephrine is associated with a high risk of arrhythmia; however, it may be given as 10-20 µg q 2-5 min in profound shock while the infusion is being prepared. Acute adrenal insufficiency requires steroid therapy, i.e., intravenous hydrocortisone with an initial bolus of 100 mg followed by daily doses of 200 mg in 2-3 divided doses.
Myocardial infarction remains the most common cause of cardiogenic shock, which requires reperfusion therapy with percutaneous coronary intervention or coronary artery bypass grafting. Mechanical circulatory support devices (e.g., intra-aortic balloon pump, percutaneous ventricular assist device, and venoarterial extracorporeal membrane oxygenation) are increasingly used for temporary hemodynamic support in cardiogenic shock.[19,64] However, consensus on the indication and timing of their use remains poorly defined. Management of the primary disease process is critical for obstructive shocks, such as thrombolysis or thrombectomy for pulmonary embolism, decompression of pneumothorax, or drainage of pericardial effusion.[1,2] Hemorrhagic shock requires blood product resuscitation and surgical interventions to achieve hemostasis (surgical, interventional radiology, or endoscopic).
This review highlights recent advances in caring for adult patients with circulatory shock. Early management in the reversible phase requires rapid shock identification with clinical signs of tissue hypoperfusion (“three windows - skin, kidney and brain”) and hyperlactatemia. Knowledge of underlying physiologic derangement (and classification) of shock is essential for appropriate treatment, including “VIP” resuscitation. Balanced crystalloids are preferred IVF for initial resuscitation. Dynamic measures, most notably PLR, should guide further fluid therapy. POCUS may have a role in diagnostic evaluation, fluid resuscitation, and treatment. Norepinephrine remains the first-line vasopressor in septic shock (strong recommendation) and profound cardiogenic shock (weak recommendation). Dopamine is no longer used in most patients with shock. Specific forms of shock require therapy directed to the underlying cause.
AKP: Conceptualization; Literature search; Writing-original draft, review and editing. The corresponding author is responsible for ensuring that the descriptions are accurate and agreed upon by all authors.
Conflicts of interest
The author (AKP) is grateful to Mrs. Sunaina Verma for her timely intellectual assistance.
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