Abstract
Background
Vasopressors are administered to critically ill patients with vasodilatory shock not responsive to volume resuscitation, and less often in cardiogenic shock, and hypovolemic shock.
Objectives
The objectives are to review safety and efficacy of vasopressors, pathophysiology, agents that decrease vasopressor dose, predictive biomarkers, β1-blockers, and directions for research.
Methods
The quality of evidence was evaluated using Grading of Recommendations Assessment, Development, and Evaluation (GRADE).
Results
Vasopressors bind adrenergic: α1, α2, β1, β2; vasopressin: AVPR1a, AVPR1B, AVPR2; angiotensin II: AG1, AG2; and dopamine: DA1, DA2 receptors inducing vasoconstriction. Vasopressor choice and dose vary because of patients and physician practice. Adverse effects include excessive vasoconstriction, organ ischemia, hyperglycemia, hyperlactatemia, tachycardia, and tachyarrhythmias. No randomized controlled trials of vasopressors showed a significant difference in 28-day mortality rate. Norepinephrine is the first-choice vasopressor in vasodilatory shock after adequate volume resuscitation. Some strategies that decrease norepinephrine dose (vasopressin, angiotensin II) have not decreased 28-day mortality while corticosteroids have decreased 28-day mortality significantly in some (two large trials) but not all trials. In norepinephrine-refractory patients, vasopressin or epinephrine may be added. A new vasopressor, angiotensin II, may be useful in profoundly hypotensive patients. Dobutamine may be added because vasopressors may decrease ventricular contractility. Dopamine is recommended only in bradycardic patients. There are potent vasopressors with limited evidence (e.g. methylene blue, metaraminol) and novel vasopressors in development (selepressin).
Conclusions
Norepinephrine is first choice followed by vasopressin or epinephrine. Angiotensin II and dopamine have limited indications. In future, predictive biomarkers may guide vasopressor selection and novel vasopressors may emerge.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Vasopressors are administered to critically ill patients with vasodilatory shock not responsive to volume resuscitation, and less commonly cardiogenic shock and hypovolemic shock. Norepinephrine as first choice may be followed by vasopressin or epinephrine. Angiotensin II and dopamine have limited indications. In future, predictive biomarkers may guide vasopressor selection and novel vasopressors may emerge. |
Objectives
The objectives are to review general clinical comments regarding vasopressor use in shock, pathophysiology, specific vasopressor characteristics, safety, and efficacy evidence, agents that decrease vasopressor dose, predictive biomarkers, β1-blockers in septic shock, vasopressors for hypovolemic and cardiogenic shock and directions for research. Vasopressors are commonly administered for vasodilatory shock, especially septic shock, not responsive to volume resuscitation. Other causes of shock for which vasopressors are administered include vasodilatory shock post-cardiovascular surgery, post-acute myocardial infarction, post-general/abdominal surgery/anesthesia or after certain drug administration as well as cardiogenic and hypovolemic shock. Most high-quality randomized controlled trials (RCTs) of vasopressors are in septic shock.
Summary of evidence
Despite international guidelines [3], the specific vasopressor chosen and vasopressor dose vary widely in clinical practice because of patient and physician practice heterogeneity [4]. For example, norepinephrine doses used in the control group of shock RCTs varied widely (mean 0.20–0.82 μg/kg min−1) [5]. Furthermore, the variable use of vasopressin clinically illustrates institution and physician practice heterogeneity. An observational cohort study (n = 584,421 patients; 532 hospitals) evaluated vasopressin use in septic shock [6]. Patients in “high vasopressin use” hospitals were 2.6-fold more likely to receive vasopressin than patients in “low vasopressin use” hospitals. Interpretation is limited because of heterogeneity of patients from many community and university-affiliated small and large hospitals.
Vasopressors are indicated for patients who have not responded to “adequate” fluid resuscitation [3] but “adequate” varies widely and is difficult to measure clinically because clinicians’ measurement tools of volume status are relatively inaccurate. Furthermore, the interactions of various fluid types, fluid loading volumes, and vasopressor effects introduce important potential bias in part because vasopressors (unlike fluids) exert their action on arteries and veins. There is scant evidence of alternative vasopressors as first line vasopressors because RCTs of vasopressors included patients on norepinephrine.
Vasopressors are hormones that vasoconstrict by receptor activation (norepinephrine/epinephrine: α1, β1, β2; vasopressin: AVPR1a, AVPR1b, AVPR2; angiotensin II: AGTR1, AGTR2; dopamine; DA1, DA2 (Fig. 1) perhaps limiting drug discovery opportunities. Novel vasopressors are modifications of natural hormones (e.g. selepressin, a specific AVPR1a agonist). There is complex cross-talk of these hormone systems (Fig. 2) further complicating vasopressor therapy.
All vasopressors frequently have adverse effects in practice, especially organ ischemia/infarction, metabolic changes (β1-induced hyperglycemia; β2-induced hyperlactatemia), β1-induced-tachycardia and -tachyarrhythmias). The target mean arterial pressure (MAP) during vasopressor use is 65 mmHg [3] but is debated; one RCT [8] found no difference in mortality between “usual” (65–70 mmHg) versus “high” MAP (80–85 mmHg). However, a clinically relevant result emerged that we use: in patients with chronic hypertension, the high MAP target decreased acute kidney injury.
Patients on vasopressors often—but not always—require arterial catheter for arterial pressure monitoring (and central venous pressure (CVP) monitoring (target CVP > 8–2 cm H2O [3]). Some clinicians use a pulmonary artery catheter and monitor pulmonary capillary wedge pressure and cardiac output. However, non-invasive cardiovascular monitoring has supplanted PA catheter monitoring in many patients.
Vasopressor management was central in Early Goal-Directed Therapy, effective in an initial RCT [9] but not in subsequent RCTs [10], so EGDT is not recommended for clinical use.
The “sepsis 3.0” definition of septic shock is recommended clinically, requiring both use of vasopressor(s) and serum lactate > 2 mmol/L [11] (sepsis 2.0 required only vasopressor use). When sepsis 3.0 was applied to a prior pivotal vasopressin RCT [12], vasopressin was most effective in patients who did not meet the sepsis 3.0 definition (i.e. vasopressor use and lactate ≤ 2 mmol/L) [13]. The observed mortality rates are higher with sepsis 3.0 versus the sepsis 2.0 definition of septic shock [14]. Thus, the use of septic shock 3.0 will change clinical practice and RCTs of septic shock. Use of septic shock 3.0 for RCTs would tighten inclusion criteria, decrease sample size (by 50% in the retrospective analysis of the VASST RCT), and increase mortality rates [13, 14].
Finally, no RCT of vasopressors shows a significant difference in 28-day mortality rate. Some strategies that decrease norepinephrine dose (vasopressin [12, 15], angiotensin II [16]) have not decreased 28-day mortality, while another (corticosteroids) has decreased 28-day mortality significantly in some (two large trials [17, 18]) but not all trials [19, 20].
For the clinician, the vasopressor field has evolved [3]: norepinephrine remains the first line vasopressor, epinephrine or vasopressin are second line, dopamine is recommended only in highly selected bradycardic patients, a new vasopressor is available clinically (angiotensin II [16]), and a novel vasopressor, selepressin [21] is in trial.
Accordingly, we review clinically relevant pathophysiology of vasodilatory shock, pivotal vasopressor RCTs, how the clinician determines whether and what vasopressor(s) to administer, and specific vasopressor pharmacology, guidelines, effects, adverse effects, dosing, monitoring, weaning, and outcomes. We discuss inotropic agents to complement vasopressors, predictive biomarkers, and novel vasopressors. We consider the ironic role of β1-blockers in septic shock. We review vasodilatory shock post-cardiovascular surgery and post-acute myocardial infarction, cardiogenic and hypovolemic shock.
Clinically relevant pathophysiology of vasodilatory shock
Vasodilatory shock is characterized by vasodilation (identified clinically by warm skin), hypotension, tachycardia, and inadequate perfusion (impaired mentation, oliguria). When ventricular dysfunction and hypovolemia contribute, features change (cold skin, increased jugular venous pressure (JVP) and CVP if there is ventricular dysfunction and low JVP and CVP if there is hypovolemia). Vascular smooth muscle relaxation is the cardinal mechanism of vasodilatory shock [22]. While not apparent to the clinician, behind the scene there is a rapid, complex, hormonal response to hypotension: secretion of multiple hormones (norepinephrine, epinephrine, vasopressin, angiotensin II, aldosterone, adrenomedullin, and cortisol) act synergistically attempting to increase vasomotor tone, heart rate and contractility. Often vasodilation persists because of β1, β2 and other receptor down-regulation [23], inter-patient receptor genotype differences [24, 25], and genetically-variable metabolism [26]. When these regulatory multi-hormone mechanisms are overwhelmed, hypotension and shock persist.
Vasodilation in sepsis is mediated mainly by nitric oxide (NO) and prostacyclin. Inducible NO synthase (iNOS) is induced by endotoxin and cytokines; an iNOS inhibitor increased NO synthesis and blood pressure, decreased vasopressor requirements but decreased survival in a large pivotal RCT so is not available clinically nor recommended [27, 28]. Prostacyclin is released by endothelial cells in response to endotoxin and inflammatory cytokines. A pivotal RCT of ibuprofen (prostaglandin synthesis inhibitor) had no effect on survival [29].
Adrenomedullin, a vasodilating and cardiac depressant hormone, increases in septic shock and is associated with mortality. Anti-adrenomedullin increased survival, responsiveness to norepinephrine and renal function in sepsis models and is a novel therapeutic target in septic shock [30].
Clinical and physiologic evaluation for the clinician to determine when and what vasopressor(s) to administer
Emergent assessment prioritizes airway, breathing and cardiovascular resuscitation based on clinical assessment of volume status and perfusion complemented by laboratory tests (arterial blood gases, lactate, hematology, renal and hepatic function) (Fig. 3). The quick SOFA (qSOFA: respiratory rate > or = 22/min, altered mentation, systolic blood pressure < or = 100 mmHg) is recommended screening for sepsis outside the ICU [11]. Volume resuscitation and vasopressor(s) should be started within the first hour [3] and resuscitation with crystalloid (30 ml/kg initially and more as needed) should precede vasopressors, added if perfusion remains inadequate [3].
In parallel with resuscitation, use clinical examination and laboratory evaluation to diagnose the cause of shock; fever, and leukocytosis suggest septic shock and the source of sepsis should be investigated. Sepsis mimics include pancreatitis, aspiration, Acute Respiratory Distress Syndrome (ARDS), recent surgery, post-acute myocardial infarction, trauma, and drugs (anesthetics and drug allergy/anaphylaxis).
There is no evidence that any diagnostic tool is effective to guide treatment, at least regarding mortality. Limited bedside echocardiography can be effective to guide fluid and vasopressor management. We use limited bedside echocardiography commonly because a case–control study of bedside echocardiography in ICU patients resuscitated but in shock found (1) volume status was often more than replete (2) fluid restriction was recommended (65% of patients), and (3) initiation of dobutamine was recommended (25% of patients) [31]. Mortality was lower in the echocardiography group than controls [31]. However, the mechanism by which bedside echocardiography leads to dobutamine prescription then leading to decreased mortality is uncertain.
Vasopressor class effects
See Table 1 for vasopressors, receptors, actions, dose, and biomarkers. Studies of early antibiotics [32, 33] and Early Goal-Direct Therapy [10, 33] taught clinicians to emphasize early recognition and treatment of septic shock within the first hour (comparable to the “golden hour” of trauma) and aligns with an artificial intelligence (AI) study. In contrast to clinical practice in a large UK cohort, the AI clinician recommended septic patients be given vasopressors more often (30% versus 17%) [34]. However, other uncontrolled observational studies found that earlier vasopressor(s) was harmful [35] suggesting equipoise regarding earlier use of vasopressors.
Pivotal vasopressor trials
Pivotal RCTs of norepinephrine vs. epinephrine [37], norepinephrine plus dobutamine vs. epinephrine [47], early vasopressin [15] vs. norepinephrine, and vasopressin vs. norepinephrine in septic shock [12] and norepinephrine vs. dopamine [48] in all types of shock established that norepinephrine is superior to dopamine and equivalent to vasopressin and epinephrine (Table 2). Some of these RCTs had only moderate sample sizes. While two RCTs had over 700 patients each (SOAP II [48] (dopamine versus norepinephrine n = 1679; VASST [12] (vasopressin versus norepinephrine n = 778)), ATHOS-3 [16] (angiotensin II versus placebo n = 479), VANISH [15] (vasopressin versus norepinephrine, n = 409, CAT [37] (epinephrine versus norepinephrine, n = 330) and CATS [47] (epinephrine versus norepinephrine plus dobutamine n = 277) were smaller.
There was no difference in mortality between vasopressin and norepinephrine in VASST [12] and VANISH [15], but vasopressin may have been more effective in less severe shock (baseline norepinephrine < 15 μg/min). Vasopressin was associated with similar outcomes to norepinephrine in a propensity matched cohort study [49]. A small RCT of early vasopressin and norepinephrine vs. norepinephrine alone found that the early vasopressin and norepinephrine group achieved MAP of 65 mmHg faster than the norepinephrine group [50].
In more severe shock, clinicians often administer combinations of vasopressors but the optimal vasopressor combination remains unknown regarding mortality. In a network meta-analysis of RCTs (43 RCTs; 5767 patients) of vasopressors [51], the efficacy was greatest for norepinephrine plus dobutamine; acute myocardial infarction incidence was highest with norepinephrine plus epinephrine; arrhythmia incidence was highest with dopamine and lowest with vasopressin. This retrospective study must be interpreted cautiously and as hypothesis-generating.
Adverse effects
The commonest serious adverse effects of vasopressors are digital and organ ischemia, tachyarrhythmias, and atrial fibrillation [52] (with increased risk of stroke [53]) (Table 3). Higher cumulative vasopressor dose is associated with organ dysfunction and mortality [54], but association studies are confounded. Many vasopressors have immune effects that may be proven important in human septic shock. Norepinephrine has moderate immunosuppressive and bacterial growth-promoting effects in pre-clinical models that could increase risk of infection, but immune risk of norepinephrine infusion is uncertain [36]. Vasopressin augments the usual decrease of cytokines more than norepinephrine, especially in less severe septic shock [55].
Serious adverse events of vasopressors were similar in most RCTs but differed significantly between dopamine versus epinephrine in SOAP 2 [48] [twice as many arrhythmias with dopamine (24.1%) than norepinephrine (12.4%, p < 0.001), mainly atrial fibrillation (Table 4)]. There was significantly more study drug withdrawal of epinephrine than norepinephrine in CAT (12.9% versus 2.8%, p = 0.002) [37].
Clinical monitoring of vasopressor(s)
Vasopressors are initiated, titrated, and weaned according to MAP, measures of perfusion (mentation, urine output, lactate), and non-invasive cardiovascular assessment (e.g. non-invasive cardiac output, echocardiographic evaluation of ventricular function and volume status (i.e. inferior vena cava collapse), microcirculation). Clinical measures (e.g. capillary refill) and laboratory measures (e.g. lactate) were equivalent in association with mortality for resuscitation monitoring in a recent RCT (n = 424) [57].
Weaning
Vasopressor weaning is less standardized than resuscitation and there are no RCTs of weaning. Patients are judged appropriate for gradual vasopressor dose decrements when “stabile” (no universal definition), i.e. adequate volume status and perfusion. Deterioration necessitates titration back to higher doses, followed when “stability” recurs by repeated weaning. Medical informatics accurately predicts successful vasopressor weaning earlier and more accurately than clinicians [58].
Outcomes in RCTs of vasopressors
Fortunately, there are several high-quality RCTs of vasopressors in septic shock. The usual primary outcome for RCTs of vasopressors in septic shock is short-term (e.g. 28-day) mortality but short-term mortality has decreased [59], so RCTs of vasopressors now focus on improving long-term outcomes and short-term organ dysfunction that aligns with long-term outcomes [60]. The pivotal RCT of selepressin in septic shock was vasopressor- and ventilation-free days [45].
Clinicians should understand pharmacology, guidelines, effects, adverse effects, and dosing of vasopressors (Table 1).
Norepinephrine
In the Surviving Sepsis Campaign (SSC) guidelines, norepinephrine is the first line vasopressor (moderate evidence) [3]. Norepinephrine’s potent α1, α2, and less potent β1, β2 receptor binding increases smooth muscle intracellular calcium concentration and vasoconstriction and some positive inotropic activity (increasing ventricular contractility).
How early clinicians should start norepinephrine in shock is uncertain. Early low-dose norepinephrine may be more effective than later norepinephrine. In a recent proof-of-principal RCT [61] (n = 310) of early low-dose norepinephrine versus placebo, the primary outcome (control of shock: MAP > 65 mmHg plus either urine output > 0.5 ml/kg/h or 10% lactate decline) occurred significantly more often (76.1% vs. 48.4%) and mortality was nominally lower (15.5% vs. 21.9%, p = 0.15) in early norepinephrine group. Cardiogenic pulmonary edema and new-onset arrhythmias were halved with early norepinephrine. Early norepinephrine may be effective by decreasing organ injury, norepinephrine doses, and/or norepinephrine’s immune effects [36] (Fig. 1). Further RCTs of early norepinephrine are needed. Norepinephrine’s adverse events rates (10–15%) were significantly less than with dopamine [48] and similar to vasopressin [12, 15] and epinephrine [37, 47].
Epinephrine
Epinephrine is a second line agent in septic shock [3] (weak recommendation, low evidence) [3, 37, 62] in patients not responding to norepinephrine. Epinephrine has more β1 agonism than norepinephrine. Although RCTs show that epinephrine is comparable to norepinephrine [37], to norepinephrine plus dobutamine [47], and to norepinephrine and vasopressin [63], epinephrine is not first line because of increased risk of splanchnic vasoconstriction, tachyarrhythmias, and hyperlactatemia [3, 37, 47]. Epinephrine may be a first-line vasopressor in countries where norepinephrine is too costly [64], because epinephrine is less expensive and had equivalent efficacy in a meta-analysis [62].
Phenylephrine
Phenylephrine is a nearly pure α1-agonist commonly used short-term for transient profound hypotension. Phenylephrine can cause baroreceptor-mediated reflex bradycardia (because of α1-induced vasoconstriction) and splanchnic ischemia and so is not recommended for resuscitation of septic shock [3]. Phenylephrine may be less effective in practice than norepinephrine based on a natural experiment arising from a recent national US shortage of norepinephrine [65]. Phenylephrine was the most commonly used vasopressor during the norepinephrine shortage and phenylephrine use was associated with a higher mortality than norepinephrine use [65], but this was a non-randomized, non-blinded low evidence experiment.
Dopamine
Dopamine was previously a first-line vasopressor in septic shock, but dopamine’s greater adverse event rates (higher heart rate and tachyarrhythmia rates) than norepinephrine [48] necessitate its use only in highly selected bradycardic patients [3]. Dopamine binds α1- and β1-adrenergic and dopaminergic DA1 and DA2 receptors, the latter causing splanchnic and renal vasodilation at low doses in pre-clinical and small trials (“low-dose dopamine”). However, a pivotal high evidence RCT of critically ill patients found no benefits of low-dose dopamine versus placebo regarding renal replacement rates, renal function or mortality [48].
Vasopressin, terlipressin, and selepressin
Vasopressin is recommended [3] as a second vasopressor in septic shock. Vasopressin stimulates AVPR1a (vasoconstriction), AVPR1b (stimulation of ACTH release), and AVPR2 (anti-diuretic effects) receptors and increases NO synthesis [66], limiting vasoconstriction and preserving renal perfusion [67], but potentially contributing to cardiac depression. Plasma vasopressin levels are low early in septic shock. Vasopressin infusion decreased norepinephrine requirements, maintained blood pressure, and increased urine output in small trials [68,69,70].
One large RCT of vasopressin versus norepinephrine (VASST) found no difference in mortality in septic shock [71]. Individual patient level meta-analysis showed no difference in renal function (primary endpoint) or mortality of vasopressin versus norepinephrine [72]. A vasopressin/corticosteroid interaction—vasopressin’s AVPR1b-induced stimulation of ACTH release—could be beneficial. However, the vasopressin/corticosteroid interaction in septic shock [73] was not confirmed beneficial in a pivotal RCT(VANISH) [15]. Vasopressin improved renal function more than norepinephrine in VASST [74] and significantly decreased use of renal replacement therapy (RRT) in VANISH [15, 72].
For the clinician, vasopressin’s adverse effects are similar to norepinephrine in practice [75] as in RCTs [15, 74]. Norepinephrine should be weaned before vasopressin because weaning vasopressin first increased hemodynamic instability in VASST [12)] and in later studies [76]. Terlipressin has more AVPR1a activity than vasopressin, and similar effects and similar mortality in recent RCTs [43, 44].
In pre-clinical studies, pure AVPR1a agonism mitigated the increased permeability of septic shock better than vasopressin and that has led to development of selepressin. Selepressin decreased lung edema and fluid balance more than vasopressin in models of peritonitis [77] and pneumonia [78]. More relevant clinically, selepressin decreased net fluid balance and some early markers of organ injury in a Phase 2 RCT in septic shock [21]. The selepressin Phase 2B/3 pivotal placebo controlled RCT in septic shock found no difference between groups in the primary endpoint, ventilator-and vasopressor-free days and there was no difference between groups in any other endpoint or adverse events so selepressin is not available for clinical use [45].
Angiotensin II
Angiotensin II, the renin-angiotensin system vasopressor, is available clinically for treatment of vasodilatory hypotension and may be useful for early resuscitation of profoundly hypotensive patients. Angiotensin II binds to angiotensin-1 and -2 receptors (AGTR1, AGTR2) inducing vasoconstriction, aldosterone synthesis, and vasopressin release. AGTR1 is down-regulated in sepsis models decreasing angiotensin II insensitivity [16, 79]. Angiotensin II more rapidly increased MAP over 3 h in the ATHOS-3 placebo-controlled RCT in refractory vasodilatory shock [80]. Larger RCTs powered for organ dysfunction and mortality are now needed. Serious adverse effects of angiotensin II (Table 4) in ATHOS 3 included ischemia (digital, gut, myocardial) and arrhythmias [16].
Metaraminol
Metaraminol, predominantly an α1 agonist that stimulates norepinephrine release, is used for complications of anaesthesia but rarely used in shock and has similar hemodynamic effects as norepinephrine but there are no RCTs of metaraminol.
Methylene blue
Methylene blue, a cyclic GMP blocker, inhibits guanylate cyclase to inhibit smooth muscle relaxation by NO and may decrease pulmonary vascular leak. Methylene blue increased MAP and decreased norepinephrine requirements in refractory hypotension post-cardiopulmonary bypass and septic shock. There are no RCTs of methylene blue, limiting recommendations for its use in septic shock [81].
Corticosteroids
Low dose corticosteroids consistently decreased norepinephrine requirements in septic shock in RCTs and are recommended in patients not responding to norepinephrine [3]. Corticosteroids reverse sepsis-associated adrenal insufficiency and mitigate the pro-inflammatory response of septic shock.
However, corticosteroids remain controversial because of conflicting results of at least four large RCTs, two finding benefit and two finding no effect on mortality. Hydrocortisone plus fludrocortisone significantly decreased mortality (35.4% versus 41.0%, p = 0.04) in one recent RCT [17] and a previous RCT [18], but not in another recent RCT [20] (mortality: hydrocortisone 27.9% versus placebo 28.8%) or another older RCT [19]. Differences in corticosteroids used and entry criteria could partially explain this RCT equipoise.
Inotropic agents to complement vasopressors in septic shock
Sepsis-induced ventricular dysfunction is common clinically and may be exacerbated by vasopressors, so inotropic agent (dobutamine > milrinone) are commonly added to norepinephrine [47] and vasopressin [71, 82] to increase cardiac output, but with side effects (tachyarrhythmias; increased heart rate, and myocardial oxygen consumption). Milrinone is a non-adrenergic inotrope/vasodilator that is a comparable inotrope to dobutamine but has greater vasodilating action and so is less recommended than dobutamine [3] but could be effective in patients recently on β-blockers. Levosimendan, a positive non-adrenergic inotropic agent, was not effective in a RCT in septic shock [37, 47]. More patients on levosimendan had tachyarrhythmias and fewer patients on levosimendan were successfully weaned from mechanical ventilation [83]. Thus, levosimendan is not recommended in septic shock.
Biomarkers to guide vasopressor selection
Predictive biomarkers are used by clinicians to better define responders to drugs (e.g. chemotherapies for cancer) and have potential for personalized vasopressor selection. A β2 single nucleotide polymorphisms (SNP) marked increased mortality and could identify responders to norepinephrine [24]. Possible vasopressin, terlipressin, and selepressin predictive biomarkers are plasma angiopoietin-2, a mediator of increased permeability [42] (selepressin decreased plasma angiopoietin-2), leucyl/cystinyl aminopeptidase (the enzyme that catalyzes vasopressin) [26], and AVPR1a SNPs [26]. Genotypes of angiotensin-II receptor associated protein (AGTRAP) are associated with mortality of septic shock and may be biomarkers for angiotensin II [25].
The ironic role of β1-blockers in septic and vasodilatory shock
Clinicians should know that there are some patients with septic shock who may benefit ironically from β1 blockers. β1-agonists have varying chronotropic and inotropic potency; dopamine and epinephrine are greatest chronotropic agents (increase heart rate by 15% versus norepinephrine [47, 48, 84]); vasopressin reduces heart rate by 10% [12]. Levosimendan, a calcium-sensitizing agent, increases heart rate 10% more than norepinephrine [83].
Younger patients often have greater tachycardia during septic shock and greater tachycardia limits diastolic filling time and stoke volume. Esmolol infusion decreased heart rate (by 30%), fluid balance, lactate, and mortality, and improved renal function in one small (n = 154) proof-of-principle RCT [85]. Despite a positive meta-analysis of esmolol [86], esmolol requires a pivotal RCT to better define patient selection, safety, and efficacy.
Cardiogenic shock and vasodilatory shock post-cardiovascular surgery (CVS)
Norepinephrine is recommended first in cardiogenic shock post-cardiovascular surgery, a minority of whom develop vasodilatory shock characterized by hypotension and low systemic vascular resistance [41]. Vasodilatory shock post-cardiovascular surgery, is more commn in patients on beta-blockers or angiotensin-converting enzyme inhibitors prior to surgery. If hypotension persists after adequate volume resuscitation, then norepinephrine is added, usually increasing MAP with no renal function impairment [87]. Targeting a higher MAP (70–80 mmHg versus 40–50 mmHg) during cardiopulmonary bypass by infusing higher doses of norepinephrine did not decrease the incidence of cerebral infarction in a well-conducted RCT [88].
There is a relative vasopressin deficiency post-cardiovascular surgery and benefits of vasopressin infusion. However, prior trials of vasopressin versus norepinephrine post-cardiovascular surgery were under-powered [89,90,91,92,93,94]. In a recent single center concealed norepinephrine-controlled RCT (VANCS n = 300) in Brazil in vasodilatory shock post-cardiovascular surgery [41], vasopressin decreased the primary endpoint (mortality or severe complications), sparing norepinephrine, while shortening ICU stay, and decreasing rates of atrial fibrillation, acute kidney injury, and RRT. There was no difference in 28-day mortality.
Vasopressin was beneficial in post-cardiovascular surgery vasodilatory shock [95] but not in septic shock [15, 71] perhaps because the primary outcomes differed: “mortality and severe complications” [41] versus 28-day mortality [71]. Mortality rates were high (15.9 and 15.4% at 28-days norepinephrine vs. vasopressin) in VANCS [95] but were not reported in prior vasopressin RCTs in vasodilatory shock post-cardiovascular surgery [89, 91, 92, 94].
Cardiogenic shock and vasodilatory shock post-acute myocardial infarction (AMI)
Norepinephrine is also recommended first in cardiogenic shock post-AMI international guidelines [96, 97] because a recent RCT found that epinephrine led to more frequent refractory shock than norepinephrine in pure cardiogenic shock post-AMI [98]. Hypotension and low systemic vascular resistance characterize vasodilatory shock post-AMI. Dopamine is not recommended in cardiogenic shock because of its greater chronotropic effects than norepinephrine [48].
Hypovolemic and hemorrhagic shock
Vasopressors are recommended in life-threatening hemorrhagic shock if MAP and perfusion cannot be maintained by fluid resuscitation [99]. European trauma guidelines recommend permissive hypotension (MAP 50–60 mmHg) and restricted volume infusion until major hemorrhage is controlled [100] and vasopressors for life-threatening hypotension if fluids do not achieve target MAP (grade 1C) [100]. Vasopressors may limit fluid overload, cerebral edema, and ARDS in hemorrhagic shock. In a small (n = 78) blinded RCT in trauma, vasopressin was associated with lower fluid balance and nominally lower mortality (13% versus 25%, p = 0.19).
Questions and future directions for research
Clinically relevant questions regarding today’s vasopressor use in shock include is whether use of several vasopressors that bind complementary receptors safer and more effective than a single vasopressor, how to predict responders by use of biomarkers, when and how to de-resuscitate, how to select patients for inotropic therapy, and who to select for β1-blockade. Future research should also focus on discovery and validation of biomarkers that predict response to vasopressors. The de-resuscitation phase to limit cumulative vasopressor toxicity deserves emphasis [101].
Conclusions and recommendations
Vasopressors bind to specific receptors inducing vasoconstriction but commonly have adverse effects. In practice, we recommend norepinephrine as first choice vasopressor in septic and vasodilatory shock after adequate volume resuscitation. In norepinephrine-refractory patients, vasopressin or epinephrine may be added. Angiotensin II may be useful for early resuscitation of profoundly hypotensive patients. Vasopressors may decrease ventricular contractility, so an inotropic agent (dobutamine > milrinone) may be added. Esmolol may be useful in selected young patients with marked tachycardia. Furthermore, personalized medicine using omics-derived predictive biomarkers, artificial intelligence derived from “big data”, closed loop systems that monitor tissue oxygenation and novel vasopressors could facilitate more effective vasopressor use increasing survival (Fig. 4).
References
Annane D, Ouanes-Besbes L, de Backer D, Du B, Gordon AC, Hernandez G et al (2018) A global perspective on vasoactive agents in shock. Intensive Care Med 44(6):833–846
Perner A, Gordon AC, Angus DC, Lamontagne F, Machado F, Russell JA et al (2017) The intensive care medicine research agenda on septic shock. Intensive Care Med 43(9):1294–1305
Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R et al (2017) Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med 45(3):486–552
de Grooth HJ, Postema J, Loer SA, Parienti JJ, Oudemans-van Straaten HM, Girbes AR (2018) Unexplained mortality differences between septic shock trials: a systematic analysis of population characteristics and control-group mortality rates. Intensive Care Med 44(3):311–322
Russell JA (2014) Is there a good MAP for septic shock? N Engl J Med 370(17):1649–1651
Vail EA, Gershengorn HB, Hua M, Walkey AJ, Wunsch H (2016) Epidemiology of vasopressin use for adults with septic shock. Ann Am Thorac Soc 13(10):1760–1767
Russell JA (2019) Shock syndromes related to sepsis. In: Chapter 100 in 26th edition Goldman-Cecil Textbook of Medicine (in press)
Asfar P, Teboul JL, Radermacher P (2014) High versus low blood-pressure target in septic shock. N Engl J Med 371(3):283–284
Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B et al (2001) Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 345(19):1368–1377
Angus DC (2017) Early, goal-directed therapy for septic shock—a patient-level meta-analysis. N Engl J Med 377(10):995
Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M et al (2016) The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 315(8):801–810
Russell JA, Walley KR, Singer J, Gordon AC, Hebert PC, Cooper DJ et al (2008) Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 358(9):877–887
Russell JA, Lee T, Singer J, Boyd JH, Walley KR et al (2017) The septic shock 3.0 definition and trials: a vasopressin and septic shock trial experience. Crit Care Med 45(6):940–948
Seymour CW, Liu VX, Iwashyna TJ, Brunkhorst FM, Rea TD, Scherag A et al (2016) Assessment of clinical criteria for sepsis: for the third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 315(8):762–774
Gordon AC, Mason AJ, Thirunavukkarasu N, Perkins GD, Cecconi M, Cepkova M et al (2016) Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock: the VANISH randomized clinical trial. JAMA 316(5):509–518
Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H et al (2017) Angiotensin II for the treatment of vasodilatory shock. N Engl J Med 377(5):419–430
Annane D, Renault A, Brun-Buisson C, Megarbane B, Quenot JP, Siami S et al (2018) Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med 378(9):809–818
Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM et al (2002) Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 288(7):862–871
Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K et al (2008) Hydrocortisone therapy for patients with septic shock. N Engl J Med 358(2):111–124
Venkatesh B, Finfer S, Cohen J, Rajbhandari D, Arabi Y, Bellomo R et al (2018) Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med 378(9):797–808
Russell JA, Vincent JL, Kjolbye AL, Olsson H, Blemings A, Spapen H et al (2017) Selepressin, a novel selective vasopressin V1A agonist, is an effective substitute for norepinephrine in a phase IIa randomized, placebo-controlled trial in septic shock patients. Crit Care 21(1):213
Angus DC, van der Poll T (2013) Severe sepsis and septic shock. N Engl J Med 369(21):2063
Bucher M, Kees F, Taeger K, Kurtz A (2003) Cytokines down-regulate alpha1-adrenergic receptor expression during endotoxemia. Crit Care Med 31(2):566–571
Nakada TA, Russell JA, Boyd JH, Aguirre-Hernandez R, Thain KR, Thair SA et al (2010) Beta2-adrenergic receptor gene polymorphism is associated with mortality in septic shock. Am J Respir Crit Care Med 181(2):143–149
Nakada TA, Russell JA, Boyd JH, McLaughlin L, Nakada E, Thair SA et al (2011) Association of angiotensin II type 1 receptor-associated protein gene polymorphism with increased mortality in septic shock. Crit Care Med 39(7):1641–1648
Nakada TA, Russell JA, Wellman H, Boyd JH, Nakada E, Thain KR et al (2011) Leucyl/cystinyl aminopeptidase gene variants in septic shock. Chest 139(5):1042–1049
Lopez A, Lorente JA, Steingrub J, Bakker J, McLuckie A, Willatts S et al (2004) Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock. Crit Care Med 32(1):21–30
Moncada S, Higgs A (1993) The l-arginine-nitric oxide pathway. N Engl J Med 329(27):2002–2012
Bernard GR, Wheeler AP, Russell JA, Schein R, Summer WR, Steinberg KP et al (1997) The effects of ibuprofen on the physiology and survival of patients with sepsis. The ibuprofen in sepsis study group. N Engl J Med 336(13):912–918
Wagner K, Wachter U, Vogt JA, Scheuerle A, McCook O, Weber S et al (2013) Adrenomedullin binding improves catecholamine responsiveness and kidney function in resuscitated murine septic shock. Intensive Care Med Exp 1(1):21
Kanji HD, McCallum J, Sirounis D, MacRedmond R, Moss R, Boyd JH (2014) Limited echocardiography-guided therapy in subacute shock is associated with change in management and improved outcomes. J Crit Care 29(5):700–705
Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S et al (2006) Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 34(6):1589–1596
Seymour CW, Gesten F, Prescott HC, Friedrich ME, Iwashyna TJ, Phillips GS et al (2017) Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med 376(23):2235–2244
Komorowski M, Celi LA, Badawi O, Gordon AC, Faisal AA (2018) The artificial intelligence clinician learns optimal treatment strategies for sepsis in intensive care. Nat Med 24(11):1716–1720
Udy AA, Finnis M, Jones D, Delaney A, Macdonald S, Bellomo R et al (2018) Incidence, patient characteristics, mode of drug delivery, and outcomes of septic shock patients treated with vasopressors in the arise trial. Shock 52(4):400–407
Stolk RF, van der Poll T, Angus DC, van der Hoeven JG, Pickkers P, Kox M (2016) Potentially inadvertent immunomodulation: norepinephrine use in sepsis. Am J Respir Crit Care Med 194(5):550–558
Myburgh JA, Higgins A, Jovanovska A, Lipman J, Ramakrishnan N, Santamaria J et al (2008) A comparison of epinephrine and norepinephrine in critically ill patients. Intensive Care Med 34(12):2226–2234
Van den Berghe G, de Zegher F (1996) Anterior pituitary function during critical illness and dopamine treatment. Crit Care Med 24(9):1580–1590
Matt SM, Gaskill PJ (2019) Where is dopamine and how do immune cells see it?: dopamine-mediated immune cell function in health and disease. J Neuroimmune Pharmacol. https://doi.org/10.1007/s11481-019-09851-4
Russell JA, Walley KR (2010) Vasopressin and its immune effects in septic shock. J Innate Immun 2(5):446–460
Hajjar LA, Vincent JL, Barbosa Gomes Galas FR, Rhodes A, Landoni G, Osawa EA et al (2017) Vasopressin versus norepinephrine in patients with vasoplegic shock after cardiac surgery: the VANCS randomized controlled trial. Anesthesiology 126(1):85–93
Fisher J, Douglas JJ, Linder A, Boyd JH, Walley KR, Russell JA (2016) Elevated plasma angiopoietin-2 levels are associated with fluid overload, organ dysfunction, and mortality in human septic shock. Crit Care Med 44(11):2018–2027
Morelli A, Ertmer C, Rehberg S, Lange M, Orecchioni A, Cecchini V et al (2009) Continuous terlipressin versus vasopressin infusion in septic shock (TERLIVAP): a randomized, controlled pilot study. Crit Care 13(4):R130
Liu ZM, Chen J, Kou Q, Lin Q, Huang X, Tang Z et al (2018) Terlipressin versus norepinephrine as infusion in patients with septic shock: a multicentre, randomised, double-blinded trial. Intensive Care Med 44(11):1816–1825
Laterre PF, Berry SM, Blemings A, Carlsen JE, Francois B, Graves T et al (2019) Effect of selepressin vs placebo on ventilator-and vasopressor-free days in patients with septic shock: The SEPSIS-ACT randomized clinical trial. JAMA. https://doi.org/10.1001/jama.2019.14607
Kirov MY, Evgenov OV, Evgenov NV, Egorina EM, Sovershaev MA, Sveinbjornsson B et al (2001) Infusion of methylene blue in human septic shock: a pilot, randomized, controlled study. Crit Care Med 29(10):1860–1867
Annane D, Vignon P, Renault A, Bollaert PE, Charpentier C, Martin C et al (2007) Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial. Lancet 370(9588):676–684
De Backer D, Biston P, Devriendt J, Madl C, Chochrad D, Aldecoa C et al (2010) Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med 362(9):779–789
Russell JA, Wellman H, Walley KR (2018) Vasopressin versus norepinephrine in septic shock: a propensity score matched efficiency retrospective cohort study in the VASST coordinating center hospital. J Intensive Care 6:73
Hammond DA, Ficek OA, Painter JT, McCain K, Cullen J, Brotherton AL et al (2018) Prospective open-label trial of early concomitant vasopressin and norepinephrine therapy versus initial norepinephrine monotherapy in septic shock. Pharmacotherapy 38(5):531–538
Cheng L, Yan J, Han S, Chen Q, Chen M, Jiang H et al (2019) Comparative efficacy of vasoactive medications in patients with septic shock: a network meta-analysis of randomized controlled trials. Crit Care 23(1):168
Asfar P, Meziani F, Hamel JF, Grelon F, Megarbane B, Anguel N et al (2014) High versus low blood-pressure target in patients with septic shock. N Engl J Med 370(17):1583–1593
Walkey AJ, Wiener RS, Ghobrial JM, Curtis LH, Benjamin EJ (2011) Incident stroke and mortality associated with new-onset atrial fibrillation in patients hospitalized with severe sepsis. JAMA 306(20):2248–2254
Dargent A, Nguyen M, Fournel I, Bourredjem A, Charles PE, Quenot JP et al (2018) Vasopressor cumulative dose requirement and risk of early death during septic shock: an analysis from the EPISS cohort. Shock 49(6):625–630
Russell JA, Fjell C, Hsu JL, Lee T, Boyd J, Thair S et al (2013) Vasopressin compared with norepinephrine augments the decline of plasma cytokine levels in septic shock. Am J Respir Crit Care Med 188(3):356–364
Dunser MW, Bouvet O, Knotzer H, Arulkumaran N, Hajjar LA, Ulmer H et al (2018) Vasopressin in cardiac surgery: a meta-analysis of randomized controlled trials. J Cardiothorac Vasc Anesth 32(5):2225–2232
Hernandez G, Ospina-Tascon GA, Damiani LP, Estenssoro E, Dubin A, Hurtado J et al (2019) Effect of a resuscitation strategy targeting peripheral perfusion status vs serum lactate levels on 28-day mortality among patients with septic shock: the ANDROMEDA-SHOCK randomized clinical trial. JAMA 321(7):654–664
Wu M, Ghassemi M, Feng M, Celi LA, Szolovits P, Doshi-Velez F (2017) Understanding vasopressor intervention and weaning: risk prediction in a public heterogeneous clinical time series database. J Am Med Inform Assoc 24(3):488–495
Kaukonen KM, Bailey M, Suzuki S, Pilcher D, Bellomo R (2014) Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000–2012. JAMA 311(13):1308–1316
Linder A, Lee T, Fisher J, Singer J, Boyd J, Walley KR et al (2016) Short-term organ dysfunction is associated with long-term (10-year) mortality of septic shock. Crit Care Med 44(8):e728–e736
Permpikul C, Tongyoo S, Viarasilpa T, Trainarongsakul T, Chakorn T, Udompanturak S (2019) Early use of norepinephrine in septic shock resuscitation (CENSER). A randomized trial. Am J Respir Crit Care Med 199(9):1097–1105
Avni T, Lador A, Lev S, Leibovici L, Paul M, Grossman A (2015) Vasopressors for the treatment of septic shock: systematic review and meta-analysis. PLoS One 10(8):e0129305
Menich BE, Miano TA, Patel GP, Hammond DA (2019) Norepinephrine and vasopressin compared with norepinephrine and epinephrine in adults with septic shock. Ann Pharmacother. https://doi.org/10.1177/1060028019843664
Dunser MW, Festic E, Dondorp A, Kissoon N, Ganbat T, Kwizera A et al (2012) Recommendations for sepsis management in resource-limited settings. Intensive Care Med 38(4):557–574
Vail E, Gershengorn HB, Hua M, Walkey AJ, Rubenfeld G, Wunsch H (2017) Association between US norepinephrine shortage and mortality among patients with septic shock. JAMA 317(14):1433–1442
Yamamoto K, Ikeda U, Okada K, Saito T, Kawahara Y, Okuda M et al (1997) Arginine vasopressin increases nitric oxide synthesis in cytokine-stimulated rat cardiac myocytes. Hypertension 30(5):1112–1120
Rudichenko VM, Beierwaltes WH (1995) Arginine vasopressin-induced renal vasodilation mediated by nitric oxide. J Vasc Res 32(2):100–105
Holmes CL, Walley KR, Chittock DR, Lehman T, Russell JA (2001) The effects of vasopressin on hemodynamics and renal function in severe septic shock: a case series. Intensive Care Med 27(8):1416–1421
Malay MB, Ashton RC Jr, Landry DW, Townsend RN (1999) Low-dose vasopressin in the treatment of vasodilatory septic shock. J Trauma 47(4):699–703 (discussion-5)
Patel BM, Chittock DR, Russell JA, Walley KR (2002) Beneficial effects of short-term vasopressin infusion during severe septic shock. Anesthesiology 96(3):576–582
Russell JA, Walley KR, Singer J, Gordon AC, Hebert PC, Cooper DJ et al (2008) Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 358(9):877–887
Nagendran M, Russell JA, Walley KR, Brett SJ, Perkins GD, Hajjar L et al (2019) Vasopressin in septic shock: an individual patient data meta-analysis of randomised controlled trials. Intensive Care Med 45(6):844–855
Russell JA, Walley KR, Gordon AC, Cooper DJ, Hebert PC, Singer J et al (2009) Interaction of vasopressin infusion, corticosteroid treatment, and mortality of septic shock. Crit Care Med 37(3):811–818
Gordon AC, Russell JA, Walley KR, Singer J, Ayers D, Storms MM et al (2010) The effects of vasopressin on acute kidney injury in septic shock. Intensive Care Med 36(1):83–91
Anantasit N, Boyd JH, Walley KR, Russell JA (2014) Serious adverse events associated with vasopressin and norepinephrine infusion in septic shock. Crit Care Med 42(8):1812–1820
Jeon K, Song JU, Chung CR, Yang JH, Suh GY (2018) Incidence of hypotension according to the discontinuation order of vasopressors in the management of septic shock: a prospective randomized trial (DOVSS). Crit Care 22(1):131
He X, Su F, Taccone FS, Laporte R, Kjolbye AL, Zhang J et al (2016) A selective V(1A) receptor agonist, selepressin, is superior to arginine vasopressin and to norepinephrine in ovine septic shock. Crit Care Med 44(1):23–31
Maybauer MO, Maybauer DM, Enkhbaatar P, Laporte R, Wisniewska H, Traber LD et al (2014) The selective vasopressin type 1a receptor agonist selepressin (FE 202158) blocks vascular leak in ovine severe sepsis*. Crit Care Med 42(7):e525–e533
Chawla LS, Busse L, Brasha-Mitchell E, Davison D, Honiq J, Alotaibi Z et al (2014) Intravenous angiotensin II for the treatment of high-output shock (ATHOS trial): a pilot study. Crit Care 18(5):534
Chawla LS, Russell JA, Bagshaw SM, Shaw AD, Goldstein SL, Fink MP et al (2017) Angiotensin II for the treatment of high-output shock 3 (ATHOS-3): protocol for a phase III, double-blind, randomised controlled trial. Crit Care Resusc 19(1):43–49
Paciullo CA, McMahon Horner D, Hatton KW, Flynn JD (2010) Methylene blue for the treatment of septic shock. Pharmacotherapy 30(7):702–715
Gordon AC, Wang N, Walley KR, Ashby D, Russell JA (2012) The cardiopulmonary effects of vasopressin compared with norepinephrine in septic shock. Chest 142(3):593–605
Gordon AC, Perkins GD, Singer M, McAuley DF, Orme RM, Santhakumaran S et al (2016) Levosimendan for the prevention of acute organ dysfunction in sepsis. N Engl J Med 375(17):1638–1648
De Backer D, Creteur J, Silva E, Vincent JL (2003) Effects of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in septic shock: which is best? Crit Care Med 31(6):1659–1667
Morelli A, Ertmer C, Westphal M, Rehberg S, Kampmeier T, Ligges S et al (2013) Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial. JAMA 310(16):1683–1691
Liu P, Wu Q, Tang Y, Zhou Z, Feng M (2018) The influence of esmolol on septic shock and sepsis: a meta-analysis of randomized controlled studies. Am J Emerg Med 36(3):470–474
Morimatsu H, Uchino S, Chung J, Bellomo R, Raman J, Buxton B (2003) Norepinephrine for hypotensive vasodilatation after cardiac surgery: impact on renal function. Intensive Care Med 29(7):1106–1112
Vedel AG, Holmgaard F, Rasmussen LS, Langkilde A, Paulson OB, Lange T et al (2018) High-target versus low-target blood pressure management during cardiopulmonary bypass to prevent cerebral injury in cardiac surgery patients: a randomized controlled trial. Circulation 137(17):1770–1780
Argenziano M, Chen JM, Choudhri AF, Cullinane S, Garfein E, Weinberg AD et al (1998) Management of vasodilatory shock after cardiac surgery: identification of predisposing factors and use of a novel pressor agent. J Thorac Cardiovasc Surg 116(6):973–980
Argenziano M, Chen JM, Cullinane S, Choudhri AF, Rose EA, Smith CR et al (1999) Arginine vasopressin in the management of vasodilatory hypotension after cardiac transplantation. J Heart Lung Transplant 18(8):814–817
Morales DL, Gregg D, Helman DN, Williams MR, Naka Y, Landry DW et al (2000) Arginine vasopressin in the treatment of 50 patients with postcardiotomy vasodilatory shock. Ann Thorac Surg 69(1):102–106
Morales DL, Garrido MJ, Madigan JD, Helman DN, Faber J, Williams MR et al (2003) A double-blind randomized trial: prophylactic vasopressin reduces hypotension after cardiopulmonary bypass. Ann Thorac Surg 75(3):926–930
Rosenzweig EB, Starc TJ, Chen JM, Cullinane S, Timchak DM, Gersony WM et al (1999) Intravenous arginine-vasopressin in children with vasodilatory shock after cardiac surgery. Circulation 100(19 Suppl):II182–II186
Yimin H, Xiaoyu L, Yuping H, Weiyan L, Ning L (2013) The effect of vasopressin on the hemodynamics in CABG patients. J Cardiothorac Surg 8:49
Hajjar AM, Vincent JL, Galas FRBG, Rhodes A, Landonni G, Osawa EA et al (2016) Vasopressin versus norepinephrine in patients with vasoplegic shock after cardiac surgery: the VANCSS randomized controlled trial. Anesthesiology 126(1):85–93
Moller MH, Granholm A, Junttila E, Haney M, Oscarsson-Tibblin A, Haavind A et al (2018) Scandinavian SSAI clinical practice guideline on choice of inotropic agent for patients with acute circulatory failure. Acta Anaesthesiol Scand 62(4):420–450
van Diepen S, Thiele H (2019) An overview of international cardiogenic shock guidelines and application in clinical practice. Curr Opin Crit Care 25:365–370
Levy B, Clere-Jehl R, Legras A, Morichau-Beauchant T, Leone M, Frederique G et al (2018) Epinephrine versus norepinephrine for cardiogenic shock after acute myocardial infarction. J Am Coll Cardiol 72(2):173–182
Russell JA, Rush B, Boyd J (2018) Pathophysiology of septic shock. Crit Care Clin 34(1):43–61
Spahn, Bouillon B, Cerny V, Duranteau J, Filipescu D, Hunt BJ et al (2019) The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition. Crit Care 23(1):98
Silversides JA, Fitzgerald E, Manickavasagam US, Lapinsky SE, Nisenbaum R, Hemmings N et al (2018) Deresuscitation of patients with iatrogenic fluid overload is associated with reduced mortality in critical illness. Crit Care Med 46(10):1600–1607
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
Dr. Russell reports patents owned by the University of British Columbia (UBC) that are related to the use of PCSK9 inhibitor(s) in sepsis and related to the use of vasopressin in septic shock. Dr. Russell is an inventor on these patents. Dr. Russell was a founder, Director and shareholder in Cyon Therapeutics Inc. Dr. Russell is a shareholder in Molecular You Corp.
Dr. Russell reports receiving consulting fees in the past 3 years from: (1) Asahi Kesai Pharmaceuticals of America (AKPA) (developing recombinant thrombomodulin in sepsis). (2) SIB Therapeutics LLC (developing a sepsis drug). (3) Ferring Pharmaceuticals (manufactures vasopressin and developing selepressin). No longer actively consulting for the following: (4) La Jolla Pharmaceuticals (developing angiotensin II; Dr. Russell chaired the DSMB of a trial of angiotensin II from 2015 to 2017)—no longer actively consulting. (5) Grifols (sells albumin)—no longer actively consulting. PAR Pharma (sells prepared bags of vasopressin)—no longer actively consulting.
Dr. Russell reports having received an investigator-initiated grant from Grifols (entitled “Is HBP a mechanism of albumin’s efficacy in human septic shock?”) that was provided to and administered by UBC.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Russell, J.A. Vasopressor therapy in critically ill patients with shock. Intensive Care Med 45, 1503–1517 (2019). https://doi.org/10.1007/s00134-019-05801-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00134-019-05801-z