Reviewed and revised 12 November 2016
- Catecholamine excess, or ‘sympathetic overload’, may be harmful in critically ill patients, including those with septic shock
- Catacholamine excess is associated with specific conditions such as Takotsubo cardiomyopathy
- Potential interventions include the use of beta-blockers, either alone or in combination with other agents, as well as alpha-2 agonists (such clonidine and dexmedetomidine) or non-catecholamine based inotropes such as levosimendan
HARMFUL EFFECTS OF CATECHOLAMINES
Catecholamines are frequently used in critical illness but have potential harmful effects
- impair immune function
- β2 up-regulation of anti-inflammatory cytokine synthesis and down-regulation of pro-inflammatory cytokine production
- modulates monocyte production and immune system apoptosis
- β2 activation of platelets and clotting factors
- impair metabolic efficiency
- increase in resting energy expenditure, proteolysis and lipolysis
- peripheral ischemia due to vasospasm at high doses
- cardiac effects
- increased contractility, heart rate and myocardial energy demand acutely
- myocardial injury and cardiomyopathy from excessive sympathetic stimulation
- dysrhythmias (especially dopamine)
- stimulate bacterial growth
- adrenaline and other B2 agonists can cause lactic acidosis (not necessarily harmful, but makes lactate clearance unreliable as a treatment target)
- Increased cardiac contractility and heart rate may initially meet the increased systemic metabolic demand, however, up to 60% of patients subsequently develop reduced ejection fraction with apical ballooning and myocardial stunning (this may be catecholamine-mediated)
- higher mortality is associated with incrementally increasing MAP above 65 mmHg using catecholamine infusions
- there is no high level evidence for the MAP of 65 mmHg target and this target is regularly exceeded in ‘real world’ ICUs
- tachycardia is associated with worse outcomes
In acute brain injury
- autonomic dysregulation is common
- sympathetic activation may mediate multi-organ dysfunction
ROLE OF BETA-BLOCKERS
- direct effects on heart rate control, better diastolic filling and reduction in myocardial oxygen demand
- reduce the inflammatory response and the degree of lung injury without creating further hypotension
- has not been found to adversely affect oxygen utilization, ATP availability, nor the macrocirculation in sepsis
- increased reactivity to noradrenaline/ catacholamines:
- prevent down-regulation of adrenergic receptors, thus preserving cardiac function, and improving outcomes
- blockade of a peripheral β2-mediated vasodilatory effect of noradrenaline
- decreased clearance of infused noradrenaline
- a centrally mediated effect on reflex activity
- inhibition of vascular endothelial nitric oxide synthase activity
- does not interfere with alpha-agonism, which counteracts vasodilatory shock primarily by causing venoconstriction and improving preload
- a series of studies showed beneficial effects of beta -adrenergic antagonists in patients after myocardial infarction
- persistent concerns that beta-blockade may contribute to myocardial depression and shock
- concerns that beta-blockade combined with catecholamine infusion may lead to ‘unopposed’ alpha agonism, increased systemic vascular resistance and hypertension
- usual side effects of beta blockers
Overall the evidence for ‘decatecholaminisation’ and beta-blockade in the critically ill very limited, with some support from laboratory and animal studies as well as observational data and small RCTs.
- Retrospective data suggests that beta-blockade is associated with improved mortality in severe TBI patients
- Herndon et al, 2001: a small RCT of children with burns found that propanolol reduced hypermetabolism and reverse muscle-protein catabolism.
- Macchia et al, 2012: a retrospective observational study of 9,465 patients found that previous prescription of ß-blockers was associated with reduced mortality among patients hospitalized in ICU for sepsis
Small clinical studies suggest that esmolol does not significantly impair cardiac or circulatory function in septic shock
- Balik et al, 2013: After correction of preload, and esmolol bolus (0.2 – 0.5 mg/kg), followed by continuous 24 hr infusion, was administered in ten septic patients. Heart rate decreased from mean 142 ± 11/min to 112 ± 9/min (p < 0.001), with parallel insignificant reduction of cardiac index (4.94 ± 0.76 to 4.35 ± 0.72 L/min/m2). Stroke volume insignificantly increased from 67.1 ± 16.3 ml to 72.9 ± 15.3 ml. No parallel change of pulmonary artery wedge pressure was observed (15.9 ± 3.2 to 15.0 ± 2.4 mmHg), as well as no significant changes of noradrenaline infusion (0.13 ± 0.17 to 0.17 ± 0.19 mg/kg/min), DO2, VO2, OER or arterial lactate.
- Morelli et al, 2013 (CCM): a small pilot study (n=25) found that heart rate control by a titrated esmolol infusion in septic shock patients was associated with maintenance of stroke volume, preserved microvascular blood flow, and a reduction in norepinephrine requirements.
Small unblinded RCTs with mortality as a secondary outcome, suggest that esmolol, or esmolol combined with milrinone, may improve mortality in septic shock.
- Morelli et al, 2013 (JAMA): a subsequent open-label phase II RCT (n=154) found that that heart rate control by a titrated esmolol infusion in septic shock patients was achievable (80-95/min target) and associated with a 28d mortality benefit: 49.4% mortality in the esmolol group vs 80.5% in the control group (adjusted hazard ratio, 0.39; 95%CI 0.26 to 0.59; P < .001). This study was small, unblinded and had high mortality in the control arm.
- Wang et al, 2015: 3-armed open-label phase II RCT (n=30 septic shock patients per group) compared control, milrinone infusion, and combined milrinone and esmolol infusions. Cardiac index was higher, at at 72h less noradrenaline was needed, in the milrinone groups. The milrinone groups needed less vasopressors, and had less renal and liver dysfunction. Mortality was less in the combination group. PiCCO, but not echocardiography, was used to monitor cardiac function. This study was small, unblinded, had high mortality in the control arm and the heart rate target (<90/min) for esmolol therapy was arbitrary in the absence of echocardiographic optimsation or other evidence.
Levosimendan, a non-catecholamine inotrope, probably isn’t beneficial in undifferentiated septic shock patients and may cause harm.
- Zangrillo et al, 2015: A meta-analysis evaluating the use of levosimendan in septic shock reported that it was associated with reduced mortality when compared with standard inotropic therapy. However, this did not include the LeoPARD trial.
- Gordon et al, 2016 (LeoPARD trial): An RCT of n=516 adult septic shock patients receiving standard therapy, who also received a 24 hour levosimendan infusion or placebo, found that the addition of levosimendan was not associated with less severe organ dysfunction or lower mortality, but was associated with a lower likelihood of successful weaning from mechanical ventilation and a higher risk of supraventricular tachyarrhythmia. The trial participants were undifferentiated septic shock, rather than septic cardiomyopathy patients.
Routine peri-operative beta-blockade for non-cardiac surgery patients is not recommended, but should be considered for patients who are intermediate or high risk for myocardial ischemia
- Devereaux et al, 2008 (POISE trial): RCT of n=8351 patients at risk of atherosclerotic disease undergoing non-cardiac surgery randomised to 30 days of metoprolol starting 2-4 ours prior to surgery, or placebo. Fewer patients in the metoprolol group than in the placebo group had a myocardial infarction (176 [4.2%] vs 239 [5.7%] patients; 0.73, 0.60-0.89; p=0.0017). However the metoprolol group had more deaths (129 [3.1%] vs 97 [2.3%] patients; 1.33, 1.03-1.74; p=0.0317) and more patients that had a stroke (41 [1.0%] vs 19 [0.5%] patients; 2.17, 1.26-3.74; p=0.0053). A criticism of this trial is that 100mg metoprolol was used in the intervention arm, and this was not adjusted according to clinical parameters.
- Peri-operative beta-blockade was previously supported by the DECREASE trials, which were discredited in 2011 for lack of appropriate consent, inappropriate collection of data, and data fabrication.
- The safety, efficacy and appropriate timing of beta-blockade in the critically ill, including septic patients, needs to be studied further and should not be part of routine clinical practice
- Beta-blockade is indicated for specific diagnoses such as Takotsubo cardiomyopathy or following myocardial infarction
References and Links
- Ackland GL, Yao ST, Rudiger A. Cardioprotection, attenuated systemic inflammation, and survival benefit of beta1-adrenoceptor blockade in severe sepsis in rats. Critical care medicine. 38(2):388-94. 2010. [pubmed]
- Balik M, Rulisek J, Leden P, et al. Concomitant use of beta-1 adrenoreceptor blocker and norepinephrine in patients with septic shock. Wiener klinische Wochenschrift. 124(15-16):552-6. 2012. [pubmed]
- Chacko CJ, Gopal S. Systematic review of use of β-blockers in sepsis. Journal of anaesthesiology, clinical pharmacology. 31(4):460-5. 2015. [pubmed]
- Coppola S, Froio S, Chiumello D. β-blockers in critically ill patients: from physiology to clinical evidence. Critical care (London, England). 19:119. 2015. [pubmed]
- De Backer D, Annane D. Beta-blockers in septic shock to optimize hemodynamics? We are not sure. Intensive care medicine. 42(10):1613-4. 2016. [pubmed]
- Devereaux PJ, Yang H, et al. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet (London, England). 371(9627):1839-47. 2008. [pubmed]
- Gore DC, Wolfe RR. Hemodynamic and metabolic effects of selective beta1 adrenergic blockade during sepsis. Surgery. 139(5):686-94. 2006. [pubmed]
- Herndon DN, Hart DW, Wolf SE, Chinkes DL, Wolfe RR. Reversal of catabolism by beta-blockade after severe burns. N Engl J Med. 2001 Oct 25;345(17):1223-9 PMID: 11680441.
- Lyte M, Freestone PP, Neal CP. Stimulation of Staphylococcus epidermidis growth and biofilm formation by catecholamine inotropes. Lancet (London, England). 361(9352):130-5. 2003. [pubmed]
- Macchia A, Romero M, Comignani PD. Previous prescription of β-blockers is associated with reduced mortality among patients hospitalized in intensive care units for sepsis. Critical care medicine. 40(10):2768-72. 2012. [pubmed]
- Magder SA. The ups and downs of heart rate. Critical care medicine. 40(1):239-45. 2012. [pubmed]
- McLean AS, Taccone FS, Vieillard-Baron A. Beta-blockers in septic shock to optimize hemodynamics? No. Intensive care medicine. 42(10):1610-2. 2016. [pubmed]
- Morelli A, Donati A, Ertmer C, Rehberg S, Kampmeier T, Orecchioni A, D’Egidio A, Cecchini V, Landoni G, Pietropaoli P, Westphal M, Venditti M, Mebazaa A, Singer M. Microvascular Effects of Heart Rate Control With Esmolol in Patients With Septic Shock: A Pilot Study. Crit Care Med. 2013 Jul 18.PMID: 23873274.
- Morelli A, Ertmer C, Westphal M, Rehberg S, Kampmeier T, Ligges S, Orecchioni A, D’Egidio A, D’Ippoliti F, Raffone C, Venditti M, Guarracino F, Girardis M, Tritapepe L, Pietropaoli P, Mebazaa A, Singer M. Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial. JAMA. 2013 Oct 23;310(16):1683-91. PMID: 24108526.
- Norbury WB, Jeschke MG, Herndon DN. Metabolism modulators in sepsis: propranolol. Crit Care Med. 2007 Sep;35(9 Suppl):S616-20. PMID: 17713418.
- Novotny NM, Lahm T, Markel TA, Crisostomo PR, Wang M, Wang Y, Ray R, Tan J, Al-Azzawi D, Meldrum DR. beta-Blockers in sepsis: reexamining the evidence. Shock. 2009 Feb;31(2):113-9.PMID: 18636043.
- Pinsky MR. Is there a role for β-blockade in septic shock? JAMA. 2013 Oct 23;310(16):1677-8. PMID: 24108438.
- Reuter DA, Russell JA, Mekontso Dessap A. Beta-blockers in septic shock to optimize hemodynamics? Yes. Intensive care medicine. 42(10):1607-9. 2016. [pubmed]
- Rudiger A, Singer M. Decatecholaminisation during sepsis. Critical care (London, England). 20(1):309. 2016. [pubmed]
- Sanfilippo F, Santonocito C, Morelli A, et al. Beta-blocker use in severe sepsis and septic shock: a systematic review. Current medical research and opinion. 31(10):1817-25. 2015. [pubmed]
- Singer M, Matthay MA. Clinical review: Thinking outside the box–an iconoclastic view of current practice. Crit Care. 2011 Jul 26;15(4):225. PMC3387582.
- Zangrillo A, Putzu A, Monaco F. Levosimendan reduces mortality in patients with severe sepsis and septic shock: A meta-analysis of randomized trials. Journal of Critical Care. 2015. [pubmed]
- Wang Z, Wu Q, Nie X, Guo J, Yang C. Combination therapy with milrinone and esmolol for heart protection in patients with severe sepsis: a prospective, randomized trial. Clinical drug investigation. 35(11):707-16. 2015. [pubmed]
FOAM and web resources
- EMLON — What to Make of Esmolol in Septic Shock? (2013)
- FET — Catecholamines Should Be Banned by Mervyn Singer (2009)
- PulmCCM.org — Esmolol infusion reduced septic shock mortality by 60% in RCT (JAMA) (2013)
- Resus.ME — Beta blockade in sepsis (2013)
- Resus Review — Is beta-blockade safe in sepsis? Is it helpful? (2013)