Beta-blocker treatment in the critically ill: a systematic review and meta-analysis

Figures & data

Figure 1. PRISMA flow diagram of the study selection process.

Table 1. Characteristics of included studies.

Author, year [ref.]	Country	Blinding, nr. of study centres	Population [type of critical illness]	Nr. of patients; total [beta-blocker/controls]	Follow-up period
Ali, A. et al. 2015 [41]	USA	Non-blinded, single-centre	Severe burns [burns covering > 30% of TBSA]	69 (35/34)	NR
Arar, C. et al. 2007 [42]	Turkey	Double-blind, single-centre	Cardiac surgery	120 (40/40/40)	Before extubation to 1 min after extubation in the ICU
Balser, J. R. et al. 1998 [43]	USA	Non-blinded, single-centre	Major non-cardiac surgery	63 (34/30*)	12 h
Bible, L. E. et al. 2014 [44]	USA	Non-blinded, single-centre	Severe trauma	45 (25/20)	30 d or until discharge from the hospital, whichever occurred first
Brunner, M. et al. 2000 [45]	Germany	Double-blind, multicenter	Unstable angina pectoris	116 (59/57)	48 h
Cheema, S. A. et al. 2020 [46]	Pakistan	Non-blinded, single-centre	Burns with 20–40% of TBSA	70 (35/35)	NR
Connolly, S. J. et al. 2003 [47]	Canada	Double-blind, single-centre	Heart surgery	1000 (500/500)	14 days or until hospital discharge
De Hert, S. G. et al. 1988 [48]	Belgium	Double-blind, single-centre	Postop treatment after neurosugical interventions for traumatic injury	30 (15/15)	30 min
Er, F. et al. 2016 [49]	Germany	Single-blind, single-centre	STEMI + successful PCI	101 (50/51)	6 months
Guillory, A. N. Et al. 2017 [50]	USA	Non-blinded, single-centre	Severe burns	26 (16/10)	NR
Hanada, K. et al. 2012 [51]	Japan	Non-blinded, single-centre	AMI patients undergoing primary PCI	96 (47/49)	24 h = acute phase + 6 months
Kakihana, Y. et al. 2020 [52]	Japan	Non-blinded, multicenter	Sepsis [+tachyarrhythmia]	151 (76/75)	28 days
Khalili, H. et al. 2020 [23]	USA	Non-blinded, single-centre	Traumatic brain injury	219 (99/120)**	8 months; during hospital stay + at 6 months
Morelli, A. et al. 2013 [16]	Italy	Single-centre, open-label	Septic shock	154 (77/77)	28 d
Sakaguchi, M. Et al. 2012 [53]	Japan	Non-blinded, single centre	Cardiac surgery; AF after valve surgery	60 (30/30)	72 h
Wang, Z. et al. 2015 [21]	China	Non-blinded, single centre	Severe sepsis	90 (30/30/30)	28 d

Explanations:

*1 Subject entered the trial twice, randomized to diltiazem group on both times.

**After randomization formed subgroup of isolated severe TBI without other injuries in which number of patients who received propral: 68 = 44%, and control 86 = 56%

Abbreviations: Ref.: reference number; NR: not reported; TBSA: total body surface area; ICU: intensive care unit; STEMI: ST-elevation myocardial infarction; PCI: percutaneous coronary intervention; AMI: acute myocardial infarction; AF: atrial fibrillation.

Table 2. Aims of included trials.

Author & year [ref.]	Aim of study
Ali, A. et al. 2015 [41]	To investigate effects of propranolol on the cardiovascular system, perioperative hemodynamics, and wound healing by decreasing baseline HR by 20%.
Arar, C. et al. 2007 [42]	To compare the effects of esmolol and Mg on hemodynamic response in the pre-extubation period in the ICU following CABG surgery.
Balser, J. R. et al. 1998 [43]	To evaluate wheather β-blockade is better in conversion of SVT than calcium channel blockers in postoperative patients with SVT (FA, flutter or other atrial tachyarrhythmias).
Bible, L. E. et al. 2014 [44]	To investigate whether propranolol would prevent bone marrow dysfunction in humans following severe injury when administered after the injury.
Brunner, M. et al. 2000 [45]	To investigate the safety and efficacy of oral carvedilol in unstable angina in addition to standardised treatment.
Cheema, S. A. et al. 2020 [46]	To compare the mean duration of wound healing and attenuation of muscle wasting in adult burn patients with propranolol and control group.
Connolly, S. J. et al. 2003 [47]	Whether treatment with p.o. metoprolol immediately after heart surgery reduces hospital length of stay and costs.
De Hert, S. G. et al. 1988 [48]	To investigate the influence of labetalol on arterial blood gas data, pulmonary hemodynamics and pulmonary shunting in patients with neurosurgical treatment for traumatic injury.
Er, F. et al. 2016 [49]	To evaluate the role of esmolol-induced tight sympathetic control in STEMI patients with successful PCI.
Guillory, A. N. et al. 2017 [50]	To determine the appropriate propranolol kinetics and dosing strategy for reducing HR in severely burned adults receiving propranolol every 6 h, every 8 h, and once daily.
Hanada, K. et al. 2012 [51]	To examine the efficacy and safety of early i.v. administration of landiolol in patients with AMI undergoing primary PCI.
Kakihana, Y. et al. 2020 [52]	To investigate the effects of landiolol on HR, mortality, and safety in patients with sepsis related tachyarrhythmias, incl. FA, atrial flutter, and sinus tachycardia, compared with patients who received conventional therapy.
Khalili, H. et al. 2020 [23]	To examine the effects of β-blockers on survival and functional outcomes in TBI patients.
Morelli, A. et al. 2013 [16]	To investigate the effects of the short-acting β-blocker esmolol in patients with severe septic shock (HR and measured subsequent effects on systemic hemodynamics, organ function, adverse events, and 28-day mortality).
Sakaguchi, M. et al. 2012 [53]	To examine the effects of landiolol hydrochloride on prevention of AF and on hemodynamics in the acute postoperative phase after heart valve surgery.
Wang, Z. et al. 2015 [21]	To assess the effects of esmolol combined with milrinone in patients with severe sepsis.

Abbreviations: ref.: reference number; HR: heart rate; Mg: magnesium; ICU: intensive care unit: CABG: coronary artery bypass graft; SVT: supraventricular tachycardia; FA: atrial fibrillation; STEMI: ST-elevation myocardial infarction; PCI: percutaneous coronary intervention; i.v.: intravenous; AMI: acute myocardial infarction; TBI: traumatic brain injury.

Table 3. Intervention, comparator and reported outcomes of included trials.

Author, year (ref.)	Name of beta-blocker	Control/comparator	Nr. of patients; total (beta-blocker/controls)	Review outcomes reported and included in meta-analysis	Review outcomes reported *
Ali, A. et al. 2015 [45]	Propranolol	Standard care	69 (35/34)	Mortality (no timepoint)	HR, vasopressor load, lactate
Arar, C. et al. 2007 [46]	Esmolol	(1) Magnesium (2) placebo (saline)	120 (40/40/40)	__	HR, MAP
Balser, J. R. et al. 1998 [47]	Esmolol	Diltiazem	63 (34/30*)	Mortality (in-hospital)	HR, MAP, vasopressor load
Bible, L. E. et al. 2014 [48]	Propranolol	Standard care	45 (25/20)	Mortality (30-d)	Organ dysfunction (ventilator days), HR, BP/MAP, lactate
Brunner, M. et al. 2000 [49]	Carvedilol	Placebo; no description of placebo or administration	116 (59/57)	Mortality (48 h), HR	BP (no MAP), TnT
Cheema, S. A. et al. 2020 [50]	Propranolol	Standard care	70 (35/35)	__	HR
Connolly, S. J. et al. 2003 [51]	Metoprolol	Placebo; no description of placebo or administration	1000 (500/500)	Mortality (in-hospital)	Mechanical ventilation, HR
De Hert, S. G. et al. 1988 [52]	Labetalol	Placebo; isotonic physiologic solution	30 (15/15)	__	HR, MAP
Er, F. et al. 2016 [53]	Esmolol	NaCl 0.9 %	101 (50/51)	Mortality (6 months), HR	Quality of life, LV EF, BNP, TnT
Guillory, A. N. Et al. 2017 [54]	Propranolol	Placebo; no description of placebo or administration	26 (16/10)	__	HR, BP (no MAP)
Hanada, K. et al. 2012 [55]	Landiolol	Standard care	96 (47/49)	Mortality (in-hospital, 6 months)	HR, BP (no MAP), LV EF, BNP
Kakihana, Y. et al. 2020 [56]	Landiolol	Standard care	151 (76/75)	Mortality (28 d), HR, MAP, vasopressor load	Organ dysfunction (kidney function, ventilator-free days); LV EF, lactate, BNP, TnI
Khalili, H. et al. 2020 [27]	Propranolol	Standard care	219 (99/120)**	Mortality (in-hospital)	HR, MAP
Morelli, A. et al. 2013 [20]	Esmolol	Standard care	154 (77/77)	Mortality (28-d)	Organ dysfunction (kidneys, liver, heart), HR, MAP, vasopressor load, TnT, lactate
Sakaguchi, M. Et al. 2012 [57]	Landiolol	Standard care	60 (30/30)	__	HR, BP (no MAP), vasopressor load
Wang, Z. et al. 2015 [25]	Esmolol	(1) Milrinone (2) standard care	90 (30/30/30)	Mortality (28-d), HR, MAP, vasopressor load	Organ dysfunction (kidney, liver), lactate, BNP, TnI, IL-6/-10

Explanations: *Review outcomes assessed in original trials but not reported as mean (SD)/reported partly/data not available and could not be included in the quantitative meta-analysis.

– = not reported.

Abbreviations: ref.: reference number; HR: heart rate; MAP: mean arterial pressure; BP: blood pressure; TnT/TnI: troponin T/I; NaCl: natrium chloride; LVEF: left ventricular ejection fraction; BNP: brain natriuretic peptide; IL-6/-10 : interleukin-6/-10.

Figure 2. Risk of bias summary.

Figure 3. Forest plot of mortality, all.

Table 4. GRADE summary of findings table.

Certainty assessment							Summary of findings
Participants (studies) Follow-up	Risk of bias	Inconsistency	Indirectness	Imprecision	Publication bias	Overall certainty of evidence	Study event rates (%)		Relative effect (95% CI)	Anticipated absolute effects
							With control	With Beta-blocker		Risk with control	Risk difference with Beta-blocker
Mortality (all)
2103 (11 RCTs)	Not serious^a	Not serious	Not serious	Not serious	None	⨁⨁⨁⨁ High	157/1072 (14.6%)	88/1031 (8.5%)	RR 0.65 (0.53 to 0.79)	146 per 1 000	51 fewer per 1 000 (from 69 fewer to 31 fewer)
Short-term mortality (<14 days)
1467 (5 RCTs)	Not serious	Serious^b	Not serious	Not serious	None	⨁⨁⨁◯ Moderate	37/740 (5.0%)	29/727 (4.0%)	RR 0.85 (0.45 to 1.60)	50 per 1 000	8 fewer per 1 000 (from 28 fewer to 30 more)
Long-term mortality (>14 days)
636 (6 RCTs)	Not serious	Not serious	Not serious	Not serious	None	⨁⨁⨁⨁ High	120/332 (36.1%)	59/304 (19.4%)	RR 0.60 (0.48 to 0.74)	361 per 1 000	145 fewer per 1 000 (from 188 fewer to 94 fewer)
Heart rate 24 h (beats/min)
426 (4 RCTs)	Not serious	Serious^c	Not serious	Not serious	None	⨁⨁⨁◯ Moderate			–		MD 11.96 lower (20.86 lower to 3.06 lower)
MAP 48 h (mmHg)
210 (2 RCTs)	Not serious	Not serious	Not serious	Not serious	None	⨁⨁⨁⨁ High			–		MD 1.66 higher (2.28 lower to 5.61 higher)
MAP 72 h (mmHg)
210 (2 RCTs)	Not serious	Not serious	Not serious	Not serious	None	⨁⨁⨁⨁ High			–		MD 2.43 lower (6.62 lower to 1.75 higher)
Vasopressor load 48 h (µkg/kg/min)
210 (2 RCTs)	Not serious	Not serious	Not serious	Not serious	None	⨁⨁⨁⨁ High			–		MD 0.02 higher (0.02 lower to 0.07 higher)
Vasopressor load 72 h (µkg/kg/min)
210 (2 RCTs)	Not serious	Not serious	Not serious	Not serious	None	⨁⨁⨁⨁ High			–		MD 0 (0.04 lower to 0.03 higher)

CI: confidence interval; MD: mean difference; RR: risk ratio.

Explanations: ^aDespite most trials were considered having high overall-risk of bias, this outcome assessment was considered robust. ^bHeterogeneity: Tau² = 0.16; Chi² = 4.02, df = 2 (p = .13); I² = 50%; ^cHeterogeneity: Tau² = 73.81; Chi² = 32.69, df = 3 (p < .00001); I² = 91%.

Figure 4. Forest plot of short-term mortality.

Figure 5. Forest plot of long-term mortality.

Figure 6. Forest plot of HR 24 h.

Figure 7. Forest plot of MAP 48 h.

Figure 8. Forest plot of MAP 72 h.

Figure 9. Forest plot of vasopressor load 48 h.

Figure 10. Forest plot of vasopressor load 72 h.

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Data availability statement

Data generated or analyzed during this study are included in this published article and its supplementary information files. All background/exctracted data are provided in included articles or their supplementary material available.