Extracorporeal treatment for poisoning to beta-adrenergic antagonists: systematic review and recommendations from the EXTRIP workgroup

Bouchard, Josée; Shepherd, Greene; Hoffman, Robert S.; Gosselin, Sophie; Roberts, Darren M.; Li, Yi; Nolin, Thomas D.; Lavergne, Valéry; Ghannoum, Marc

doi:10.1186/s13054-021-03585-7

Critical Care

Table 5 Extracorporeal treatments + standard care versus standard care in β-adrenergic antagonists poisoning (evidence profile table)

From: Extracorporeal treatment for poisoning to beta-adrenergic antagonists: systematic review and recommendations from the EXTRIP workgroup

Quality assessment							Summary of findings				Importance
Drug	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	ECTR + standard care	Standard care (controls)	Impact	Quality
Mortality
All β-adrenergic antagonists^a n = 10	Observational studies	Very serious^b	Not serious	Serious ^c	Serious ^d	Publication bias strongly suspected ^e	13.5% (5/37)	ICU data 8.2% (9/110) admitted in 1 ICU 2002–9 [23] PCC and hospital data 3.8% (63/1678) 0/858: German PCC 2001–11 single-substance [32] 1/11: children, self-harm [50] 2/73:1 hospital 1993–7 [37] 0/40: 1 hospital 1966–80 [25] 4/280: 2 PCCs 1992–8, [22] 60/416: US PCCs 2017–19, at least major effect [21, 51, 52]	Comparable mortality between the ECTR group and the control group admitted to ICU (risk difference = 53 more deaths per 1000 patients in the ECTR group (with a 95% CI from 68 less to 175 more deaths per 1000)	⨁◯◯◯ VERY LOW	CRITICAL
Propranolol^f n = 5	Observational studies	Very serious^b	Not serious	Serious ^c	Serious ^d	Publication bias strongly suspected ^e	11.1% median dose 3.1 g (1/9)	Ranging from 0 to 2.1% 0/41 German PCC 2001–11 single substance median dose 0.4–0.5 g [32] 7/339 UK PCC 2017–18, median dose 0.6 g [321] 0/50: 1 hospital 1993–7 mean dose 1.3 g [37] 0/18 1979–1985 mean dose 1.6 g [36]	Groups not comparable	⨁◯◯◯ VERY LOW	CRITICAL
Sotalol^g n = 3	Observational studies	Very serious^b	Not serious	Serious ^c	Serious ^d	Publication bias strongly suspected ^e	11.1% median 8.0 g (1/9)	Overall = 0% 0/31: German PCC 2001–11 single substance [32] 0/6: Case in Finland 1977–1980, mean dose 5.7 g [12]	Groups not comparable	⨁◯◯◯ VERY LOW	CRITICAL
Atenolol^h n = 3	Observational studies	Very serious^b	Not serious	Serious ^c	Serious ^d	Publication bias strongly suspected ^e	11.1% median 4.5 g (1/9)	Overall = 0% 0/48: German PCC 2001–11, single substance, median dose 0.5–0.8 g [32] 0/10: 1 hospital 1993–7 mean dose 2.0 g [37]	Groups not comparable	⨁◯◯◯ VERY LOW	CRITICAL
Duration of QT interval prolongation
Sotalolⁱ n = 4	Observational studies	Very serious^b	Not serious	Serious ^c	Serious ^d	Publication bias strongly suspected ^e	Median = 37 h [33.5, 78.5] 3 pts, median 8 g	Median = 75 h [57, 87.5] 6 pts median dose 6.2 g 1977–80 [12]	No formal comparison possible due to the small sample size of the ECTR group	⨁◯◯◯ VERY LOW	IMPORTANT
Serious complications of catheter insertion ^j
n = 5 ^k	Observational studies	Not serious	Not serious ^l	Not serious ^m	Not serious ⁿ	Strong association ^o	Rate of serious complications of catheter insertion varies from 0.1% to 2.1%	≈ 0	Absolute effect is estimated to be varying from 1 to 21 more serious complications per 1000 patients in the ECTR group	⨁⨁⨁◯ MODERATE	CRITICAL
Serious complications of ECTR ^p
n = 4^q	Observational studies	Not serious	Not serious	Not serious	Not serious	Strong association ^r	Rate of serious complications of ECTR varies according to the type of ECTR performed from 0.005% (IHD and CKRT), to 0.6% (TPE) and up to 1.9% (HP)	≈ 0	Absolute effect is estimated to be varying from > 0 to 19 more serious complications per 1000 patients in the ECTR group depending of the type of ECTR performed	⨁⨁⨁◯ MODERATE	CRITICAL

ECTR: Extracorporeal treatments, IHD: Intermittent hemodialysis, TPE: Therapeutic plasma exchange, CKRT: Continuous kidney replacement therapy, HP: Hemoperfusion, Pts = patients, PCC: Poison control center
“Requirement for extracorporeal life support,” “Length of requirement of vasopressors,” “Length of hospital stay,” “Length of ICU stay,” and “Sequelae” were outcomes ranked important or critical although no data were reported in the control group, so no comparison with the ECTR group could be performed
^aIncludes our systematic review of the literature on ECTR (37 patients from 32 case reports or case series) and 9 cohorts on standard care alone in β-adrenergic antagonists. No exclusion was based on the presence of co-ingestants or interventions
^bCase reports published on effect of ECTR. Uncontrolled and unadjusted for confounders such as severity of poisoning, co-ingestions, supportive and standard care, and co-interventions. Confounding-by-indication is inevitable since ECTR was often attempted after other therapies had failed
^cECTR and standard care performed may not be generalizable to current practice (literature pre-dating 2000)
^dFew events in small sample size, optimal information size criteria not met
^ePublication bias is strongly suspected due to the study design (case reports published in toxicology either report very severe poisoning with/without impressive recovery with treatments attempted)
^fIncludes our systematic review of the literature on ECTR (9 case reports) and 4 cohorts on standard care alone in propranolol poisoning
^gIncludes our systematic review of the literature on ECTR (9 case reports) and 2 cohorts / case series on standard of care alone in sotalol poisoning
^hIncludes our systematic review of the literature on ECTR (9 case reports) and 2 cohorts on standard of care alone in atenolol poisoning
ⁱIncludes our systematic review of the literature on ECTR (3 case reports) and 1 case series on standard of care alone in sotalol poisoning
^jFor venous catheter insertion: serious complications include hemothorax, pneumothorax, hemomediastinum, hydromediastinum, hydrothorax, subcutaneous emphysema retroperitoneal hemorrhage, embolism, nerve injury, arteriovenous fistula, tamponade, and death. Hematoma and arterial puncture were judged not serious and thus excluded from this composite outcome. Deep venous thrombosis and infection complications were not included considering the short duration of catheter use
^kBased 5 single-arm observational studies: 2 meta-analyses comparing serious mechanical complications associated with catheterization using or not an ultrasound, which included 6 RCTs in subclavian veins [322] and 11 in internal jugular veins [323]; 2 RCTs comparing major mechanical complications of different sites of catheterization [324, 325]; one large multicenter cohort study reporting all mechanical complications associated with catheterization [326]. Rare events were reported from case series and case reports
^lNot rated down for inconsistency since heterogeneity was mainly explained by variation in site of insertion, use of ultrasound, experience of the operator, populations (adults and pediatric), urgency of catheter insertion, practice patterns, and methodological quality of studies
^mNot rated down for indirectness since cannulation and catheter insertion was judged similar to the procedure for other indications
ⁿNot rated down for imprecision since wide range reported explained by inconsistency
^oThe events in the control group are assumed to be zero (since no catheter is installed for ECTR); therefore, the magnitude of effect is at least expected to be large, which increases the confidence in the estimate of effect. Furthermore, none of the studies reported 95%CI which included the null value and all observed complications occurred in a very short timeframe (i.e., few hours)
^pFor IHD and CKRT: serious complications (air emboli, shock, and death) are exceedingly rare. Minor bleeding from heparin, transient hypotension, and electrolytes imbalance were judged not serious. For HP, serious complications include severe thrombocytopenia, major bleeding, and hemolysis. Transient hypotension, hypoglycemia, hypocalcemia, and thrombocytopenia were judged not serious. For TPE, serious complications include citrate toxicity, severe allergic reaction, arrhythmia, and vasovagal reaction. Hypotension, hypocalcemia, and urticaria were judged as not serious. All non-serious complications were excluded from this composite outcome
^qIHD/CKRT: Based on 2 single-arm studies describing severe adverse events per 1000 treatments in large cohorts of patients [327, 328]. TPE: based on the 2 most recent one-arm studies reporting potential life-threatening adverse events [329, 330]. HP: Based on 2 small single-arm studies in poisoned patients [331, 332]. Rare events were reported in case series and case reports
^rAssuming that patients in the control group would not receive any form of ECTR, the events in the control group would be zero; therefore, the magnitude of effect is at least expected to be large, which increases the confidence in the estimate of effect. Furthermore, none of the studies reported 95%CI which included the null value and all observed complications occurred in a very short timeframe (i.e., few hours)

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