Bridge will be prolonged because RRT will remove

Bridge to antidote ECMO can be helpful in life threatening arrhythmia or
cardiovascular collapse with those toxins which can be managed successfully
with antidote but which is not available readily due to short shelf life and
cost. Digoxin-specific antibodies fragments
(Fab) rapidly improves the digitalis induced arrhythmias and cardiac toxicity.
However, Digoxin poisoning is uncommon and Fab fragments are expensive with
limited shelf life. Patient can be supported with ECMO until Fab is
administered. (41, 42)

Bridge to toxin elimination with renal replacement therapy

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salicylate intoxication has been managed successfully with dialysis, which help
in substantial amount of salicylate removal. (43) So far, around 142
dialyzable poisons have been identified. (44)

decision about dialyzing the poison depends on the molecular weight, protein
binding and volume of distribution of the toxin. Large molecular weight
medications are poorly dialyzed. Toxic substances which are highly protein bound
are less available for removal through renal replacement therapy (RRT). If the
toxic substance has large volume of distribution, elimination of toxic
substance will be prolonged because RRT will remove toxic substance from plasma
space only. If the patient has hemodynamic instability in spite of adequate supportive
therapy, VA ECMO may be considered to maintain the haemodynamics. The RRT may
be added to ECMO circuit or may be started separately to eliminate the toxin.(45)
The various techniques used for toxin removal include dialysis,
haemoperfusion, hemofiltration and plasmapheresis with plasma exchange. The
basic principle of dialysis involves diffusion through a semepermeable
membrane, whereas in hemoperfusion the toxin is adsorbed on the adsorbent
surface of dialyzer. The mechanism of hemofiltration is convection across the
membrane. These therapies may be used as single or in combination. The
plasmapheresis is used for acute poisoning with the toxins which are highly
protein bound. (46, 47) Continuous Renal Replacement Therapy (CRRT)
and Slow Low Efficiency Dialysis (SLED) are preferred over Intermittent
Hemodialysis during ECMO. However peritoneal dialysis is not suitable as it
does not remove toxins effectively.

Bridge to Transplant Toxins with the potential with irreversible and rapid progression
of pulmonary fibrosis can be supported with VV ECMO as bridge to transplant
when lung transplant is not possible immediately due to either unavailability of
viable donor or waiting for toxin metabolism and clearance from the tissues. (48)
Even VA ECMO can be useful as bridge to
permanent assist device in patients with persistent cardiac failure.



Renal replacement therapy may be
useful in acute severe intoxication in several ways: it not only helps in
removing certain toxins but help in optimizing haemodynamics by metabolic
acidosis correction, This improved haemodynamics further help in
redistribution, enhance metabolism and elimination of toxic substance.

various modalities which may be helpful during acute severe intoxication can be
divided as continuous or intermittent therapies: Intermittent therapies include
intermittent hemodialysis (IHD) and Sustained Low Effeciency Dialysis (SLED)
whereas continuous therapies are continuous renal replacement therapy (CRRT) or
Peritoneal dialysis (PD). Hemoperfusion may be used alone or in combination
with these intermittent or continuous therapies. The elimination of toxic
substance is influenced by the principle of chosen therapy and the
characteristics of toxic substance. The basic principle of dialysis is
diffusion of toxic substance through a semipermeable membrane. The blood and
dialysate move in a counter current manner. The removal of toxin depends on
surface area and pore size of artificial kidney, type and quantity of
administered dialysate and blood flow rate. (49) Low molecular
weight substance (< 500 dalton) with poor protein binding, small volume of distribution and low lipid solubility are easily dialyzable. This includes salicylates, methanol, lithium, ethylene glycol and theophylline. The higher molecular weight substances even as high as 40000 dalton can be removed by haemofiltration using convective principle. The removal of toxin depends on protein binding and sieving coefficient. The various toxins which can be successfully eliminated with haemofiltration vancomycin, methanol, Paraquat, procainamide, thallium, lithium methotrexate and hirudin. CRRT may be helpful in acute intoxicated patient with haemodynamic compromise for even non dialyzable toxins. The metabolic acidosis due to haemodynamic compromise has been associated with reduced cardiac contractility and leads to further worsening of haemodynamics. In ICU a pH<7.2 is usually associated with haemodynamic instability and usually responds to metabolic correction. (50) The metabolic acidosis associated myocardial dysfunction has been demonstrated in animal model (51, 52, 53) however these effects may be masked in human due to increased catecholamine and calcium levels. Lactate production due to shock alters both intracellular and extracellular pH. (54) Patients having severe acidosis are relatively resistant to the action of vasopressors. (55) Moreover, an initial response with vasopressors decreases and requires higher doses with the development of metabolic acidosis. The correction of acidosis has shown in the improvement of cardiac function and haemodynamics. (56) The main principle for acidosis correction is correction of underlying cause, however in some severely hypotensive patients renal replacement therapy (RRT) helps in correcting metabolic acidosis and improving the haemodynamics as bridge till the underlying cause has been addressed. (57) Continuous therapies are preferred for correction of pH and more effective clearance of lactate and prevention of rebound. Furthermore, patients with severe metabolic acidosis can be effectively managed with CRRT in correcting the acid–base disturbances. (58) Lactate clearance with CRRT may be <3% as compared to normal kidney but probably improvement in haemodynamics with metabolic acidosis correction may improve the lactate clearance. (59) CRRT uses both diffusive and convective principle forsolute removal depending on chosen therapy. The advantages of CRRT include not only the institution of therapy in haemodynamically unstable acutely intoxicated patients, but also for prevention of rebound phenomenon in certain toxins due to large volume of distribution and slow redistribution among the various body compartments. (60)   EVIDENCE REGARDING USE OF ECMO There are no randomised trials on the use of ECMO in patients with severe intoxication having refractory shock or having ARDS. So, the available evidences are basically few animal studies, case reports, case series and case cohort studies. A cautious interpretation of results is indicated due to potential for bias. Drug toxins Most of the available literature is from the western countries and describe the use of ECMO in acute drug intoxication. The experimental evidences with three different trial using lidocain (61), desipramine (62) and amitryptaline (63) in dogs & swine respectively has shown better outcome with extra corporeal life support (ECLS) in comparison to the conventional treatment using fluid, vasopressor, inotropes, antiarrhythmic agents etc. The major drawback about all three studies was that the animals were put on ECLS immediately after collapse and the duration of ECLS was short. This may not hold true in actual human intoxication because they are not supported with ECLS immediately and duration of ECLS is longer. However these results are promising and encourage the use of ECMO in refractory shock due to poisoning. The experiences in human subject include an observational cohort which shows better outcome in six patients with severe intoxication with profound shock who received VA-ECMO as compared to use of ECMO for other indications. The toxic substances were chloroquine, a tricyclic antidepressant, propafenone, a sclerotic agent and diuretics. (64) In another cohort of 17 patient where ECLS was initiated for refractory cardiac arrest. VA ECMO was instituted in all patients and stable ECLS was achieved in 14 patients.  The survival was better in patients with shock due to poisoning (25%) versus none survived in the cardiogenic shock group. (65) A retrospective cohort analysis in two hospitals in France analyzed all poisoning patients presented to the hospital. There was statistically significant favourable outcome (86% vs 48%) in severely intoxicated patients with refractory shock or cardiac arrest, who were managed with VA ECMO as compared to conventional management with fluid, vasopressors & other supportive measures.(66) However due to small number of patients treated with VA ECMO in this cohort, the interpretation of results should be done carefully. Besides this there are several case reports of successful management of drug intoxication with refractory shock using ECMO. The acute intoxication of drugs which has been supported successfully supported with ECMO include flecainide, (67,68) an antiarrhythmic agent, beta blocker, (69) calcium channel blockers, (70) digoxin, (71) tricyclic antidepressant, (41,72) buprioprion, (73) methamphetamine,(74) and mepivacaine, a local anaesthetic. (75) These included both adult and paediatric patients, all of them were supported with VA ECMO but the time of initiation of ECMO and duration of ECMO was different in different cases. Common complications similar to any case of VA ECMO were reported such as bleeding, hypotension, thromboembolism or minor neurological events. There is always a chance of reporting and publication bias in case reports but recovery and survival in such a critical population definitely encourages the use of ECMO in poisoned patients with profound shock. Another case series of 17 patients, who were severely intoxicated with different cardiotoxic drugs including membrane stabilizing agents. Nearly 90% patients were successfully weaned off from Emergency Cardiopulmonary Bypass (ECPB), and 76% were discharged without significant cardiac and neurological dysfunction. Though few of them required Cardiopulmonary resuscitation (CPR) before commencing ECPB and four patients required renal replacement therapy during ECPB to manage acute kidney injury. Though there were certain complication such as bleeding, limb ischemia and thrombus formation but author concluded that ECPB is safe and effective in the management of severely poisoned patients. (45) Other substances The ECMO has not been used much in the severe intoxication and refractory shock or severe ARDS with other toxic substances such pesticides, carbon monoxide, cyanide and plant toxins. The available literature is restricted to case reports or case series with few patients only. These substances are commonly used as poison in developing world with high mortality but ECMO is still not frequently available in this population, this may be a probable reason of underutilization of this modality. Carbon monoxide (CO) rapidly binds to hemoglobin to form carboxyhemoglobin, leading to tissue hypoxia, multiple-organ failure, and cardiovascular collapse. Both VV & VA ECMO may be used to manage tissue hypoxia depending on haemodynamic stability. (76)  Aluminium phosphide, a deadly poison used as pesticide causing severe myocardial dysfunction, arrhythmia and death has been successfully managed with VA ECMO at different centres. (29, 77, 78, 79) The plant toxin, Taxus induced cardiogenic shock with ventricular arrhythmia has been successfully managed with VA ECMO. (80) ARDS induced with organophosphorus poisoning has also been supported with VV ECMO. (39)  Even poison induced lung fibrosis patient awaiting lung transplant is put on VV ECMO to improve gas exchange. (48)   SUMMARY The use of ECMO in acutely poisoned patients with refractory cardiogenic shock or refractory hypoxemia to conventional therapies is getting popular among the emergency physicians and intensivists as salvage therapy. However ECMO is still an underutilized modality both in developed and developing countries. The available evidences are limited to case reports and case series, which may have reporting and publication bias but randomized trial may be ethically unacceptable. Poisoning is a unique subject, not only because of huge number of toxic substances available but also each substance has different pharmacological, metabolism and elimination profile. It is understandable that ECMO may be helpful in supporting the haemodynamics irrespective of poisoning substances if cardiovascular dysfunction is unresponsive to standard therapies. The complications associated with ECMO may be life threatening and is minimized with expertise. The selection of ECMO (VA or VV) depends on the affected organ and haemodynamics at the time of initiation. Our understanding regarding the use of ECMO in poisoning is still limited and several issues are yet to be answered. This include the right time of ECMO initiation in acute intoxication, when to combine renal replacement therapy to facilitate metabolic correction, cost effective management, clarifications regarding the prognostic factors in poisoning prior to ECMO initiation,  decision regarding the withdrawal of ECMO support after improvement. All these issues may be addressed in future research and publications. However Extracorporeal Life Support Organization (ELSO), the largest world organization for ECMO data registry may provide an excellent platform by encouraging global data collection on the ECMO use in poisoning. The decision regarding ECMO support in poisoning must be made carefully since ethical issues may arise in a situation of bridge to nowhere if the patient has developed irreversible organ damage.