See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/353929904

Management of Acute Aluminum Phosphide Poisoning: Has Anything Changed?

Article  in  Drug Metabolism Letters · August 2021

DOI: 10.2174/1872312814666210813115625

CITATIONS READS
6 480

3 authors, including:

Lokhesh C Anbalagan Navneet Arora

Postgraduate Institute of Medical Education and Research Postgraduate Institute of Medical Education and Research
5 PUBLICATIONS   45 CITATIONS    36 PUBLICATIONS   84 CITATIONS   

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Infections View project

All content following this page was uploaded by Navneet Arora on 10 November 2021.

The user has requested enhancement of the downloaded file.

 Send Orders for Reprints to reprints@benthamscience.net
Drug Metabolism Letters, хххх, хх, 1-0 1
REVIEW ARTICLE

Management of Acute Aluminum Phosphide Poisoning: Has Anything

Changed?
Lokhesh Chockalingam Anbalagan1, Navneet Arora1 and Ashok Kumar Pannu1,*

1
Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh 160012,
India

ARTICLE HISTORY
Received: April 01, 2021
Revised: July 14, 2021
Accepted: July 15, 2021
DOI:
10.2174/1872312814666210813115625
Abstract: Due to its easy availability, rapid and severe toxicity, and no specific antidote, alu-
minum phosphide has emerged as a lethal toxin, commonly used for suicidal intent in agricultural
communities. Despite various advances in medicine, this compound’s toxicity is poorly unders-
tood, and it still has a very high case fatality rate with no definitive treatment options available.
This review aims to understand the mechanism of toxicity, clinical toxidrome of acute aluminum
phosphide poisoning, and the available therapeutic options, including recent advances. A literature
review was performed searching PubMed, EMBASE Ovid, and Cochrane Library, using the follow-
ing search items: (“aluminum phosphide poisoning” OR “aluminum phosphide poisoning toxicity”
OR “aluminum phosphide ingestion”) AND (“management” OR “therapy” OR “treatment”). Select-
ed articles were discussed amongst all the authors to shape this review. High case fatality rate and
lack of any specific antidote are persisting challenges. Therapeutic measures need to be implement-
ed from all fronts – reducing easy access to the poison, developing less toxic alternatives for use as
a pesticide, and more studies directed at developing an effective reversal agent for phosphine. The
advent of promising agents like glucose-insulin-potassium infusion and lipid emulsion is a new ray
of hope in the complete recovery in this fatal poisoning. The need of the hour is to find an agent
that rapidly and effectively reverses aluminum phosphide's toxic effects. Large multicenter con-
trolled trials are required to establish the role of glucose-insulin-potassium and lipid emulsion.

Keywords: Aluminum phosphide, poisoning, toxicity, management, therapy, glucose-insulin-potassium, lipid emulsion.

1. INTRODUCTION and mortality among poisoning agents, commonly available

Metal phosphides, mainly aluminum phosphides, are
widely used insecticides. They have the full potency of
killing pests and decomposing them into harmless end-prod-
ucts and are primarily used as pesticides and rodenticides for
fumigating rice and other grains in storage facilities and tran-
sportation in agricultural communities. Annually, pesticide
ingestion accounts for at least one in seven suicides and re-
sults in 260,000 deaths worldwide [1]. Approximately 25
million agricultural workers from developing countries suf-
fer from self-poisoning episodes each year [2, 3]. Poisoning
by pesticides is on the rise since the introduction of readily
available potent pesticides in the market, with several glob-
al, national, and domestic factors playing a role in the in-
creasing incidence.
The rapid onset of a severe toxidrome after aluminum
phosphide’s ingestion and the non-availability of an effec-
tive antidote is responsible for very high case fatality rates,
making it a typical ‘suicide poison’. In recent times, it has
emerged as the leading cause of emergency hospitalization
*Address correspondence to this author at the Department of Internal
Medicine, Postgraduate Institute of Medical Education and Research,
Chandigarh 160012, India; Tel: +919914291115, +918264786277;
E-mail: gawaribacchi@gmail.com
in Asian countries [4, 5]. The majority of aluminum phos-
phide toxicities are mainly suicidal compared to western da-
ta, where most cases are accidental inhalation [5]. The num-
ber of reported cases may be just the tip of the iceberg be-
cause the poisoning cases from rural areas suffer a delay in
receiving treatment, fatality due to the delay, and lack of ade-
quate reporting from primary health care centers [4].
Aluminum phosphide is available under many brand
names such as CelphosTM (Excel Crop Care Ltd., India),
QuickphosTM (UPL Ltd., India), PhostekTM (Concept Agri-
Tek, USA), etc., in local communities. The familiarity of the
local brands is essential for the physicians because many
times, the patients do not bring the compound or the contain-
er at the time of hospital admission for recognition, which re-
sults in misdiagnosis or delayed diagnosis. Aluminum phos-
phide is marketed as solid pellets or tablets, powder sachets,
and compressed discs. The commonly available over the
counter 3 g tablets release around 1 g of phosphine gas in
contact with water. Change in the formulation as the granu-
lated powder form (usually marketed as a 10 g sachet) usual-
ly decreases the potency. Exposure to the environment caus-
es a reaction of aluminum phosphide with atmospheric mois-
ture, resulting in phosphine liberation and less toxicity. The
primary mode of toxicity is ingestion or, less commonly in-
halation and rarely, absorption through broken skin [6]. The

1872-3128/хх $65.00+.00 © хххх Bentham Science Publishers

2 Drug Metabolism Letters, хххх, Vol. хх, No. хх
fatal dose of the poison for an adult individual (weighing
about 70 kg) is approximately 150-500 mg [7, 8]. Many for-
mulations also contain other chemicals like ammonium car-
bamate, ammonium bicarbonate, urea, methanethiol, and
paraffin, which play a crucial role in regulating the release
of phosphine gas, suppressing flammability and regulating
moisture uptake.
1.1. Mechanism of Toxicity
On ingestion, aluminum phosphide reacts with water
molecules (or gastric acid) to form aluminum hydroxide (or
aluminum chloride) and phosphine, which is absorbed
through the gastric mucosa. On inhalation of the phosphine
gas, it combines with the moisture in the lungs, leading to
phosphoric acid production, which causes damage to the
lung at the alveolar-capillary interface. The phosphine's
blood levels correlate positively with the clinical grades of
toxicity, the ingested dose, and mortality. The fatal effects
of phosphine are seen when the blood levels exceed ~1
mg/dl. After acute ingestion of aluminum phosphide, mean
blood concentrations of 0.10 mg/dL, 1.07 mg/dL, and 3.73
mg/dL correlate with mild toxicity, severe toxicity with sur-
vival, and fatal toxicity, respectively. A rapid fall in blood
concentration is positively associated with survival, whereas
a progressive rise is fatal [9]. LD50 in mice following inhala-
tion is 0.68 g/m3 (~500 ppm) after ~1 hour of exposure, 1.47
3
g/m after 35 to 50 mins of exposure, and 25 ppm for cats af-
ter 2 to 4 hours daily for three days [10]. The toxin is excret-
ed via urine with minor excretion through exhaled air [9]. In
cases of occupation exposure of phosphine, a concentration
above 50 ppm causes life-threatening systemic effects, and
concentration above 400 ppm for 30 minutes or less may be
rapidly fatal [11].
Orally ingested aluminum phosphide liberates phosphine
in the stomach. The phosphine is then absorbed through the
gastric mucosa and subsequently targets the mitochondrial
respiratory mechanisms, decreasing the ATP production and
reducing the membrane potential leading to electron leak-
age, especially in cardiac myocytes and lungs [12-14]. The
toxin inhibits complex IV (cytochrome C oxidase) of the mi-
tochondrial electron transport chain, causing a shift from aer-
obic to anaerobic metabolism and lactate accumulation
[14-16]. The electron leakage leads to the formation of free
radicals inside the cell, resulting in depletion of the cellular
stores of antioxidants like glutathione, catalase and super-
oxide dismutase [17]. The increasing free radicals and deplet-
ing endogenous antioxidant levels lead to DNA damage and
cell membrane damage, finally leading to cell death [12].
The toxin’s metallic component may interact with free or in-
tracellular hemoglobin and cause methemoglobinemia and
hemolysis [12].
1.2. Clinical Features
Aluminum phosphide toxicity affects many vital organs
and results in multi-systemic toxicity features.
Anbalagan et al.
1.2.1. Cardiovascular System
Because the cardiovascular system is the most affected
organ system by phosphine-related cellular oxidative dam-
age, circulatory failure remains the core of toxidrome in se-
vere poisoning. The patients usually present with heart fail-
ure, cardiogenic shock, and cardiac arrhythmias [18]. The
cardiac electrophysiological abnormalities typically include
sinus tachycardia in the initial 3-6 hours of acute poisoning,
followed by ST-T changes and conduction disturbances in
the next 6-12 hours. Tachyarrhythmias are common and
may consist of ventricular tachycardia, ventricular fibrilla-
tion, supraventricular tachycardia, atrial fibrillation, or atrial
flutter [19, 20]. Usually, cardiac manifestations and ECG
changes are seen in the first 24 hours of acute aluminum
phosphide poisoning [21]. Echocardiography usually reveals
hypokinesia of the left ventricle and interventricular septum
and significantly reduced ejection fraction in most patients
with cardiovascular manifestations. Regional wall motion ab-
normalities may mimic changes seen in acute myocardial in-
farctions [22, 23]. Autopsy findings consist of congestion, se-
paration, or fragmentation of myocardial fibers, nonspecific
vacuolation of myocytes, focal necrosis, and neutrophil and
eosinophil infiltration [24].
The circulatory failure and hypotension after acute alu-
minum phosphide poisoning are difficult to treat, and have
various mechanisms, including arrhythmias or conduction
disturbances, reduced ejection fraction from myocardial dam-
age, peripheral vasodilatation secondary to widespread small-
-vessel injury, hypovolemia due to vomiting, and decreased
cortisol levels from direct toxic effects of phosphine on the
adrenal cortex [8, 18, 25]. Post-mortem findings usually
show congestion, hemorrhagic necrosis, or areas of fat deple-
tion in adrenal glands [24].
1.2.2. Respiratory System
The early respiratory manifestations include tachypnoea,
dyspnoea, crepitations, and rhonchi. Pulmonary edema oc-
curs commonly either due to direct cardiotoxicity or se-
condary to noncardiogenic causes. Diffuse alveolar damage
and adult respiratory distress syndrome may occur due to
phosphoric acid formed from phosphine [26]. Few cases of
obstructive airway disease have been reported among sur-
vivors [27]. Chest radiography reveals hilar and perihilar in-
filtrates similar to acute respiratory distress syndrome from
other causes. Aspiration with chemical pneumonitis may oc-
cur with a superadded bacterial infection. Central respiratory
depression or hypoventilation is rare but might complicate
respiratory failure [28]. Post-mortem findings of lungs in-
clude congestion, edema, and thickening of alveoli by hae-
molysed red blood cells and dilated capillaries.
1.2.3. Gastrointestinal System
The early symptoms of aluminum phosphide ingestion
are nausea, vomiting, retrosternal burning, epigastric discom-
fort, and diarrhea [29]. Recurrent emesis may cause hypov-
olemia, hypokalemia, or metabolic alkalosis. Upper gastroin-
testinal endoscopy examination following acute ingestion
Management of Acute Aluminum Phosphide Poisoning
usually reveals multiple corrosive lesions of the esophagus
and stomach. Esophageal strictures and tracheoesophageal
fistula may develop in patients who have survived acute toxi-
drome as late complications and can present with dysphagia
[30]. Post-mortem findings show congestion, edema, and ne-
crosis of the stomach mucosa [24].
1.2.4. Hepatobiliary System
Hepatic abnormalities usually manifest as a transient ele-
vation of serum aspartate and alanine aminotransferase lev-
els due to direct hepatotoxic injury and secondary to is-
chemic hepatitis [31]. Because acute hypoperfusion or hy-
poxia remains the principal mechanism, serum aminotrans-
ferase levels typically increase without serum bilirubin or al-
kaline phosphatase elevation. Significant ischemic injury re-
sults in a rapid rise of transaminases, usually in 25 to 250
times the upper limit of normal. The enzymes return to nor-
mal with the recovery of hemodynamic insult. Nevertheless,
few patients may develop jaundice because of direct hepato-
toxicity or hemolysis. Acute liver failure is rare but associat-
ed with fatal outcomes. Autopsy findings may reveal intrahe-
patocyte cytoplasmic vacuolization, nuclear fragmentation,
congestion of sinusoids, and sinusoidal clusters of polymor-
phonuclear leukocytes [32].
1.2.5. Central Nervous System
Characteristic neurological features of aluminum phos-
phide toxicity include headache, dizziness, altered mental
status, and limb paraesthesia or tremors [33]. The late clini-
cal features in survivors are persistent headaches and pe-
ripheral neuropathy [27]. Neuropathological findings usual-
ly consist of neuronal degeneration, the disappearance of
Nissls granules in neurons, eccentricity or degeneration of
the nucleus, and disappearance of the nucleolus. The patho-
logical changes have been attributed to interference in neuro-
nal oxidation caused by phosphine and subsequent hypoxic
damage [34].
1.2.6. Metabolic and Electrolyte Abnormalities
The dyselectrolytemia can either be from hypokalemia
(due to vomiting and catecholamine release) to hyper-
kalemia (due to acute kidney injury) and likewise, hypomag-
nesemia or hypermagnesemia [21, 35, 36]. Specific acid-
base abnormality observed in acute aluminum phosphide
toxicity is metabolic acidosis secondary to hypotension, lac-
tic acidosis, or acute kidney injury [35]. Mixed acid-base ab-
normalities such as metabolic acidosis and respiratory alkalo-
sis (due to associated hyperventilation), metabolic acidosis
and metabolic alkalosis (due to associated vomiting), or
metabolic acidosis and respiratory acidosis (due to respirato-
ry muscle fatigue or central hypoventilation) can occur.
Hypocalcemia may occur due to respiratory alkalosis and
manifests as tetany.
1.2.7. Urinary System
Renal involvement usually takes the form of acute tubu-
lar necrosis manifesting as oliguric or anuric acute kidney in-
Drug Metabolism Letters, хххх, Vol. хх, No. хх 3
jury [25, 29]. It further worsens pulmonary edema or
metabolic and electrolyte abnormalities (e.g., hyperkalemia,
hypermagnesemia, metabolic acidosis).
1.2.8. Endocrine System
Impaired glucose homeostasis secondary to adrenal dam-
age may lead to hypoglycemia [8, 37, 38]. However, hyperg-
lycemia has also been observed in patients with severe toxi-
drome with unknown mechanisms [39, 40].
1.2.9. Hematological Manifestations
Intravascular hemolysis or methemoglobinemia have
been demonstrated in acute aluminum phosphide toxicity
[41]. It is attributes to phosphine-induced alteration of the
circulatory dichroitic spectra of hemoglobin and modifica-
tion of the conformation of the prosthetic group of heme
iron, leading to the formation of Heinz bodies and oxidized
hemoglobin [42]. Methemoglobinemia is typically suspected
with an “oxygen saturation gap”, i.e., a low oxygen satura-
tion (SPO2) on pulse oximetry (and/or generalized cyanosis
poorly responsive to oxygen) in the presence of a normal or
high arterial oxygen (PaO2). Diagnosis is made by multiple
wavelength co-oximetry, blood methemoglobin levels, or by
placing a blood drop on filter paper and observing a brown
color that does not change with exposure to air.
Other uncommon manifestations include disseminated in-
travascular coagulation, pancreatitis, and rhabdomyolysis
[43].
1.3. Diagnosis
The immediate diagnosis of acute aluminum phosphide
poisoning is primarily clinical. It depends on the history of
toxin ingestion, characteristic features such as vomiting and
typical garlic odor breath, metabolic acidosis, and cardiac or
circulatory failure evident with hypotension or arrhythmias
[13]. Garlicky odor breath is specific but is difficult to appre-
ciate and frequently missed in a busy medical emergency.
Laboratory diagnosis is based on the detection of phosphine
by the use of phosphine detector tubes, silver nitrate test, or
gas chromatography. Silver nitrate test has high sensitivity
up to 100%. The test is done employing filter papers impreg-
nated with silver nitrate, which turn black when exposed to
phosphine gas in the exhaled air or gastric aspirate samples
of patients [44-47]. Gas chromatography is gold-standard
with high sensitivity and specificity and can be performed
on blood or post-mortem specimens of liver and gastric con-
tents [48-51]. Gas chromatography and phosphine detector
tubes are more specific than the silver nitrate test but are
technically challenging, expensive, and not routinely avail-
able.
Laboratory investigations are principally aimed at early
recognition of organ dysfunction, such as blood gas analysis
with lactate level, plasma glucose (preferably not capillary
blood if hypotension is present), serum electrolytes (mainly
magnesium and potassium), renal function test, liver func-
tion test, electrocardiography, chest radiography, and echo-
cardiography.
4 Drug Metabolism Letters, хххх, Vol. хх, No. хх
1.4. Prognosis
The prognosis depends on toxin-related factors, toxi-
drome at presentation, available therapeutic options, and in-
tensive care facilities. The toxin-related factors related to
poor prognosis include a low socio-economic status, rural
background, suicidal intent to poisoning, consumption of pel-
lets as compared to powder, lack of reconstitution of the poi-
son, and the dose of poison intake (with the fatal dose being
150-500 mg) [52, 53]. The toxidrome features associated
with a high risk of mortality are severe metabolic acidosis
(pH <7.2 or serum bicarbonate <15 mmol/L), the need for
mechanical ventilation, shock requiring vasopressor support
at admission, presence of dysrhythmia, a low score on the
Glasgow coma scale, high score of Acute Physiology and
Chronic Health Evaluation (APACHE)- II, acute kidney in-
jury (serum creatinine >1.0 mg/dL), hyperleukocytosis, coag-
ulopathy (raised prothrombin time), hypomagnesemia and
hyperglycemia [54, 55]. A prolonged QTc interval (>490
milliseconds) along with metabolic acidosis (bicarbonate
<18 mmol/L) has recently been found to predict mortality
[56]. Delay in the administration of gastric lavage, delay in
timely initiation of appropriate intensive care support (e.g.,
ventilator or vasopressor), and failure to maintain high nor-
mal serum magnesium levels tend to increase the mortality
risk [57, 58]. A recent prognostic tool consisting of blood
pH <7.25, Glasgow coma scale score <13, and systolic
blood pressure <90 mm Hg, called ‘PGI’ score (stands for
blood pH, Glasgow coma scale, and Impaired systolic blood
pressure), is a toxidrome-specific scoring system. It is a sim-
plified three-point clinical score, which accurately identifies
high-risk patients at in-hospital mortality, and predicts those
at low risk [59, 60].
1.5. Management
1.5.1. Emergent Care
Primary emergency medical care addressing the airway,
breathing, and circulation (ABC) was the main priority at
emergency department admission. The patients should be
placed on a cardiac monitor (including electrocardiography)
and pulse oximetry. Oxygen supplementation is recommend-
ed for low oxygen saturation, respiratory distress, or hy-
potension. After establishing peripheral or central venous
cannulation, crystalloid intravenous fluids or vasopressor
therapy are required in appropriate circumstances.
1.5.1.1. Decontamination
Gastric decontamination should ideally be done if the pa-
tient is brought to the hospital within the first one to two
hours of poison ingestion and after the airway is secured.
Many agents have long been used for gastric decontamina-
tion, such as activated charcoal, potassium permanganate
(1:10000), coconut oil or vegetable oil, and liquid paraffin.
Single-dose of 50-100 g of activated charcoal is postulated
to have strong adsorption action on phosphine. However,
studies have shown that aluminum phosphide's molecular
weight is 58 daltons that fall well below the adsorbing prop-
erty of activated charcoal. Even if some of the molecules are
Anbalagan et al.
adsorbed by the activated charcoal, it is unknown if alu-
minum atoms retain weak bonds with phosphorus [61]. Few
studies found potassium permanganate useful given the po-
tent oxidizing property, which converts phosphine to nontox-
ic phosphates [62]. However, studies have shown that oxida-
tion of phosphine is chemically challenging because of its
complex nucleophile nature. Moreover, potassium permanga-
nate being a strong oxidizing agent can cause hemolysis and
methemoglobinemia [63]. Activated charcoal or potassium
permanganate, being water-soluble, can induce more phos-
phine generation [64]. The use of vegetable oils in lavage
with coconut oil and sodium bicarbonate has shown a survi-
val benefit [57, 65]. Administration of castor oil may inhibit
phosphine liberation by cutting off the contact with gastric
mucosal moisture [66]. It may also accelerate gastric motili-
ty and help to remove the toxic compound from the gastroin-
testinal tract. Liquid paraffin has also been tried for gastric
decontamination in small case series. However, most of th-
ese decontamination agents have a heightened potential of
aspiration and require large-scale studies to establish their ef-
ficacy.
A new school of thought focuses on thermal damage
caused by aluminum phosphide poisoning [67-69]. Ways to
lessen thermal injury by adopting novel interventions such
as lavage with vegetable oils and avoiding potassium per-
manganate due to its exothermic properties both in research
and practice have been suggested to improve outcomes in
this fatal poisoning [70].
In inhalational exposures, the person should be brought
to fresh air. All clothes should be removed with washing of
skin and eyes to minimize phosphine absorption. The health--
care professionals must wear appropriate personnel protec-
tive equipment to avoid phosphine exposure. Oxygen supple-
mentation should be avoided unless the person is cyanosed
or has documented hypoxemia.
1.5.2. Intensive Supportive Care
Because no specific antidote is available, immediate
recognition of the toxidrome and initiation of high-quality
supportive care remain essential in managing acute alu-
minum phosphide poisoning. Ideally, all severe toxidrome
cases should be admitted to an intensive care unit or high de-
pendency unit.
1.5.3. Management of Circulatory Shock
Refractory hypotension is the most critical component
during toxidrome management. Initial fluid resuscitation
may require to restore intravascular volume. However,
overzealous intravenous fluids result in pulmonary edema;
the minimum amount should be administered to ensure ade-
quate perfusion with monitoring of central venous pressure
or inferior vena cava diameter (and its variation with respira-
tory phases) for the volume status [71]. Aluminum phos-
phide results in disruption in the vascular wall integrity, lead-
ing to congestion of vital organs, transudation of fluid into
the serous cavities, and inadequate response to vasopressors
and crystalloids. Hydroxyethyl starch has been used in man-
Management of Acute Aluminum Phosphide Poisoning
aging refractory hypotension since it may stay in the intra-
vascular compartment; however, a large study may be re-
quired to show its beneficial effects and ensure a safety pro-
file in view of its nephrotoxic potential [72, 73]. Vasopres-
sors should be started early in shock not responding to fluid
therapy. Norepinephrine, epinephrine and vasopressin are
the initial choices [74, 75]. Vasoactive agents with higher
affinity for beta receptors like dopamine and dobutamine are
prone to induce arrhythmias in susceptible patients, thus
need to be used with caution [75]. Because of frequent titra-
tion of vasopressors and/or the presence of arrhythmias, the
non-invasive blood pressure measurements can be highly in-
accurate; thus, intra-arterial pressure monitoring is recom-
mended.
While the benefit of steroids for refractory shock is not
established, they might be considered in aluminum phos-
phide poisoning with documented low serum cortisol levels
as adrenocortical insufficiency is described [8]. Their rou-
tine use is not recommended.
1.5.4. Management of Myocardial Dysfunction
Cardiac myocytes are highly prone to oxidative stress
and result in heart failure, typically with reduced ejection
fraction. The patients with sustained and severe myocardial
damage usually require management similar to other causes
of severe heart failure, such as using cardiac glycosides (di-
goxin) and intra-aortic balloon counterpulsation [76-78].
Concomitant presence of electrolyte disturbances like hy-
pokalemia, hypocalcemia, and hypomagnesemia should be
corrected [79]. Similarly, the management of severe
metabolic acidosis (pH <7.0) with sodium bicarbonate has
been advocated. Arrhythmias requires specific anti-arrhyth-
mic agents and correction of dyselectrolytemia [76, 79].
Commonly used anti-arrhythmic agents, such as amiodarone
or lidocaine, may worsen circulatory shock.
Many studies have demonstrated magnesium sulfate's
role in reducing aluminum phosphide-associated cardiovas-
cular mortality. The suggested mechanism of action of mag-
nesium is the stabilization of the cell membrane, thereby rais-
ing the threshold for arrhythmias. It is also postulated to pro-
duce an antioxidant effect that combats reactive free radicals
due to phosphine [80]. The effective dosage of magnesium
used differs in different studies, with most using a treatment
duration of 5-7 days [81]. The following intravenous dosing
regimens are commonly used – (1) 3 g infusion over 3
hours, followed by 6 g per 24 hours for 3-5 days; (2) 1 g
loading dose, then 1 g per hour for the next 2 hours, fol-
lowed by 1-1.5 grams every 6 hours for 5-7 days; (3) 4 g
loading dose, followed by 2 g after 1 hour and then 1 g ev-
ery 3 hours; and (4) 3 g loading dose followed by 6 g infu-
sion over 12 hours for 5-7 days. A meta-analysis of various
magnesium sulfate studies showed no mortality benefit with
normal serum and tissue magnesium levels [82]. Therefore,
its routine use is questionable as hypermagnesemia might be
present at admission. It is recommended to check serum
magnesium levels before the therapy and restrict use only in
patients with documented hypomagnesemia.
Hyperinsulinemia-euglycemia therapy or glucose-in-
sulin-potassium (GIK) infusion offers a novel leap in the
Drug Metabolism Letters, хххх, Vol. хх, No. хх 5
treatment of aluminum phosphide poisoning. The energy-de-
pleted cardiac myocytes use free fatty acids for the produc-
tion of ATP. The fatty acids can form toxic intermediates,
which in turn cause altered ion channel activity, membrane
breakdown, and apoptosis leading to dangerous arrhythmias.
Infusion of GIK infusion decreases circulating free fatty
acids and promotes the uptake of glucose into cells, thereby
restoring the membrane ion channel activity and cardiac my-
ocytes' cellular viability [83]. GIK infusion helps the injured
heart tide over the acute cardiotoxic crisis mediated by the
toxin. The role of GIK in cardiac dysfunction was first eluci-
dated in cardiac ischemia from acute coronary syndromes
[83]. Extrapolating its use to cardiotoxicity in aluminum
phosphide poisoning was first suggested by Hassanian-
Moghaddam et al. in a case series followed by a prospective
case-control study [84]. These preliminary data found an in-
crease in blood pressure, correction of metabolic acidosis,
and reduced mortality in the treatment group [84]. These
promising results were further confirmed by a randomized
controlled study from our academic center in north India.
The results showed a significant reduction in mortality, the
need for mechanical ventilation, improvement in cardiody-
namics (e.g., blood pressure) among those who received
GIK infusion over those who received conventional treat-
ment only [85]. Further large multicenter controlled studies
need the hour to establish the role of GIK infusion as a vital
cog in managing life-threatening poisoning. The recommend-
ed GIK protocol consists of: (1) Intravenous Insulin regular
as bolus dosing of 0.1-0.2 U/kg (5-10 U for an adult) fol-
lowed by 0.2- 0.5 U/kg/hour (10-25 U/hr for adults), with
the dose can be titrated up to 3 U/kg/hour (150 U/hour). (2)
Intravenous glucose is given to maintain the blood glucose
level between 150-200 mg/dL. (3) Intravenous or oral potas-
sium is supplemented to maintain serum potassium at 3.5-
4.5 meq/L [84, 85].
Extracorporeal membrane oxygenation (ECMO) can be
employed in patients with vasopressor refractory cardio-
genic shock. It provides mechanical circulatory support for
refractory cardiogenic shock for a short duration (few days)
until the acceptable myocardial function is restored [23, 86].
Veno-arterial ECMO might significantly impact the amelio-
ration of toxicity and improvement in outcomes, principally
for high-risk patients. In cases where swift recognition of se-
vere toxidrome that is unlikely to improve with conventional
therapeutic methods, decision-making on the use of ECMO
before the onset of considerable deterioration in ventricular
ejection fraction is pivotal for a good prognosis [87].
1.5.5. Management of Metabolic Acidosis
Correction of metabolic acidosis has been the proverbial
thorn in the rose in this toxidrome management, blunting the
cardiovascular responses to inotropes. Severe metabolic aci-
dosis decreases the calcium sensitivity of intracellular myo-
filament by altering calcium binding to troponin. The num-
ber of adrenoreceptors is reduced on the cell membrane by
internalizing receptors due to extra and intracellular acido-
sis. Intracellular acidosis causes cellular hyperpolarisation
by potassium extrusion and stimulates apoptosis [88].
6 Drug Metabolism Letters, хххх, Vol. хх, No. хх Anbalagan et al.

The role of systemic alkalinization in severe metabolic
acidosis and its benefit remains controversial in many criti-
cal medical conditions [89]. Sodium bicarbonate has been re-
moved from the treatment algorithm in advanced cardiac life
support. The sepsis guidelines also recommend against us-
ing bicarbonate therapy for improving hemodynamic param-
eters or reducing vasopressor requirements in patients with
lactic acidosis with pH >7.15. Despite these guidelines,
emergency physicians consider using bicarbonate therapy
for severe metabolic acidosis. In the context of acute alu-
minum phosphide poisoning, a recent study found using in-
travenous bicarbonate for the aggressive correction of acido-
sis protocol resulted in improvement in outcomes; however,
there was no significant difference in base excess or pH
among survivors and non-survivors [90]. Accordingly, be-
cause the leading cause of severe metabolic acidosis is gener-
alized tissue hypoperfusion, bicarbonate therapy is less like-
ly to correct severe acidosis in these patients [91]. Bicarbo-
nate, after reaction with proton, forms water and carbon
dioxide in the extracellular space. The carbon dioxide diffus-
es rapidly across the cell membrane and results in intracellu-
lar hypercapnic acidosis that further impairs organ function.
The rise of carbon dioxide in blood also increases hemo-
globin affinity for oxygen which causes decreased oxygen
delivery to tissues and subsequent increase of lactate levels,
even after bicarbonate therapy [88]. Additionally, bicarbo-
nate decreases ionized intracellular calcium necessary for
myocardial contractility. The development of intracellular
acidosis offsets the attractive prospect of raising extracellu-
lar pH.
There is currently no consensus regarding the routine
use of bicarbonate infusion in aluminum phosphide toxicity.
Hence, it is recommended to focus all efforts on the correc-
tion of severe hypotension by administration of hydrox-
yethyl starch solution in addition to crystalloids to overcome
symptoms of shock and restore tissue perfusion [73]. The in-
fusion of sodium bicarbonate should be primarily limited to
pH <7.0 [91, 92].
1.5.6. Other Intensive Organ Support
Ischemic acute tubular necrosis can be managed with va-
sopressors and appropriate fluid-electrolyte management. Re-
fractory acidosis or advanced azotemia may require hemo-
dialysis, but shock may worsen. Continuous renal replace-
ment therapy (CRRT) has been tried successfully with a bi-
carbonate-based solution, both as a substitute as well as
dialysate [93]. CRRT may help in maintaining the metabolic
milieu and hemodynamic parameters until the toxin is ex-
cret-

Fig. (1). Proposed management algorithm for acute aluminum phosphide toxicity. (Adr- adrenaline, ARDS- acute respiratory distress syn-
drome, BP- blood pressure, CRRT- continuous renal replacement therapy, ECG- electrocardiography, Echo- echocardiography, ECMO- ex-
tracorporeal membrane oxygenation, ED- emergency department, GIK- glucose-insulin-potassium, HES- hydroxyethyl starch, IABP- in-
tra-aortic balloon counter-pulsation, IV- intravenous, NS- normal saline, NAd- noradrenaline, RRT- renal replacement therapy, SPO2- oxy-
gen saturation).
Management of Acute Aluminum Phosphide Poisoning
ed. Few studies showed that CRRT, which employed hemo-
diafiltration with convection as the underlying principle
(continuous venovenous hemofiltration) - a diffusion-based
therapy, was superior to hemodialysis [94]. Hepatic impair-
ment due to ischemic hepatitis or drug-induced hepatitis,
mounting to acute liver failure, has been managed with N-
acetyl cysteine successfully in few cases. Hemolysis and
methemoglobinemia caused by phosphine have been success-
fully treated with intravenous vitamin C (1 g 6-hourly) and
methylene blue (1 mg/kg of 1% solution) in some reports
[63].
1.5.7. Definitive Management
There is no specific antidote that reverses the effects of
aluminum phosphide. Antioxidants like N-acetylcysteine,
sodium selenite, vitamin E, liothyronine, calcitriol and mela-
tonin have been tried as antidotes to aluminum phosphide
but with very limited success [95-100]. Intravenous lipid
emulsion (ILE) has been reported to reverse the toxic sys-
temic effect of acute aluminum phosphide self-ingestion.
ILE aims to dissolve the circulating phosphine gas that has
diffused into the systemic circulation through the gastric bar-
rier [101]. However, large studies are lacking to establish
the efficacy of this novel agent. Recent animal studies de-
monstrated an improvement in cardiodynamics in aluminum
phosphide poisoning with taurine treatment [102]. Taurine
ameliorates the detrimental effects of phosphine on the elec-
tron transport chain, mitochondrial membrane potential and
reduces oxidative stress [102]. The hunt for the ‘ideal anti-
dote’ that can reverse phosphine's toxic effects at the cellu-
lar level and promote excretion of the toxin remains elusive
mainly, and the search continues.
A proposed algorithm for management of acute alu-
minum phosphide poisoning in a medical emergency is giv-
en in Fig. (1).
CONCLUSION
Due to its easy availability, rapid and severe toxicity,
and no specific antidote, aluminum phosphide has emerged
as a lethal toxin, commonly used for suicidal intent in agri-
cultural communities of low-middle-income countries. Ther-
apeutic measures need to be implemented from all fronts –
reducing easy access to the poison, developing less toxic al-
ternatives for use as a pesticide, and more studies directed at
developing an effective reversal agent for phosphine. The ad-
vent of promising agents, like GIK infusion and ILE, are
new rays in the hope of a complete recovery in this fatal poi-
soning. Still, large multicenter controlled trials need the
hour to establish their role effectively as viable agents.
LIST OF ABBREVIATIONS
APACHE II = Acute Physiology And Chronic Health
Evaluation II
ATP = Adenosine Tri Phosphate
CRRT = Continuous Renal Replacement Therapy
DNA = Deoxyribose Nucleic Acid
ECMO = Extra-corporeal Membrane Mxygenation
Drug Metabolism Letters, хххх, Vol. хх, No. хх 7
GIK = Glucose Insulin Potassium Infusion
IABP = Intra Aortic Balloon Counterpulsation
ILE = Intravenous Lipid Emulsion
PGI score = pH of blood, Glasgow coma scale score,
Impaired systolic blood pressure
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
None.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
Declared none.
REFERENCES
[1] Mew, E.J.; Padmanathan, P.; Konradsen, F.; Eddleston, M.;
Chang, S.S.; Phillips, M.R.; Gunnell, D. The global burden of fa-
tal self-poisoning with pesticides 2006-15: Systematic review. J.
Affect. Disord., 2017, 219, 93-104.
http://dx.doi.org/10.1016/j.jad.2017.05.002 PMID: 28535450
[2] Jeyaratnam, J. Acute pesticide poisoning: A major global health
problem. World Health Stat. Q., 1990, 43(3), 139-144.
PMID: 2238694
[3] Gupta, S.K.; Peshin, S.S.; Srivastava, A.; Kaleekal, T. A study of
childhood poisoning at National Poisons Information Centre, All
India Institute of Medical Sciences, New Delhi. J. Occup. Health,
2003, 45(3), 191-196.
http://dx.doi.org/10.1539/joh.45.191 PMID: 14646297
[4] Banjaj, R.; Wasir, H.S. Epidemic aluminium phosphide poisoning
in northern India. Lancet, 1988, 1(8589), 820-821.
http://dx.doi.org/10.1016/S0140-6736(88)91676-5 PMID:
2895333
[5] Singh, D.; Dewan, I.; Pandey, A.N.; Tyagi, S. Spectrum of unnatu-
ral fatalities in the Chandigarh zone of north-west India--a 25 year
autopsy study from a tertiary care hospital. J. Clin. Forensic Med.,
2003, 10(3), 145-152.
http://dx.doi.org/10.1016/S1353-1131(03)00073-7 PMID:
15275009
[6] Sudakin, D.L. Occupational exposure to aluminium phosphide
and phosphine gas? A suspected case report and review of the liter-
ature. Hum. Exp. Toxicol., 2005, 24(1), 27-33.
http://dx.doi.org/10.1191/0960327105ht496oa PMID: 15727053
[7] Ranga, G.; Dwivedi, S.; Agarwal, M.; Kumar, D. Aluminium phos-
phide poisoning in a young adult: A suicidal cardiotoxin simulat-
ing myocardial ischaemia. J Indian Acad Clin Med., 2004, 5(4),
369.
[8] Chugh, S.N.; Ram, S.; Sharma, A.; Arora, B.B.; Saini, A.S.; Mal-
hotra, K.C. Adrenocortical involvement in aluminium phosphide
poisoning. Indian J. Med. Res., 1989, 90, 289-294.
PMID: 2620956
[9] Chugh, S.N.; Pal, R.; Singh, V.; Seth, S. Serial blood phosphine
levels in acute aluminium phosphide poisoning. J. Assoc. Physi-
cians India, 1996, 44(3), 184-185.
PMID: 9251315
[10] Mittra, S.; Peshin, S.S.; Lall, S.B. Cholinesterase inhibition by alu-
minium phosphide poisoning in rats and effects of atropine and
pralidoxime chloride. Acta Pharmacol. Sin., 2001, 22(1), 37-39.
PMID: 11730559
8 Drug Metabolism Letters, хххх, Vol. хх, No. хх
[11] Ferner, R.E. Disposition of toxic drugs and chemicals in man.
Clin. Toxicol., 2020, 1-2.
http://dx.doi.org/10.1080/15563650.2020.1843661
[12] Anand, R.; Binukumar, B.K.; Gill, K.D. Aluminum phosphide poi-
soning: An unsolved riddle. J. Appl. Toxicol., 2011, 31(6),
499-505.
http://dx.doi.org/10.1002/jat.1692 PMID: 21607993
[13] Singh, S.B.A. Aluminum phosphide poisoning. J Mahatma Gand-
hi Inst Med Sci., 2015, 2015(20), 15-19.
[14] Hsu, C.H.; Quistad, G.B.; Casida, J.E. Phosphine-induced oxida-
tive stress in Hepa 1c1c7 cells. Toxicol. Sci., 1998, 46(1),
204-210.
http://dx.doi.org/10.1093/toxsci/46.1.204 PMID: 9928684
[15] Nakakita, H.; Katsumata, Y.; Ozawa, T. The effect of phosphine
on respiration of rat liver mitochondria. J. Biochem., 1971, 69(3),
589-593.
PMID: 5551650
[16] Valmas, N.; Zuryn, S.; Ebert, P.R. Mitochondrial uncouplers act
synergistically with the fumigant phosphine to disrupt mitochon-
drial membrane potential and cause cell death. Toxicology, 2008,
252(1-3), 33-39.
http://dx.doi.org/10.1016/j.tox.2008.07.060 PMID: 18755236
[17] Sciuto, A.M.; Wong, B.J.; Martens, M.E.; Hoard-Fruchey, H.;
Perkins, M.W. Phosphine toxicity: A story of disrupted mitochon-
drial metabolism. Ann. N. Y. Acad. Sci., 2016, 1374(1), 41-51.
http://dx.doi.org/10.1111/nyas.13081 PMID: 27219283
[18] Bogle, R.G.; Theron, P.; Brooks, P.; Dargan, P.I.; Redhead, J. Alu-
minium phosphide poisoning. Emerg. Med. J., 2006, 23(1), e3.
http://dx.doi.org/10.1136/emj.2004.015941 PMID: 16373788
[19] Siwach, S.B.; Singh, H.; Jagdish; Katyal, V.K.; Bhardwaj, G. Car-
diac arrhythmias in aluminium phosphide poisoning studied by on
continuous holter and cardioscopic monitoring. J. Assoc. Physi-
cians India, 1998, 46(7), 598-601.
PMID: 12152839
[20] Katira, R.; Elhence, G.P.; Mehrotra, M.L.; Srivastava, S.S.; Mitra,
A.; Agarwala, R.; Ram, A. A study of aluminum phosphide (AlP)
poisoning with special reference to electrocardiographic changes.
J. Assoc. Physicians India, 1990, 38(7), 471-473.
PMID: 2292551
[21] Singh, R.B.; Singh, R.G.; Singh, U. Hypermagnesemia following
aluminum phosphide poisoning. Int. J. Clin. Pharmacol. Ther.
Toxicol., 1991, 29(2), 82-85.
PMID: 2026469
[22] Sahoo, D.; Kujur, S.T.; Das, D.S.; Dey, A.; Devi, S. Aluminium
Phosphide Poisoning: Early Suspicion of Cardiotoxicity Is Neces-
sary for Improved Outcomes. Cureus, 2020, 12(9), e10237.
http://dx.doi.org/10.7759/cureus.10237 PMID: 33042678
[23] Rao, C.C.; Himaaldev, G.J. STEMI in Young Befogged by Alu-
minum Phosphide Toxicity-Role of ECMO as Salvage Therapy
and Trimetazidine and Magnesium to Suppress Arrhythmias. In-
dian J. Crit. Care Med., 2020, 24(8), 727-730.
http://dx.doi.org/10.5005/jp-journals-10071-23533 PMID:
33024386
[24] Ashok, K.; Jain; Nigam, M.; Dubey, B.; Arora, A. Aluminium
phosphide poisoning.Autopsy findings; JIAFM, 2005, p. 27.
[25] Bayazit, A.K.; Noyan, A.; Anarat, A. A child with hepatic and re-
nal failure caused by aluminum phosphide. Nephron J., 2000,
86(4), 517.
http://dx.doi.org/10.1159/000045849 PMID: 11124609
[26] Chugh, S.N.; Ram, S.; Mehta, L.K.; Arora, B.B.; Malhotra, K.C.
Adult respiratory distress syndrome following aluminium phos-
phide ingestion. Report of 4 cases. J. Assoc. Physicians India,
1989, 37(4), 271-272.
PMID: 2613620
[27] Brautbar, N.; Howard, J. Phosphine toxicity: report of two cases
and review of the literature. Toxicol. Ind. Health, 2002, 18(2),
71-75.
http://dx.doi.org/10.1191/0748233702th133oa PMID: 12868795
[28] Pannu, A.K. Pulmonary Management in Aluminum Phosphide Poi-
soning. Indian J. Crit. Care Med., 2017, 21(1), 63-64.
http://dx.doi.org/10.4103/0972-5229.198334 PMID: 28197059
[29] Chugh, S.N.; Dushyant; Ram, S.; Arora, B.; Malhotra, K.C. Inci-
dence & outcome of aluminium phosphide poisoning in a hospital
Anbalagan et al.
study. Indian J. Med. Res., 1991, 94, 232-235.
PMID: 1937606
[30] Kochhar, R.; Dutta, U.; Poornachandra, K.S.; Vaiphei, K.; Bhagat,
S.; Nagi, B.; Singh, K. Clinical profile and outcome of aluminum
phosphide-induced esophageal strictures. J. Med. Toxicol., 2010,
6(3), 301-306.
http://dx.doi.org/10.1007/s13181-010-0082-x PMID: 20407857
[31] Memiş, D.; Tokatlioglu, D.; Koyuncu, O.; Hekimoglu, S. Fatal alu-
minium phosphide poisoning. Eur. J. Anaesthesiol., 2007, 24(3),
292-293.
http://dx.doi.org/10.1017/S0265021506001451 PMID: 17054805
[32] Saleki, S.; Ardalan, F.A.; Javidan-Nejad, A. Liver histopathology
of fatal phosphine poisoning. Forensic Sci. Int., 2007, 166(2-3),
190-193.
http://dx.doi.org/10.1016/j.forsciint.2006.05.033 PMID: 16806774
[33] Wilson, R.; Lovejoy, F.H.; Jaeger, R.J.; Landrigan, P.L. Acute
phosphine poisoning aboard a grain freighter. Epidemiologic, clini-
cal, and pathological findings. JAMA, 1980, 244(2), 148-150.
http://dx.doi.org/10.1001/jama.1980.03310020024020 PMID:
7382074
[34] Tripathi, S.K.; Pandey, S.K. The effect of aluminium phosphide
on the human brain: A histological study. Med. Sci. Law, 2007,
47(2), 141-146.
http://dx.doi.org/10.1258/rsmmsl.47.2.141 PMID: 17520959
[35] Proudfoot, A.T. Aluminium and zinc phosphide poisoning. Clin.
Toxicol. (Phila.), 2009, 47(2), 89-100.
http://dx.doi.org/10.1080/15563650802520675 PMID: 19280425
[36] Singh, R.B.; Saharia, R.B.; Sharma, V.K. Can aluminium phos-
phide poisoning cause hypermagnesaemia? A study of 121 pa-
tients. Magnes. Trace Elem., 1990, 9(4), 212-218.
PMID: 2095165
[37] Jamshed, N.; Ekka, M.; Aggarwal, P.; Narayan, S. Severe hypog-
lycemia as a presenting feature of aluminum phosphide poisoning.
Ann. Saudi Med., 2014, 34(2), 189.
http://dx.doi.org/10.5144/0256-4947.2014.189 PMID: 24894792
[38] Mehrpour, O.; Aghabiklooei, A.; Abdollahi, M.; Singh, S. Severe
hypoglycemia following acute aluminum phosphide (rice tablet)
poisoning; a case report and review of the literature. Acta Med.
Iran., 2012, 50(8), 568-571.
PMID: 23109032
[39] Mehrpour, O.; Alfred, S.; Shadnia, S.; Keyler, D.E.; Soltaninejad,
K.; Chalaki, N.; Sedaghat, M. Hyperglycemia in acute aluminum
phosphide poisoning as a potential prognostic factor. Hum. Exp.
Toxicol., 2008, 27(7), 591-595.
http://dx.doi.org/10.1177/0960327108096382 PMID: 18829736
[40] Sharma, A.; Balasubramanian, P.; Gill, K.D.; Bhalla, A. Prognos-
tic Significance of Blood Glucose Levels and Alterations Among
Patients with Aluminium Phosphide Poisoning. Sultan Qaboos
Univ. Med. J., 2018, 18(3), e299-e303.
http://dx.doi.org/10.18295/squmj.2018.18.03.006 PMID:
30607269
[41] Malakar, S.; Negi, B.D.; Dutt, K.; Raina, S. Intravascular Hemoly-
sis in Aluminum Phosphide Poisoning. Indian J. Crit. Care Med.,
2019, 23(2), 106-107.
http://dx.doi.org/10.5005/jp-journals-10071-23128 PMID:
31086458
[42] Potter, W.T.; Rong, S.; Griffith, J.; White, J.; Garry, V.F. Phos-
phine-mediated Heinz body formation and hemoglobin oxidation
in human erythrocytes. Toxicol. Lett., 1991, 57(1), 37-45.
http://dx.doi.org/10.1016/0378-4274(91)90117-O PMID: 2048160
[43] Verma, S.K.; Ahmad, S.; Shirazi, N.; Barthwal, S.P.; Khurana, D.;
Chugh, M.; Gambhir, H.S. Acute pancreatitis: A lesser-known
complication of aluminum phosphide poisoning. Hum. Exp. Toxi-
col., 2007, 26(12), 979-981.
http://dx.doi.org/10.1177/0960327107087793 PMID: 18375644
[44] Chugh, S.N.; Ram, S.; Chugh, K.; Malhotra, K.C. Spot diagnosis
of aluminium phosphide ingestion: An application of a simple
test. J. Assoc. Physicians India, 1989, 37(3), 219-220.
PMID: 2768165
[45] Mital, H.S.; Mehrotra, T.N.; Dwivedi, K.K.; Gera, M. A study of
aluminium phosphide poisoning with special reference to its spot
diagnosis by silver nitrate test. J. Assoc. Physicians India, 1992,
40(7), 473-474.
Management of Acute Aluminum Phosphide Poisoning
PMID: 1282918
[46] Khosla, S.N.; Nand, N.; Khosla, P. Aluminium phosphide poison-
ing. J. Trop. Med. Hyg., 1988, 91(4), 196-198.
PMID: 3404567
[47] Demange, M.; Elcabache, J.M.; Grzebyk, M.; Peltier, A.; Proust,
N.; Thénot, D.; Ducom, P.; Fritsch, J. Phosphine sampling and
analysis using silver nitrate impregnated filters. J. Environ.
Monit., 2000, 2(5), 476-482.
http://dx.doi.org/10.1039/b001990i PMID: 11254053
[48] Musshoff, F.; Preuss, J.; Lignitz, E.; Madea, B. A gas chromato-
graphic analysis of phosphine in biological material in a case of
suicide. Forensic Sci. Int., 2008, 177(2-3), e35-e38.
http://dx.doi.org/10.1016/j.forsciint.2007.12.007 PMID: 18294792
[49] Chan, L.T.; Crowley, R.J.; Delliou, D.; Geyer, R. Phosphine analy-
sis in post mortem specimens following ingestion of aluminium
phosphide. J. Anal. Toxicol., 1983, 7(4), 165-167.
http://dx.doi.org/10.1093/jat/7.4.165 PMID: 6314042
[50] Yan, H.; Xiang, P.; Zhang, S.; Shen, B.; Shen, M. Diagnosis of
aluminum phosphide poisoning using a new analytical approach:
forensic application to a lethal intoxication. Int. J. Legal Med.,
2017, 131(4), 1001-1007.
http://dx.doi.org/10.1007/s00414-017-1562-1 PMID: 28243772
[51] Mohammadinejad, A.; Rizi, K.S.; Oskuee, R.K.; Aryan, E.;
Meshkat, Z.; Ulianas, A.; Rezayi, M. Development of detection
methods for the diagnosis and analysis of highly toxic metal phos-
phides: A comprehensive and critical review. Biotechnol. Appl.
Biochem., 2021.
http://dx.doi.org/10.1002/bab.2190 PMID: 33987922
[52] Etemadi-Aleagha, A.; Akhgari, M.; Iravani, F.S. Aluminum Phos-
phide Poisoning-Related Deaths in Tehran, Iran, 2006 to 2013.
Medicine (Baltimore), 2015, 94(38), e1637.
http://dx.doi.org/10.1097/MD.0000000000001637 PMID:
26402837
[53] Sharma, A.; Dishant; Gupta, V.; Kaushik, J.S.; Mittal, K. Alu-
minum phosphide (celphos) poisoning in children: A 5-year expe-
rience in a tertiary care hospital from northern India. Indian J.
Crit. Care Med., 2014, 18(1), 33-36.
http://dx.doi.org/10.4103/0972-5229.125434 PMID: 24550611
[54] Mathai, A.; Bhanu, M.S. Acute aluminium phosphide poisoning:
Can we predict mortality? Indian J. Anaesth., 2010, 54(4),
302-307.
http://dx.doi.org/10.4103/0019-5049.68372 PMID: 20882171
[55] Louriz, M.; Dendane, T.; Abidi, K.; Madani, N.; Abouqal, R.; Zeg-
gwagh, A.A. Prognostic factors of acute aluminum phosphide poi-
soning. Indian J. Med. Sci., 2009, 63(6), 227-234.
http://dx.doi.org/10.4103/0019-5359.53386 PMID: 19602756
[56] El-Sarnagawy, G.N.; Shaban, A.E.; Lashin, H.I. Validation of Cor-
rected and Dispersed QT as Predictors of Adverse Outcomes in
Acute Cardiotoxicities. Cardiovasc. Toxicol., 2021.
http://dx.doi.org/10.1007/s12012-020-09629-8 PMID: 33400130
[57] Bajwa, S.J.; Bajwa, S.K.; Kaur, J.; Singh, K.; Panda, A. Manage-
ment of celphos poisoning with a novel intervention: A ray of
hope in the darkest of clouds. Anesth. Essays Res., 2010, 4(1),
20-24.
http://dx.doi.org/10.4103/0259-1162.69301 PMID: 25885082
[58] Chugh, S.N.; Kamar, P.; Sharma, A.; Chugh, K.; Mittal, A.; Aro-
ra, B. Magnesium status and parenteral magnesium sulphate thera-
py in acute aluminum phosphide intoxication. Magnes. Res., 1994,
7(3-4), 289-294.
PMID: 7786693
[59] Pannu, A.K.; Bhalla, A.; Sharma, A.; Sharma, N. “PGI Score”: A
Simplified Three-point Prognostic Score for Acute Aluminum
Phosphide Poisoning. Indian J. Crit. Care Med., 2020, 24(9),
790-793.
http://dx.doi.org/10.5005/jp-journals-10071-23555 PMID:
33132561
[60] Pannu, A.K.; Bhalla, A. A Simple Tool Predicts Mortality in Alu-
minum Phosphide Self-poisoning. Indian J. Crit. Care Med.,
2020, 24(9), 755-756.
http://dx.doi.org/10.5005/jp-journals-10071-23583 PMID:
33132555
[61] Marashi, S.M.; Majidi, M.; Raji Asadabadi, H.; Nasri-Nasrabadi,
Z. A common misconception in the management of aluminium
Drug Metabolism Letters, хххх, Vol. хх, No. хх 9
phosphide poisoning. Arh. Hig. Rada Toksikol., 2013, 64(3),
475-476.
http://dx.doi.org/10.2478/10004-1254-64-2013-2404 PMID:
24084356
[62] Pajoumand, A.; Jalali, N.; Abdollahi, M.; Shadnia, S. Survival Fol-
lowing Severe Aluminium Phosphide Poisoning. Journal of Phar-
macy Practice and Research., 2002, 32, 297-299.
http://dx.doi.org/10.1002/jppr2002324297
[63] Sanaei-Zadeh, H. Aluminum phosphide poisoning and develop-
ment of hemolysis and methemoglobinemia. Indian J. Crit. Care
Med., 2012, 16(4), 248-249.
http://dx.doi.org/10.4103/0972-5229.106519 PMID: 23559744
[64] Sanaei-Zadeh, H.; Marashi, S.M. Gastric decontamination in alu-
minium phosphide poisoning: A case against the use of wa-
ter-based solutions. Arh. Hig. Rada Toksikol., 2016, 67(4),
364-365.
http://dx.doi.org/10.1515/aiht-2016-67-2900 PMID: 28033095
[65] Shadnia, S.; Rahimi, M.; Pajoumand, A.; Rasouli, M.H.; Abdol-
lahi, M. Successful treatment of acute aluminium phosphide poi-
soning: possible benefit of coconut oil. Hum. Exp. Toxicol., 2005,
24(4), 215-218.
http://dx.doi.org/10.1191/0960327105ht513oa PMID: 15957538
[66] Goswami, M.; Bindal, M.; Sen, P.; Gupta, S.K.; Avasthi, R.; Ram,
B.K. Fat and oil inhibit phosphine release from aluminium phos-
phide--its clinical implication. Indian J. Exp. Biol., 1994, 32(9),
647-649.
PMID: 7814045
[67] Mirakbari, S.M. The convergence of considerations in aluminum
phosphide poisoning: The occurrence of injuries beyond the
metabolic manifestations. J. Res. Med. Sci., 2017, 22, 94.
http://dx.doi.org/10.4103/jrms.JRMS_313_17 PMID: 28900450
[68] Mirakbari, S.M. Hot charcoal vomitus in aluminum phosphide poi-
soning - A case report of internal thermal reaction in aluminum
phosphide poisoning and review of literature. Indian J. Anaesth.,
2015, 59(7), 433-436.
http://dx.doi.org/10.4103/0019-5049.160952 PMID: 26257417
[69] Mirakbari, S.M. Proposal for a new mechanism of action for alu-
minum phosphide (ALP) for causing local injuries in ALP poison-
ing: Should treatment strategies be modified? Hum. Exp. Toxicol.,
2016, 35(10), 1145-1146.
http://dx.doi.org/10.1177/0960327115619221 PMID: 26628002
[70] Senthilkumaran, S.; Ananth, C.; Menezes, R.G.; Thirumalaikolun-
dusubramanian, P. Aluminium phosphide poisoning: Need for re-
vised treatment guidelines. Indian J. Anaesth., 2015, 59(12),
831-832.
http://dx.doi.org/10.4103/0019-5049.171624 PMID: 26903686
[71] Siwach, S.; Katyal, V.; Dhall, A.; Bhardwaj, G. Prognostic indices
in aluminium phosphide poisoning: Observations on acidosis and
central venous pressure. J. Assoc. Physicians India, 1997, 45(9),
693-696.
[72] Marashi, S.M.; Nasri Nasrabadi, Z.; Jafarzadeh, M.; Mohammadi,
S. Hydroxyethyl Starch Could Save a Patient With Acute Alu-
minum Phosphide Poisoning. Acta Med. Iran., 2016, 54(7),
475-478.
PMID: 27424021
[73] Kafi, G.; Akbarpour, S.; Arefi, M.; Behnoush, B.; Ahmadi
Pishkuhi, M.; Barzegari, N. Effect of hydroxyethyl starch on acido-
sis in patients with aluminum phosphide poisoning. Caspian J. In-
tern. Med., 2019, 10(3), 271-275.
PMID: 31558987
[74] Nandkeolyar, S.; Ryu, R.; Mohammed, A.; Cordero-Caban, K.;
Abramov, D.; Tran, H.; Hauschild, C.; Stoletniy, L.; Hilliard, A.;
Sakr, A. A Review of Inotropes and Inopressors for Effective Util-
ization in Patients with Acute Decompensated Heart Failure. J.
Cardiovasc. Pharmacol., 2021.
http://dx.doi.org/10.1097/FJC.0000000000001078 PMID:
34117179
[75] Yagi, T.; Nagao, K.; Tachibana, E.; Yonemoto, N.; Sakamoto, K.;
Ueki, Y.; Imamura, H.; Miyamoto, T.; Takahashi, H.; Hanada, H.;
Chiba, N.; Tani, S.; Matsumoto, N.; Okumura, Y. Treatment With
Vasopressor Agents for Cardiovascular Shock Patients With Poor
Renal Function; Results From the Japanese Circulation Society
Cardiovascular Shock Registry. Front. Med. (Lausanne), 2021, 8,
10 Drug Metabolism Letters, хххх, Vol. хх, No. хх
648824.
http://dx.doi.org/10.3389/fmed.2021.648824 PMID: 34012971
[76] Karami-Mohajeri, S.; Jafari, A.; Abdollahi, M. Comprehensive re-
view of the mechanistic approach and related therapies to cardio-
vascular effects of aluminum phosphide. Int. J. Pharmacol., 2013,
9(8), 493-500.
http://dx.doi.org/10.3923/ijp.2013.493.500
[77] Chu, S; Sun, P; Zhang, Y; Li, J; Liu, L; Shi, Y Intra-aortic balloon
pump on in-hospital outcomes of cardiogenic shock: findings
from a nationwide registry, China. ESC Heart Fail, 2021.
[78] Changal, KH; Latief, M; Parry, M; Abbas, F Aluminium phos-
phide poisoning with severe cardiac dysfunction and the role of di-
goxin. BMJ Case Rep., 2017, 2017.
http://dx.doi.org/10.1136/bcr-2017-220125
[79] Voultsos, P.; Bazmpani, M.A.; Papanastasiou, C.A.; Papadopou-
los, C.E.; Efthimiadis, G.; Karvounis, H.; Kalogeropoulos, A.P.;
Karamitsos, T.D. Magnesium disorders and prognosis in heart fail-
ure: A systematic review. Cardiol. Rev., 2021.
http://dx.doi.org/10.1097/CRD.0000000000000397 PMID:
34001688
[80] Chugh, S.N.; Kolley, T.; Kakkar, R.; Chugh, K.; Sharma, A. A
critical evaluation of anti-peroxidant effect of intravenous magne-
sium in acute aluminium phosphide poisoning. Magnes. Res.,
1997, 10(3), 225-230.
PMID: 9483483
[81] Chugh, S.N.; Kumar, P.; Aggarwal, H.K.; Sharma, A.; Mahajan,
S.K.; Malhotra, K.C. Efficacy of magnesium sulphate in alumini-
um phosphide poisoning--comparison of two different dose sched-
ules. J. Assoc. Physicians India, 1994, 42(5), 373-375.
PMID: 7829435
[82] Siwach, S.B.; Singh, P.; Ahlawat, S. Magnesium in aluminium
phosphide poisoning--where have we erred? J. Assoc. Physicians
India, 1994, 42(3), 193-194.
PMID: 7860504
[83] Grossman, A.N.; Opie, L.H.; Beshansky, J.R.; Ingwall, J.S.; Rack-
ley, C.E.; Selker, H.P. Glucose-insulin-potassium revived: current
status in acute coronary syndromes and the energy-depleted heart.
Circulation, 2013, 127(9), 1040-1048.
http://dx.doi.org/10.1161/CIRCULATIONAHA.112.130625
PMID: 23459576
[84] Hassanian-Moghaddam, H.; Zamani, N. Therapeutic role of hy-
perinsulinemia/euglycemia in aluminum phosphide poisoning.
Medicine (Baltimore), 2016, 95(31), e4349.
http://dx.doi.org/10.1097/MD.0000000000004349 PMID:
27495040
[85] Pannu, A.K.; Bhalla, A.; Gantala, J.; Sharma, N.; Kumar, S.;
Dhibar, D.P. Glucose-insulin-potassium infusion for the treatment
of acute aluminum phosphide poisoning: An open-label pilot
study. Clin. Toxicol. (Phila.), 2020, 58(10), 1004-1009.
http://dx.doi.org/10.1080/15563650.2020.1719131 PMID:
32129101
[86] Mohan, B.; Singh, B.; Gupta, V.; Ralhan, S.; Gupta, D.; Puri, S.;
Goyal, A.; Aslam, N.; Tandon, R.; Wander, G.S. Outcome of pa-
tients supported by extracorporeal membrane oxygenation for alu-
minum phosphide poisoning: An observational study. Indian
Heart J., 2016, 68(3), 295-301.
http://dx.doi.org/10.1016/j.ihj.2016.03.024 PMID: 27316480
[87] Mohan, B.; Gupta, V.; Ralhan, S.; Gupta, D.; Puri, S.; Mahajan,
R.; Goyal, A.; Chhabra, S.; Tandon, R.; Aslam, N.; Wander, G.S.;
Singh, B. Impact of extra-corporeal membrane oxygenation on out-
come of aluminium phosphide poisoning complicated with myo-
cardial dysfunction. Clin. Toxicol. (Phila.), 2019, 57(11),
1095-1102.
http://dx.doi.org/10.1080/15563650.2019.1584297 PMID:
30856020
[88] Kimmoun, A.; Novy, E.; Auchet, T.; Ducrocq, N.; Levy, B. Hemo-
dynamic consequences of severe lactic acidosis in shock states:
from bench to bedside. Crit. Care, 2015, 19, 175.
http://dx.doi.org/10.1186/s13054-015-0896-7 PMID: 25887061
[89] Waskowski, J.; Hess, B.; Cioccari, L.; Irincheeva, I.; Pfortmueller,
C.A.; Schefold, J.C. Effects of sodium bicarbonate infusion on
mortality in medical-surgical ICU patients with metabolic acido-
DISCLAIMER: The above article has been published, as is, ahead-of-print, to provide early visibility but is not the
final version. Major publication processes like copyediting, proofing, typesetting and further review are still to be
done and may lead to changes in the final published version, if it is eventually published. All legal disclaimers that
apply to the final published article also apply to this ahead-of-print version.
View publication stats
Anbalagan et al.
sis-A single-center propensity score matched analysis. Med. Inten-
siva, 2021, S0210-5691(21)00106-6.
PMID: 34120787
[90] Jaiswal, S.; Verma, R.K.; Tewari, N. Aluminum phosphide poison-
ing: effect of correction of severe metabolic acidosis on patient
outcome. Indian J. Crit. Care Med., 2009, 13(1), 21-24.
http://dx.doi.org/10.4103/0972-5229.53111 PMID: 19881175
[91] Marashi, S.M.; Nasri-Nasrabadi, Z. Can sodium bicarbonate really
help in treating metabolic acidosis caused by aluminium phos-
phide poisoning? Arh. Hig. Rada Toksikol., 2015, 66(1), 83-84.
http://dx.doi.org/10.1515/aiht-2015-66-2637 PMID: 25816308
[92] Marashi, S.M.; Nasri-Nasrabadi, Z. Response to Professor Rum-
boldt’s reaction to our letter on hydroxyethyl starch use in manag-
ing aluminium phosphide poisoning. Arh. Hig. Rada Toksikol.,
2015, 66(3), 221-223.
http://dx.doi.org/10.1515/aiht-2015-66-2649 PMID: 26444345
[93] Nasa, P.; Gupta, A.; Mangal, K.; Nagrani, S.K.; Raina, S.; Yadav,
R. Use of continuous renal replacement therapy in acute alu-
minum phosphide poisoning: A novel therapy. Ren. Fail., 2013,
35(8), 1170-1172.
http://dx.doi.org/10.3109/0886022X.2013.815565 PMID:
23865388
[94] Prowle, J.R.; Bellomo, R. Continuous renal replacement therapy:
recent advances and future research. Nat. Rev. Nephrol., 2010,
6(9), 521-529.
http://dx.doi.org/10.1038/nrneph.2010.100 PMID: 20644583
[95] Karimani, A.; Mohammadpour, A.H.; Zirak, M.R.; Rezaee, R.;
Megarbane, B.; Tsatsakis, A.; Karimi, G. Antidotes for aluminum
phosphide poisoning - An update. Toxicol. Rep., 2018, 5,
1053-1059.
http://dx.doi.org/10.1016/j.toxrep.2018.10.009 PMID: 30406022
[96] Halvaei, Z.; Tehrani, H.; Soltaninejad, K.; Abdollahi, M.; Shad-
nia, S. Vitamin E as a novel therapy in the treatment of acute alu-
minum phosphide poisoning. Turk. J. Med. Sci., 2017, 47(3),
795-800.
http://dx.doi.org/10.3906/sag-1512-6 PMID: 28618724
[97] Goharbari, M.H.; Taghaddosinejad, F.; Arefi, M.; Sharifzadeh,
M.; Mojtahedzadeh, M.; Nikfar, S.; Baeeri, M.; Rahimifard, M.;
Abdollahi, M. Therapeutic effects of oral liothyronine on alu-
minum phosphide poisoning as an adjuvant therapy: A clinical
trial. Hum. Exp. Toxicol., 2018, 37(2), 107-117.
http://dx.doi.org/10.1177/0960327117694074 PMID: 29233028
[98] Hafez, A.A.; Samiei, S.; Salimi, A.; Jamali, Z.; Khezri, S.;
Sheikhghaderi, H. Calcitriol attenuates the cytotoxicity induced by
aluminium phosphide via inhibiting mitochondrial dysfunction
and oxidative stress in rat isolated cardiomyocytes. Pestic.
Biochem. Physiol., 2021, 176, 104883.
http://dx.doi.org/10.1016/j.pestbp.2021.104883 PMID: 34119212
[99] Asghari, M.H.; Moloudizargari, M.; Baeeri, M.; Baghaei, A.;
Rahimifard, M.; Solgi, R.; Jafari, A.; Aminjan, H.H.; Hassani, S.;
Moghadamnia, A.A.; Ostad, S.N.; Abdollahi, M. On the mech-
anisms of melatonin in protection of aluminum phosphide cardio-
toxicity. Arch. Toxicol., 2017, 91(9), 3109-3120.
http://dx.doi.org/10.1007/s00204-017-1998-6 PMID: 28551710
[100] Hosseini, S.F.; Forouzesh, M.; Maleknia, M.; Valiyari, S.; Ma-
niati, M.; Samimi, A. The Molecular Mechanism of Aluminum
Phosphide poisoning in Cardiovascular Disease: Pathophysiology
and Diagnostic Approach. Cardiovasc. Toxicol., 2020, 20(5),
454-461.
http://dx.doi.org/10.1007/s12012-020-09592-4 PMID: 32712815
[101] Baruah, U.; Sahni, A.; Sachdeva, H.C. Successful management of
aluminium phosphide poisoning using intravenous lipid emulsion:
Report of two cases. Indian J. Crit. Care Med., 2015, 19(12),
735-738.
http://dx.doi.org/10.4103/0972-5229.171412 PMID: 26816450
[102] Samadi, M.; Baeeri, M.; Haghi-Aminjan, H.; Rahimifard, M.; Gho-
lami, M.; Hassani, S.; Sattari, M.; Azarmi, Y.; Bameri, B.; Arman-
deh, M.; Hooshangi Shayesteh, M.R.; Eghbal, M.A.; Abdollahi,
M. On the mechanisms of taurine in alleviating electrocardiograph-
ic, hemodynamic, and biochemical parameters following alu-
minum phosphide cardiotoxicity. Food Chem. Toxicol., 2021, 154,
112347.
http://dx.doi.org/10.1016/j.fct.2021.112347 PMID: 34139304