Critical Care & Pulmonology, OP Poisoning Dr Samir Sahu Senior Consultant, Critical Care & Pulmonology, Apollo Hospitals

Case 60 yr F found unconscious on 30.10.2012 morning & rushed to MKCG MCH On examination frothing, gastric lavage done - suspected as a case of poisoning Husband sent home to look for container & found 9 tabs of Alprax & anti termite bottle missing(Chlorpyrifos). Given 1 dose of PAM & Atropine & sent to Apollo Hospital pre-empting ventilation

On arrival GCS 4, HR 115, BP 80/50, RR 16, SpO2 91%RA, T 99. pH 7.38, PCO2 40, HCO3 23.7, Lac 1.8 Intubated in emergency, Vasopressors & Atropine started, PAM 1 g IV 4 hrly advised. In ICU after 2 hrs pupils fully dilated, ventilated. CXR revealed pneumonia rt base.

Flumazenil given on 31.10.2012 & patient became conscious Off vasopressors & Extubated on 1.11.12. Shifted to ward on 4.11.2012 9.11.2012(D 11) – not feeling well since morning, dysarthria, difficulty in swallowing. 2.26 pm – pH 7.429, PCO2 40.6 10.45 pm - pH 7.384, PCO2 50.5 Became unconscious & hypoxic; intubated & ventilated, patient became conscious

11.11.2012 – pH 7.241, PCO2 65.2, HCO3 23.5. Extubated & reintubated 3 times 14.11.12 - Serum Cholinesterase – 0.11 (3.9-10.1) Ultimately extubated on 16.11.2012.

Organophosphorus insecticide poisoning. Senanayake N. Ceylon Med J Organophosphorus insecticide poisoning. Senanayake N. Ceylon Med J. 1998 Mar;43(1):22-9. Organophosphorus insecticides (OPI) are the commonest cause of poisoning in Sri Lanka. Being inhibitors of esterases, OPI cause an acute cholinergic crisis as the initial phase of neurotoxicity. The intermediate syndrome (IMS) which develops 24 to 96 hours after poisoning, The delayed polyneuropathy (OPIDP) which manifests several weeks later, A triphasic effect of OP intoxication. OPI may also cause extrapyramidal manifestations.

Cholinergic Symptoms S – Salivation L - Lacrimation U - Urination D - Diarrhoea G - Gastrointestinal Distress E - Emesis Miosis Bradycardia

Nicotinic Symptoms Hypertension Tachycardia Pupillary Dilatation Sweating Muscle Weakness Paralysis Fasciculations

CNS Symptoms Restlessness Confusion Coma Respiratory Failure

Atropine Infusion Targets HR around 80/min Pupil – normal size Control of secretions from tracheo-bronchial tree

Oximes OP bearing two methoxy groups (malathion, paraoxon-methyl, dimethoate) is considered to be rather resistant to oxime therapy. Enzyme reactivation being absent as long as the concentrations of ethyl and methyl parathion remained >30 ug/mL Other factors apart from poison load are likely to play a role

Oximes The reactivation potentials of butyryl cholinesterase (the difference between oxime reactivated and unreactivated enzyme activity) declined significantly with time after OP poisoning. The reactivation potential of the enzyme at admission decreased significantly with increasing severity of poisoning.

Oximes Aging and reactivation kinetics of the individual OP agent would play an important role in determining time-effects. Once AChE is “aged,” regeneration is not possible. Aging and regeneration of the AChE occur concomitantly, with the portion of the aged enzyme being dependent on the presence of excess inhibitor (in this instance the OP compound).

Oximes The half-lives of aging of dimethyl and diethyl phosphorylated AChE, as determined in isolated human red cells in vitro, are 3.7 and 33 hrs, respectively. Thus, the potential therapeutic window for the administration of the antidote, taken as four times the half-life, works out to a maximum of 15 hrs for the dimethyl phosphoryl group and 132 hrs in the diethyl phosphoryl group.

Oximes It is believed that 1 day after intoxication with a dimethyl phosphoryl insecticide, virtually all AChE will be in the aged form so that oxime therapy will be useless by that time It is possible that the time of administration, toxin load, pharmacodynamics (aging, POXs), and toxicity of the oximes contributed to the observed tendency for harm in humans.

Evaluation of two treatment regimens of pralidoxime (1 gm single bolus dose vs 12 gm infusion) in the management of organophosphorus poisoning. Johnson S, J Assoc Physicians India. 1996 44(8):529-31. P2AM 12 gm as a continuous infusion over the next 4 days. High dose P2AM infusion has no role in the routine management of patients with OP poisoning. Subgroup analysis of patients who received at least 1 gm of P2AM within 12 hours of ingestion of the OP poison with those who received P2AM after 12 hours, showed that there was a significant reduction of intermediate syndrome (p = 0.05) but no significant difference was noted in number ventilated.

Oximes Initial studies in 1990’s noted that low-dose infusions of pralidoxime might cause harm. Two RCTs in CMC Vellore, India by Johnson S et al. J Assoc Physicians India 1996; 44: 529–31 Cherian AM et al. J Assoc Physicians India 1997; 45: 22–24).

Oximes But the absence of clinical benefit could relate to trial design (suboptimum dose, or bias in allocation). Alternatively, this result could suggest that pralidoxime is ineffective in the patients seen at this hospital, perhaps because of the specific pesticide ingested, the amount ingested, or the patients’ long delay before pralidoxime is given.

We, at the Christian Medical College, Vellore, India (a tertiary care university teaching hospital), stopped using oximes for the treatment of acute poisoning with organophosphorus pesticides from 1999 following the results of studies reported in literature. Our data in the “no oxime era” (1999–2005) for patients admitted in the adult medical intensive care unit are as shown. George John

CMC Vellore Year Total Patient % of OP Adm Mortality 1999 758 111(14.6%) 15(13.5%) 2000 787 118(15%) 17(14.4%) 2001 790 112(14.2%) 19(17%) 2002 759 99(13%) 14(14.1%) 2003 735 102(13.9%) 15(14.7%) 2004 697 101(14.5%) 14(13.9%) 2005 702 82(11.7%) 12(14.6%) Crit Care Med 2006; 34: 2265, Table on p 2267

WHO recommendations Dose recommendations of 30 mg/kg bolus of pralidoxime followed by infusions of 8 mg/kg/hr. WHO recommends (although not revised since 2000) that oximes be given to all symptomatic patients who need atropine. (Johnson MK et al. Emerg Med 2000; 12: 22–37, WHO International Programme on Chemical Safety. Poisons information monograph G001. Organophosphorus pesticides. Geneva: World Health Organization, 1999).

A Cochrane review (Buckley NA et al A Cochrane review (Buckley NA et al. Cochrane Database Syst Rev 2005; 1: CD005085) reported no clear evidence of benefit or harm. Two other meta-analyses had concluded that oximes are harmful. Peter JV et al. Crit Care Med 2006; 34: 502–10, Rahimi R et al. Hum Exp Toxicol 2006; 25:157–62

Increased morbidity and mortality in acute human organophosphate-poisoned patients treated by oximes: a meta-analysis of clinical trials. Rahimi R, Hum Exp Toxicol. 2006 Mar;25(3):157-62. It can be concluded that oximes are not effective in the management of organophosphate-poisoned patients and, surprisingly, they can be dangerous and worsen the patient's clinical situation.

Oxime therapy and outcomes in human organophosphate poisoning: an evaluation using meta-analytic techniques. Peter JV, Crit Care Med. 2006 Feb;34(2):502-10.  Based on the current available data on human organophosphate poisoning, oxime was associated with either a null effect or possible harm. The lack of current prospective randomized controlled trials, with appropriate patient stratification, mandates ongoing assessment of the role of oximes in organophosphate poisoning.

Continuous pralidoxime infusion versus repeated bolus injection to treat organophosphorus pesticide poisoning: a randomised controlled trial. Pawar KS, Lancet. 2006;368:2136-2141. A high-dose regimen of pralidoxime, consisting of a constant infusion of 1 g/h for 48 h after a 2 g loading dose, reduces morbidity and mortality in moderately severe cases of acute organophosphorus-pesticide poisoning. Then 1 g every 4 hours till recovery.

A randomized controlled trial in Baramati, India by (Pawar KS et al A randomized controlled trial in Baramati, India by (Pawar KS et al. Lancet 2006; 368: 2136–41) studied the effect of very-high-dose pralidoxime iodide (2 g loading dose, then 1 g either every hour or every 4 h for 48 h, then 1 g every 4 h until recovery) in 200 patients with moderate organophosphorus poisoning (excluding severely ill patients). The high-dose regimen was associated with reduced case fatality, fewer cases of pneumonia and reduced time on mechanical ventilation.  This study suggests that large doses of pralidoxime could have benefit if patients are treated early and have good supportive care. Further studies are needed to establish whether this benefit remains for severe poisoning.

Observational studies of pralidoxime and obidoxime suggest that the ability to reverse acetylcholinesterase inhibition with oximes varies with the pesticide ingested. The clinical effects can also be limited by high concentrations of organophosphorus in the blood after ingestion of a large dose—the pesticide simply re-inhibits any acetylcholinesterase that the oximes reactivate. Oximes will also not be effective for improvement of outcomes if the patient develops severe complications such as aspiration pneumonia or hypoxic brain injury before treatment.

Intermediate syndrome First described in the mid-1980s Occurs in approximately 20% of patients It usually becomes established 2-4 days after exposure when the symptoms and signs of the acute cholinergic syndrome (e.g. muscle fasciculations, muscarinic signs) are no longer obvious.

Intermediate syndrome The characteristic features of the IMS are weakness of the muscles of respiration (diaphragm, intercostal muscles and accessory muscles including neck muscles) and of proximal limb muscles. Accompanying features often include weakness of muscles innervated by some cranial nerves. It is now emerging that the degree and extent of muscle weakness may vary following the onset of the IMS.

Intermediate syndrome Some patients may only have weakness of neck muscles whilst others may have weakness of neck muscles and proximal limb muscles. These patients may not require ventilatory care but close observation and monitoring of respiratory function is mandatory. Delays in instituting ventilatory care will result in death

Prolonged mechanical ventilation The duration of ventilatory care required by patients may differ considerably and it is usual for patients to need ventilatory support for 7-15 days and even up to 21 days The mean value of mechanical ventilation days was 16 +/- 6 days for the PMV group, which was significantly greater than 1 +/- 1 days for the non PMV group (p < 0.01). Recovery from the intermediate syndrome is normally complete and without any sequelae

Extrapyramidal syndrome Among the 633 patients ever admitted to our hospital with organophosphate poisoning, three patients were found exhibiting impermanent neuromuscular dysfunction, including blepharoclonus, oculogyric crisis, intermittent dystonia, rigidity, and tremor, with two of them developing mask face, dyskinesia and akathisia later, following acute cholinergic crisis. The symptoms appeared within 4 days with the duration ranging from 25 days to 2 months.

Extrapyramidal syndrome Extrapyramidal symptoms occurred between 5 and 15 d Characterized by dystonia of arms and legs, resting tremor, cogwheel rigidity, and hypereflexia. An extrapyramidal syndrome appeared suddenly nine days after the onset with ocular and buccal crisis, neck and trunk dystonic movements, and hypertonia and tremors.

DOPE: Delayed-onset encephalopathy and coma in acute organophosphate poisoning in humans Peter JV, Delayed-onset coma appears to have a distinct clinical profile and course with complete resolution of symptoms with supportive therapy. Although persistent cholinesterase inhibition is likely to have contributed to the manifestations, the mechanism of coma and encephalopathy need to be explored in further trials. The good outcomes in these patients suggest that therapy should not be limited in OP-poisoned patients developing profound coma or encephalopathy during hospitalization.

Dr KS Anand I/C - Intensive Respiratory Care Unit, Madurai Intermediate syndrome or Type II Paresis is commonly seen with 3  Notorious agents – 1. Monocrytophos 2. Dimethioate  (Roger) 3. Chlorpyrifos. We have seen IMS even on day 7th or 9th with classical proximal muscle weakness and seen patients collapsing & dropping down who were strong enough just few hours earlier ! We have stopped using P2AM from Feb 1998 onwards and Results are No Inferior ! in terms of Mortality / Morbidity and Number of Vent days ..... better oximes with BBB Penetration aren't available with us.

Levels of Serum Cholinesterase are always Non-specific & misleading Levels of Serum Cholinesterase are always Non-specific & misleading ! ..Patient with 400 IU/L may be walking but another Patient with 4000 IU/L may be requiring Ventilatory support ! ....Go for True Cholinesterase estimation !...We have discharged Patients with Count of 200 IU/L too !!!! Early extubation is always harmful for the patient .....2nd or 3rd day extubation is never recommended.......Extubate only once the Atropine is tappered off gradually. We have seen cases of OP Poisoning who develop both IMS and Delayed Onset Polyneuropathy  ! and they take 3 - 4 weeks to recover !....avoiding VAP and other lethal Non-ambulatory complications  is a challenge in these cases !

Delayed onset Poly Neuropathy when occurs - patients lands up in deep coma ! ..appears Vegetative....not even able to flicker his eye lids ! If Intubation  and Mechanical vent support was genuinely  indicated for OPC then never go for early extubation unless The Atropine is gradually tapered off. Always ask for the Container !! On most of the occasions - the patient is referred as OPC but sometimes it turns out to be -Organo-Carbamate !! where Oximes are not indicated ! It becomes pathetic when you realize that the poison consumed is Pyrethrin, Herbicide or Fungicide !!

Our Case Frothing at BHM No Brady, miosis – Pneumonia/Benzo Benzodiazepine poisoning reversed with Flumazenil Cholinesterase – OP poisoning confirmed PAM - ? Dose & cost IMS on day 11 Needed Ventilation for 5 days

Learning Points Bradycardia may not be present if others predominate(Pneumonia, Hypotension) PAM doses – rethinking & further studies needed Intermediate Syndrome may last for few days Cholinesterase only used for diagnosis & not treatment.

KHL Data: 1999-2010 OP poisoning – 44 ventilated out of 139 Extrapyramidal Symptoms - 1 Mortality - nil