Death Adder Envenoming Causes Neurotoxicity Not Reversed by Antivenom - Australian Snakebite Project (ASP-16)

Background Death adders (Acanthophis spp) are found in Australia, Papua New Guinea and parts of eastern Indonesia. This study aimed to investigate the clinical syndrome of death adder envenoming and response to antivenom treatment. Methodology/Principal Findings Definite death adder bites were recruited from the Australian Snakebite Project (ASP) as defined by expert identification or detection of death adder venom in blood. Clinical effects and laboratory results were collected prospectively, including the time course of neurotoxicity and response to treatment. Enzyme immunoassay was used to measure venom concentrations. Twenty nine patients had definite death adder bites; median age 45 yr (5–74 yr); 25 were male. Envenoming occurred in 14 patients. Two further patients had allergic reactions without envenoming, both snake handlers with previous death adder bites. Of 14 envenomed patients, 12 developed neurotoxicity characterised by ptosis (12), diplopia (9), bulbar weakness (7), intercostal muscle weakness (2) and limb weakness (2). Intubation and mechanical ventilation were required for two patients for 17 and 83 hours. The median time to onset of neurotoxicity was 4 hours (0.5–15.5 hr). One patient bitten by a northern death adder developed myotoxicity and one patient only developed systemic symptoms without neurotoxicity. No patient developed venom induced consumption coagulopathy. Antivenom was administered to 13 patients, all receiving one vial initially. The median time for resolution of neurotoxicity post-antivenom was 21 hours (5–168). The median peak venom concentration in 13 envenomed patients with blood samples was 22 ng/mL (4.4–245 ng/mL). In eight patients where post-antivenom bloods were available, no venom was detected after one vial of antivenom. Conclusions/Significance Death adder envenoming is characterised by neurotoxicity, which is mild in most cases. One vial of death adder antivenom was sufficient to bind all circulating venom. The persistent neurological effects despite antivenom, suggests that neurotoxicity is not reversed by antivenom.

1. Standard care 2. Additional research bloods whenever routine bloods are taken 3. Antivenom use as indicated, e.g. for neurotoxicity

No Yes
1. Repeat research blood just prior to antivenom 2. Give appropriate antivenom according to local snake species or venom detection kit (VDK) results. We recommend two vials as the maximum dose of brown snake antivenom. 4. At 3 hours post-antivenom take research blood tubes only 5. At 6 hours and 12 hours post-antivenom and then every 12 hours until discharge repeat routine bloods (including COAGS) + take research blood tubes. Please call us on one of the phone numbers below just prior to discharge so that we can make appropriate follow-up arrangements with the patient.

Guidelines for the management of anaphylaxis to antivenom (i) Preparation prior to commencing antivenom.
a. We do not recommend routine premedication with antihistamines or steroids b. Dedicate one small bore (18-20 G in adults) IV line to antivenom administration and one large bore IV line (16-14 G in adults) for emergency resuscitation.
c. Prepare 1L Normal Saline (20 ml/kg in children) ready to give under pressure.
e. Prepare an i.v. infusion of adrenaline 1mg in 100 mL (controlled by infusion pump or syringe driver) ready to attach by a side arm to the resuscitation line. Anti-reflux valves must be attached above the side arm on any other infusions using this i.v., to prevent adrenaline going back up into the other fluid bags. To prevent erroneous administration, do not attach the adrenaline infusion unless it is needed.
f. Record blood pressures on the other side to the fluid/adrenaline infusion, to avoid pronged cuff inflations and thus extravasation of infusion fluids.

(ii) Management of a reaction (In addition to study procedures -see ASP Datasheet 4)
a. Most reactions are related to the rate of antivenom infusion, and cause flushing, hypotension and bronchospasm. Some mild reactions resolve with temporary cessation of the antivenom infusion and recommencing it at a slower rate.
b. Envenomed patients may be severely coagulopathic, so it is important to be cautious when giving adrenaline to avoid blood pressure surges, which might lead to intracerebral haemorrhage.
c. Initial management of severe reactions (sudden hypotension, bronchospasm): i. Suspend the antivenom infusion. ii.
Lie the patient flat (if not already), commence high flow/100% oxygen and support airway/ventilation as required.
iv. Adrenaline i.m. into the lateral thigh, 0.01 mg/kg to maximum of 0.3 mg (alternatively, those experienced with i.v. adrenaline infusions may proceed directly to this, as below).
v. Liaise with toxicology service regarding ongoing management.
d. For reactions that do not respond to initial management: i. If hypotensive, repeat Normal Saline bolus as above (up to 50 mL/kg may be required).
ii. Commence i.v. infusion of adrenaline (0.5-1 mL/kg/hour, of 1 mg in 100 mL) and titrate according to response; monitor BP every 3-5 minutes (using the arm opposite to the infusion); beware that as the reaction resolves adrenaline requirements will fall, the blood pressure will rise and the infusion rate will need to be reduced.
iii. Consider nebulised salbutamol for bronchospasm, nebulised adrenaline for upper airway obstruction, and i.v. atropine for severe bradycardia. iv.
Seek advice urgently from the local/regional ED

Background and Aims of the Study
Spider and snake bites are not uncommon in Australia and antivenoms exists for the treatment of many of these bites. However, despite this, there are still many questions about the effects of different venoms and about the exact amount of antivenom that is required for treatment.
This study will measure the venom levels in blood after a sting or bite by a venomous animal (snake or spider). This aims to help us determine whether venom levels are important in predicting the severity of certain envenomations, and whether they correlate with the effects of the bite or sting. The study will also be able to determine how long the human body takes to excrete the toxins ie. how long the effects of the envenomation will take to wear off. Finally the study will look at the effects that treatment with antivenom has on venom levels to help establish the correct amount of antivenom to use.

Your Involvement
If you agree to take part in this study you will be required to give a number of extra blood samples while you are in hospital to measure the venom and antivenom levels in your blood. This will require the insertion of an intravenous cannula into a vein in your hand or arm at the start of the study. This will then be used to take a number of samples of blood throughout the course of the study to minimise the discomfort.
Depending on how long you need to remain in hospital, up to 4 samples of blood will be taken each day. In the majority of cases the blood will be taken at the same time as you would have blood collected for the treatment of the sting or bite.
The only risk to being involved in the study is the additional need for an intravenous cannula. This will be inserted by experienced health care staff. There are minimal risks from venepuncture, but they include a small risk of bruising at the site and the small chance of an infection developing from the presence of the cannula. The standard precautions of using a sterile technique to collect blood and insert the cannula will significantly reduce the risk of this and will be adhered during the study.

Participation in the Study
Participation in the study is completely voluntary and you will suffer no disadvantage if you elect to not be involved in the study and will continue to receive optimal ongoing care. You may withdraw from the study at any time.
If you do participate in the study you will receive exactly the same treatment as if you were not involved in the study. The only difference will be the collection of extra blood samples.

Use of the data collected
The information collected from this study will be stored in a de-identified fashion. You can be assured that all records dealing with your participation in this study will be kept under safe storage for 15 years after completion. Authorised persons within the institution may also inspect records for purposes of data audit only. Individual participants in the study will not be identifiable in any reports of the data from the protocol or any publications resulting from the research.

Australian Snakebite Project (ASP)
I, …………………………………………….. have been asked to participate in the above study under the direction of Dr Geoff Isbister. I understand that while the study will be under his supervision, other professional persons may assist or act on his behalf.
I have been given clear verbal information about this study and have read the attached 'Information Sheet'. I understand the general purposes and methods of the study and have been given time to consider whether I want to take part.
I have been told that there is no additional risk to being involved in this study, as the only requirement is that more blood be taken when bloods are normally taken as part of the routine care for snakebite. I have been able to ask questions and all questions have been answered satisfactorily.
I know that I do not have to take part in the study and that I can withdraw or be withdrawn by the doctor in charge at any time during the study and continue to receive appropriate treatment. My participation in the study does not affect any right to compensation, which I may have under statute or common law. I agree to the publishing of results of this study, provided my name or other identifying information is not used. I agree to be contacted by phone for follow up once I am discharged.
I consent to additional blood samples being taken and donate those specimens for the purpose of this study. In making my donation of blood, I understand and agree that the blood, and all its constituents, will be used only in relation to the above clinical research purpose. The blood, and all its constituents, may be stored to enable future testing in relation to this research project and related future research. No other researchers have access to blood samples. I hereby voluntarily consent and offer to take part in this study. ……………………………..……………… (patient name) to participate in the above study under the direction of Dr Geoff Isbister. I understand that while the study will be under his supervision, other professional persons may assist or act on his behalf.

I have been given clear verbal information about this study and have read the attached 'Information
Sheet'. I understand the general purposes and methods of the study and have been given time to consider whether I want the above person to take part. I have been told that there is no additional risk from the patient being involved in this study, as the only requirement is that more blood be taken when bloods are normally taken as part of the routine care for snakebite. I have been able to ask questions and all questions have been answered satisfactorily.
I know that the study is voluntary and that the patient can withdraw or be withdrawn by the doctor in charge at any time during the study without affecting his/her future medical care. I agree to publishing of results of this study provided the patient's name or other identifying information is not used. I agree for the patient to be contacted by phone for follow up once I am discharged.
I consent to additional blood samples being taken from the patient. I understand and agree that the blood, and all its constituents, will be used only in relation to the above clinical research purpose. The blood, and all its constituents, may be stored to enable future testing in relation to this research and related future research. No other researchers have access to blood samples.