If you have suffered anaphylaxis
and want to talk about your experience, or if you have questions about anaphylaxis
, head for the Anaphylaxis Event forum
I had intended to summarise many articles I'd read about anaphylaxis for my site. I was well in the process of completing my summary, when I stumbled on the following article, which I found to be all encompassing and much, much better that anything else I had read on the topic. Importantly, It opens a debate which I did not know existed (I'm won't reveal what the debate is yet, just read read on, it's well worth it!)
So, reluctantly, I threw my own summary I'd slaved on for a couple of hours in the wastebasket and decided to include the whole article, with some minor edits.
This post is an edited version from Asthma and Allergy Information Research. Click on the link if you wish to see the unedited version. The opinions expressed below reflect the opinions of the original author and not necessarily the opinions of the webmaster. Always take the guidance of your doctor, in spite of what you read on the internet.
What is anaphylaxis?
Anaphylaxis is the word used for serious and rapid allergic reactions usually involving more than one part of the body which, if severe enough, can kill.
The word anaphylaxis was coined when scientists tried to protect dogs against a poison by immunising them with small doses. Far from being protected, the dogs died suddenly when they got the poison again. The word used for protection by immunisation is ‘prophylaxis', so the scientists coined the word ‘anaphylaxis' to mean the opposite of protection. What the scientists saw in the dogs helped them to understand that the same can happen in humans.
Scientists now use the word ‘anaphylaxis' to mean any immune reaction of this type, even if it is not serious. But most doctors use it to mean a life-threatening rapid allergic reaction.
Unfortunately this kind of ‘harmful immunisation' happens to a few of us not just from injections but from ordinary foods such as nuts. Quite literally, “one man's meat is another man's poison”. Our immune system, which is there to protect us from infection, goes wrong and harms or even kills us.
Injections of many kinds occasionally cause anaphylaxis. Penicillin, injected clot-busting drugs used after heart attacks, and a host of other kinds of injection can occasionally do to human beings what the experiments did to dogs.
What happens in the body during anaphylaxis
Anaphylaxis happens when the body makes the ‘wrong' kinds of antibody to protein in our food or to something like a drug. The ‘wrong' kind of antibody is called immunoglobulin E or IgE for short. IgE sticks to mast cells and basophils in our bodies. When the same protein or drug reaches the IgE on the cells, these substances are released, causing blood vessels to relax, which makes them leaky and can cause swellings and a fall in blood pressure. At the same time they can make the breathing passages become narrow.
Histamine is one of these substances released from the cells. Antihistamines are medicines which stop histamine from working. So you might think that they would be good for nut allergy, and so they can be when the reaction is mild. But as tablets, they take about an hour to get into the bloodstream properly, and this is far too slow to save lives in serious reactions.
Antihistamines also don't prevent all the effects of histamine, for example effects of histamine on the heart, in serious reactions.
More importantly, histamine is not the only dangerous substance released during anaphylaxis. Antihistamines do not protect you against these other substances. This is another reason why antihistamines used alone will not save life in some really serious attacks of anaphylaxis.
Fortunately, adrenaline (epinephrine), the standard treatment for life-threatening anaphylaxis, works against all the most dangerous aspects of anaphylaxis, not just those caused by histamine.
What are the common causes of anaphylaxis?
- Foods: especially nuts, some kinds of fruit, fish and less commonly spices
- Drugs: Especially penicillins, anaesthetic drugs, some intravenous infusion liquids, and things injected during x-rays. Aspirin and other painkillers (called NSAIDs) can produce very similar reactions.
- Latex: mainly in rubber latex gloves, catheters, other medical products, but also in many things encountered in daily life. Sufferers are nearly always health care workers, mainly nurses, or have other occupational contact with latex. They may get anaphylaxis from bananas, avocados, kiwi fruit, figs, or other fruits and vegetables including even potatoes and tomatoes.
- Bee or wasp (yellow jacket) stings when these cause faintness, difficulty in breathing, or rash or swelling of a part of the body which has not been stung. If you just get a very large swelling of the part of your body which was stung, you are probably not going to have anaphylaxis if stung again.
- Unknown: A substantial proportion of sufferers have no cause found despite all efforts, even in the most expert clinics. Doctors call such unexplained attacks ‘idiopathic anaphylaxis' The word ‘idiopathic' in practice means we don't know the cause. Worrying as it is, death from this is very rare indeed. However, there must be a cause or causes. Some cases are bound to be simple failure to find a cause. The explanation is NOT psychological in the vast majority. So in most cases this is a disease for which medical science has not yet discovered the cause.
- Exercise may precipitate such reactions in some (‘exercise-induced anaphylaxis'), and so may exercise after food, sometimes apparently irrespective of what the food is, but in other people after specific foods. This is called ‘exercise-induced food-dependent anaphylaxis'.
- Medicines called beta blockers used for heart disease or high blood pressure can change mild reactions from another cause into severe anaphylaxis because they block the body's main defence against anaphylaxis.
- Wrong diagnosis of anaphylaxis: a proportion (about 10%) of people sent to specialists with a diagnosis of anaphylaxis have a mistaken diagnosis and have not had anaphylaxis. If this might be true in your case, it is well worth finding this out as you may be spared unnecessary fear and wrong treatment.
How can you tell if someone is having anaphylaxis?
Anaphylaxis usually happens quickly. Anaphylaxis can produce:
- An itchy nettlerash (urticaria, hives)
- Faintness and unconsciousness due to very low blood pressure. Unlike an ordinary fainting attack, this does not improve so dramatically on lying down.
- Swelling (angioedema)
- Swelling in the throat, causing difficulty in swallowing or breathing
- Asthma symptoms
- Cramping tummy pains
- A tingling feeling in the lips or mouth if the cause was a food such as nuts
- Death due to obstruction to breathing or extreme low blood pressure (anaphylactic shock)
Faintness with a nettle rash or swelling coming on quickly is probably anaphylaxis. Ff there is also difficulty in breathing, the danger is greater. Faintness with difficulty in breathing alone will sometimes be due to a panic attack, but can also be due to anaphylaxis.
In the early stages it may be difficult, even for a doctor, to be sure whether the cause of symptoms is anaphylaxis or fainting or a panic attack. If there is doubt, it is sometimes best to use the treatment for anaphylaxis, but the treatment should then be reviewed with a doctor because unnecessary treatment for anaphylaxis is a bad idea. Learn the rules for knowing when to treat, to minimise the chance that you will use the treatment when you should not.
Fainting and Anaphylaxis: clues which may help you tell the difference
(this guide is not perfect; you need a doctor if in doubt.)
Can remain low lying down
Normal when lying down
Other features which may be present
Tummy pain or diarrhoea
The person has probably fainted before.(Some people do faint, others don't.)
People who are allergic to foods often notice the effect in seconds, and their life may be in jeopardy within a few minutes. Sometimes, a reaction takes much longer to start, an hour or so, but can still be extremely serious. Improvement can also happen quickly, especially with the right treatment. A few people then have a second wave of anaphylaxis, so people who have had a serious anaphylactic reaction should be observed medically for about six hours or overnight.
Fortunately there is a highly effective treatment: adrenaline (epinephrine). But adrenaline (epinephrine) needs to be given as an injection, and is dangerous if used incorrectly. If you need to have adrenaline (epinephrine) available for yourself or someone in your family, it is important that you and anyone else who may have to give the adrenaline (epinephrine) should be properly trained.
It is possible for anaphylaxis to be mild and to need little or no treatment. You would not think so from most of the information you read. Of course a life-threatening attack of anaphylaxis may look mild in its early stages, so you need to go for medical help just in case, and need to have the emergency treatment immediately available in case things start to go more badly wrong. In most cases it is better to err on the side of treating anaphylaxis early rather than to leave treatment rather late. But the fact is that many people get over anaphylaxis even without treatment.
The fact that previous anaphylaxis has been mild does not guarantee that it will not be dangerous in future. Most sufferers with mild attacks do seem to have relatively mild ones if they occur again. But deaths have occurred in people who had only mild attacks before. The answer is to be prepared.
What is the best treatment for anaphylaxis?
There is one drug which will work against all the effects of all the dangerous substances released in anaphylaxis. It is adrenaline (epinephrine). For serious attacks, it is a vital treatment. You need to inject it; inhalers may no longer be an option.
All these devices with adrenaline (epinephrine) are only reliable if you follow the instructions. They can be dangerous if used the wrong way. If you need them it is important that someone teaches you how to use them properly. If you cannot get such teaching (and you should be able to), then make sure you read the instructions with great care.
Adrenaline (epinephrine) cannot help you if you do not have it with you.
Keep the adrenaline (epinephrine) in a clearly marked robust pouch or case so that it is easy to keep with you. Protect it from light and from high temperatures. In hot climates, keep the container out of direct sunlight and overheated locations such as parked cars. For example in a bag of beach things you can keep it wrapped in several layers of clothing, while it is still rapidly retrievable by tying one end of a cord to the container and the other end to the handle of the beach bag.
How long will the epinephrine (adrenaline) keep?
Not forever. Make sure that you check the expiry date on the syringe and make sure that you have a replacement by the time this date comes. It really can lose a lot of its effectiveness if you let it go out of date.
Some manufacturers will let you know when the time comes to replace the kit. But you have to fill in a coupon and send it to them when you get your kit. Otherwise they obviously can't give you this service.
Be sure to follow the storage instructions. The Epipen must not be kept in a refrigerator, and no epinephrine injection device must be allowed to freeze (replace if this happens accidentally, e.g. in a car left in freezing conditions long enough).
Often the adrenaline (epinephrine) solution goes yellow or brown when it is becoming useless, but you can't rely on this. It can also become useless without changing colour. So do take care to follow the manufacturer's storage instructions.
Carrying the injection kit around: special containers
Special pouches for injection kits and inhalers are available from the Allergypack website.
What is adrenaline (epinephrine)?
Adrenaline (epinephrine) is a quick-acting hormone. Our body produces it from two glands sitting just above each kidney. Adrenaline (epinephrine) production happens naturally in the body when we meet an emergency; the adrenaline (epinephrine) makes our heart pump faster, widens the air passages in the lungs, and tightens up our blood vessels. We get the well-known feeling of alertness and the feeling of a rapid heartbeat and tremor which comes from suddenly being in an emergency. Not only does adrenaline (epinephrine) ready the body and the mind for ‘fight or flight', but adrenaline (epinephrine) also works against all the effects of anaphylaxis.
So adrenaline (epinephrine) is the body's own natural quick-acting hormone for emergencies. When we inject it from a syringe, we can give more than the body can produce quickly.
This means you get more benefit, but also more side-effects and some dangers. In most people adrenaline (epinephrine) is very safe if you use the right dose in the right way, but it is important to understand what you are being asked to use.
When should I inject adrenaline (epinephrine)?
Some specialists say you should inject adrenaline (epinephrine) for any reaction. We don't agree.
Our recommendation is the 3D Rule
- Definite reaction: evidence of a reaction should be obvious.
- Deterioration: the aim is to inject BEFORE life is in immediate danger. If the reaction is improving by the time you get the adrenaline (epinephrine), just keep the adrenaline (epinephrine) handy for six hours in case it gets worse again.
- Death seems any sort of possibility if the deterioration continues another 5 to 10 minutes.
Only two things cause death: the '2D' RULE
- Difficult breathing whether due to swelling in the throat or to asthma. If it really seems to be just asthma, an asthma inhaler may work. But adrenaline (epinephrine) will help in both asthma and throat swelling.
- Deteriorating consciousness: once the child or adult patient is unconscious, life is in danger, if only from inhaling vomit, quite likely in a food allergy reaction. Make sure you know the ‘recovery position' known to every competent first-aider. But give adrenaline (epinephrine) to prevent unconsciousness if that seems increasingly possible.
Finally, the '1D' RULE
- Do give adrenaline (epinephrine) if in doubt! If you think there may be any risk to life because of difficulty in breathing or because it seems possible the patient is beginning to feel faint or ‘pass out', then the earlier you give the adrenaline (epinephrine), the better it will work.
Do I need to use more than one injection of adrenaline (epinephrine)?
Sometimes, in really bad anaphylaxis, someone may need more than one adrenaline (epinephrine) injection, but nearly always one injection is enough to save life. Too many injections of adrenaline (epinephrine) can definitely be dangerous. For example a young man who gave himself five injections probably died from the injections and not from the anaphylaxis. So your doctor's advice is vital; you may be able to stand more or less adrenaline (epinephrine) than the next patient, and your doctor can give you advice which is right for you.
Some doctors recommend carrying more than one injection dose, and others do not. Some of the injection kits can give more than one dose, but the spring-loaded automatic injectors can only give one dose.
The dose of adrenaline (epinephrine) in the injection kits is usually 0.3 mg for an adult, which is rather low for a really dangerous reaction in a full-sized adult. The reason for this is safety. We know that this dose works in the vast majority of people, but that a few people would get bad side effects from a higher dose. So we recommend this smallish dose because it is the safest overall. But your doctor may be able to give advice more appropriate for you. Hospital doctors would often give 0.5 mg, nearly twice as much. Some would give 1.0 mg, but our opinion is that this is an uncomfortably large dose even for most young adults to give all at once unless the situation is much more desperate than it usually is.
We recommend that the decision on whether you need one or two injection kits is one for which you need your doctor's advice.
How long will an adrenaline (epinephrine) injection carry on working after I have injected it?
Many doctors say that the adrenaline (epinephrine) will wear off in 15 to 20 minutes. This would often mean you might not get to a hospital in time, e.g. if you reacted whilst on holiday. The published evidence suggests that adrenaline (epinephrine) injected under the skin (subcutaneously) works for much longer than this, perhaps longer than the 150 minutes for which one set of research workers carried on measuring adrenaline (epinephrine) in the blood of their volunteers. Our feeling is that the same would be true for injections in to the muscle at the side of the thigh (intramuscular).
The bottom line is that single doses from the widely used injectors have an excellent record for patient survival. So in practice one injection does seem to do the job and enable people to get any extra help they need under nearly all circumstances.
But if you are in a remote area, you should carry more than one dose.
What are the side effects of adrenaline (epinephrine)?
In the doses we recommend, trembling, palpitations (feeling your heart beating fast), and a feeling of tension or anxiousness. These are normal effects of the adrenaline (epinephrine) and soon wear off. Higher doses cause an extremely unpleasant feeling and may be dangerous to the heart.
If you have high blood pressure, or an abnormal heart rhythm, or narrowing of the coronary arteries, or if you are treated for depression with an unusual medicine called a monoamine oxidase inhibitor, special caution is needed with adrenaline (epinephrine), and a specialist should advise you.
Injecting adrenaline (epinephrine) in the wrong place can be dangerous. People have accidentally injected adrenaline (epinephrine) into their thumb when trying to figure out how the syringe worked or when trying to check why it did not work (probably because they did not apply it to the skin at right angles, jamming the mechanism). This is dangerous. Adrenaline (epinephrine) can shut off the whole blood supply by constricting the blood vessels at the base of the finger or thumb. The result is likely to be gangrene.
Injecting other places can be dangerous too. Inject adrenaline (epinephrine) into the muscle of the side of the thigh, nowhere else, unless you are a doctor and know exactly what you are doing.
Is adrenaline (epinephrine) being prescribed far more often than necessary?
Deaths of young children from anaphylaxis are very rare. Yet huge numbers of children now go around with adrenaline (epinephrine) injection kits. All medical treatments have side effects and dangers. Although adrenaline (epinephrine) injections given correctly are remarkably safe, they may be more dangerous than the disease if the risk to life from the disease is small enough.
A group of paediatricians in the UK suspects that the dangers of adrenaline do indeed outweigh the benefits. They are planning to find out how many children with food allergies under the age of 16 years actually die or nearly die from anaphylaxis per year. Their aim is to find better rules for deciding whether a child's life is in danger, so that far fewer children with allergies will need adrenaline kits.
If such research succeeds, vast numbers of parents would be able to heave a sigh of relief. Their families and their children's teachers and carers would be spared unnecessary fear and the burden of keeping and using adrenaline.
It is amazing but true that we don't have even remotely reliable figures for the number of deaths and near-deaths from food allergy. This is because of the way death certificates are filled in and turned into statistics, and to some extent because of the low importance given to allergy in the training of doctors. Without this knowledge we can't tell parents how the risk without treatment balances up against the risk of treatment. Widespread prescription of adrenaline is recent and we don't know the risks as well as we would like. What we are doing now is the best we can manage with inadequate information. Better information offers a definite hope of better treatment, which, according to the research group, could mean much less treatment.
Why do we prescribe adrenaline (epinephrine) for so many children ?
A few years ago it was a real rarity for a child in the UK to have adrenaline (epinephrine) to use for anaphylaxis. Now hundreds of children in Leicestershire alone have adrenaline (epinephrine), and the same is true in other parts of the UK and world-wide. Almost every school in Leicestershire now has at least one child with adrenaline (epinephrine) for food allergy, and most schools have more than one.
In Leicestershire there seem to have been three children who have died from nut allergy in the last five years, and we found out about each these through newspaper reports or by chance. So there may well have been other deaths we do not know about.
Parents with nut-allergic children tell me that they would happily see tens or hundreds of thousands of children given adrenaline (epinephrine) to save one child's life. So even just taking our local experience, it looks as if we are doing what parents want.
Since we know that national statistics on deaths from food allergy are very unreliable, they may be a big underestimate, so the risk may be greater than we know.
People who have died from nut allergy have often not had particularly life-threatening reactions before. This means that we have to regard almost all nut allergy as life-threatening. We knowingly prescribe adrenaline (epinephrine) for children in whom we are perfectly aware that the risk is very low. We say so to their parents. We prescribe adrenaline because this is what parents in general want and on balance it is what we feel we would want for our own children if we faced the same problem.
Not infrequently we find ourselves under pressure from a parent to prescribe adrenaline when we feel that the risk really is far too low to justify that; these discussions are difficult because of the great uncertainties.
Personally, I regard the prescribing of an adrenaline kit as an evil, but the lesser of two evils in an inadequately understood situation. If there were a safe way of prescribing less, I would welcome that with great relief.
What are the disadvantages of adrenaline (epinephrine)?
Having to keep adrenaline kits at home, at school and when out and about is a serious nuisance. Having to remember to take it wherever you go is another burden on your life.
The fact that you have been told you need the adrenaline is a constant reminder of the risk of death. If that risk is in fact vanishingly small (for example much smaller than the risks from accidents, infections, or drug abuse), then the very fact that you have the adrenaline may harm you and your family by imposing another stress on your life on top of the others which you may face.
The cost of repeated and duplicated prescriptions and the time of your specialist and family doctor and nurses at clinics and at school is not trivial. These funds could otherwise be spent on other health care.
For all these reasons we should not take the view that we may as well prescribe adrenaline just because ‘at least it can't do any harm'. It can and it does.
But if the risk of not having adrenaline is bigger than the risk from having it then we should offer adrenaline. We should then not be swayed by prejudice against the treatment, perhaps based on the fact that ‘we never did it before' (when there was not so much nut allergy) or on under-reporting of the dangers of nut allergy because the medical statistics are unreliable.
What are the flaws in the argument that adrenaline is prescribed far more often than necessary?
There seem to be flaws in the argument and research plan as we have seen it in print. This may be because the authors were asked to be brief.
The job of doctors and experts is to establish the facts as well as possible, to explain these clearly, to make recommendations where we feel that known facts justify these, but to make final decisions after letting parents tell us what their priorities are. The reason for this is that such decisions are never a question of fact alone, but necessarily involve value judgements. Experts may be no better than lay people when it comes to these. Parents and patients have a right to have their views taken into account.
The authors seem overconfident that we can count the number of deaths from anaphylaxis accurately. Our information is that Death Certificate information is not accurate for this, and that not all deaths will become known to paediatricians. Over-busy paediatricians may not be as reliable at reporting incidents as the researchers hope. Standards of expertise and practice vary so much that treatment is an inadequate indicator of severity.
Most important of all is this question. How many children is it worth issuing with adrenaline kits to save the life of one child? I have debated this with groups of parents of nut-allergic children. Always they have come up with figures which astonish me, typically in the region of 100,000 children issued with kits to save one life.
Of course these parents would change their minds if it became clear that the risk of death from adrenaline was greater than the risk of death from the allergy. But this argument is likely to be difficult, because both figures should be very low.
People will reject the argument that deaths are unimportant because they are few if safe and acceptable measures can prevent them. Society provides other examples of public insistence on safety measures which seem hard to justify on quantitative grounds.
When it comes to judging the psychological disadvantages of having adrenaline around, doctors really cannot make the decision without serious discussion with parents, and even with the children.
The arguments against adrenaline kits are serious ones, which need to be explored and debated. My feeling is that we will become more restrictive about adrenaline prescription as we learn more.
The most important reason why there is an argument is that we do not know as much as we need to know. Research to establish the facts is necessary.
Doctors must recognise the value judgements involved, and the right of parents in making those value judgements. As in the case of other difficult medical decisions, this will not be simple because both doctors and parents vary in their personal qualities and judgements. There will always remain instances of disagreement. But exercising humanity and good sense does not mean that a doctor must always give way to a parent.
Debate fuelled by careful research is necessary and healthy.
Other treatments for anaphylaxis
Remember that this or any web page cannot give reliable individual advice. Your own expert medical adviser will be able to give you better individual advice. You may however find the page useful for discussion.
Before adrenaline (epinephrine). (But do not delay adrenaline / epinephrine).
- Lie the patient down if there is faintness or low blood pressure, or unconsciousness But if there is swelling in the throat with difficulty in breathing and there is not a serious problem with faintness, it is better to sit the patient up to avoid making the throat swelling worse. What if you have faintess and throat swelling? Decide which is most life-threatening. Get help quickly.
- Ensure the patient does not choke or inhale vomit. Vomiting is especially likely if food allergy was the cause of anaphylaxis. Put the patient in the recovery position'. If you don't know what that is, ask a doctor or nurse, or a well-trained first-aider.
After giving adrenaline (epinephrine), OR some of the following may be appropriate if adrenaline (epinephrine) is clearly unnecessary but you are nevertheless concerned.
- Get prompt medical help. In Britain, the ideal is often a paramedic ambulance to rush the patient to the nearest hospital which has an Accident and Emergency Department.
- Antihistamine tablets or syrups are helpful for really mild anaphylaxis but unlikely to save someone's life in serious anaphylaxis. Firstly, they get into the bloodstream too slowly. Secondly they don't protect against all the things which happen in anaphylaxis.
- Antihistamine injection: probably helps, but there is no need to carry one about; carry adrenaline (epinephrine) instead.
- Steroid injection: Usually given by doctors for severe anaphylaxis treated in the surgery or in hospital. Probably makes no difference to saving life, but may prevent other symptoms once the emergency is over. They take four to eight hours to start doing anything noticeable.
- Intravenous fluids: regularly used in hospital for treating the low blood pressure and bad circulation in anaphylaxis, and very important as part of the treatment.
- Oxygen may be given by ambulance crew or doctors.
- There are other treatments which doctors know about. There is no substitute for prompt medical care, preferably in an Accident and Emergency Department (Casualty, Emergency Room) or Children's emergency department. Often, of course, the nearest family doctor will be the only doctor you can get quickly enough.
- Six to twelve hours observation in hospital. A small proportion of people who have anaphylaxis will have a second attack after the first one has passed. These second or ‘late' reactions can on occasion be dangerous. Just how often such reactions happen is controversial, but experts on anaphylaxis recommend that the patient should be kept under observation overnight or for at least six hours. It is surely sufficient to spend this time in a waiting area where the patient will never be left unobserved; provided the patient is reasonably well there is no need to occupy an expensive hospital bed for this.
When the immediate emergency is over
Sometimes it is not certain that the patient had anaphylaxis. There may be other explanations if the features were not typical. There are at least two useful tests which can be done during the hours after the emergency. One is to take a clotted blood sample (the doctor will know what this means) and test for sormething called ‘mast cell tryptase'. The other is to collect urine for a few hours (the exact timing is not always regarded as all that important, but emptying the bladder immediately after the reaction and then collecting for 2 or 4 hours is fine) and test this to measure something called ‘methylhistamine' (this is what histamine turns into when your body inactivates it).
Referral to a specialist is necessary if the cause of your anaphylaxis is not known and you have not seen a specialist. Whether or not the cause is known, a specialist will be able to help you to guard against future attacks.
Some medicines can make anaphylaxis worse: Beta blockers
Beta blockers are medicines used to treat high blood pressure, some heart rhythm problems, and some other conditions. Unfortunately they can make asthma worse, even when they are only used in the form of eye drops for an eye problem called glaucoma (increased pressure in the eye).
Anaphylaxis can also be made worse by beta blockers, and beta blockers will make treatment with drugs like adrenaline (epinephrine) less effective. In fact some patients who have only urticaria or angioedema (angiedema, angioneurotic edema) when off beta blockers will collapse with a drop in blood pressure when they are on beta blockers. So beta blockers can turn bearable skin reactions into dangerous reactions with shock.