Friday, 13 April 2007

Ways to Improve Treatment in Emergencies

There have been a few cases I would briefly like to discuss where I consider the use of evidence based medicine and protocol guidance could have made a difference.

A young male was seen with an influenzal illness and then wheezing. The patient had a back ground of severe asthma having been previously ventilated. It would appear that this patient continued to smoke cigarettes and took aminophylline and inhaled therapy, although at the time of admission, the inhaler therapy was unknown.

The patient had severe-life threatening asthma-- he could not speak, respiratory rate was 25, pulse 120 although BP was high rather than low. The patient was using accessory muscles and had severe diffuse wheeze.

ABG- revealed a respiratory acidosis and hypoxaemia, and it was decided to intubate and ventilate the patient under propofol sedation.

The problem began a few days earlier when he was seen at a clinic and where he was given iv steroids and sent home. The next day he went to another hospital and was given aminophylline and steroids and discharged after just 24 hours. He worsened at his home which precipitated his admission to a different hospital.

Firstly, the only safe way to discharge patient is to know that their Peak Flow measurements are stable and not less than 25% of the normal predicted value for the patient's age and sex. If Peak Flow is not measured, the doctor has no formal means of assessing the severity of asthma and whether it is getting better or worse. Asthma patients can only be switched to inhalers once Peak Flow is stable and they still need to be hospitalised for at least another 24 hours and be stable on inhaler therapy before allowed to go home. Moreover, patients usually need several days of steroid therapy orally to reduce bronchial oedema associated with asthma and this cannot be cured by a 'one-off' shot of methylprednisolone.

Secondly, he was quite rightly intubated and ventilated, but when the patient was seen by a senior doctor, although the ABG had significantly improved, the patient was poorly sedated, respiratory rate was higher at 32/min, pulse was 150 (sinus tachycardia) and the patient had severe wheeze, on the left more than the right.

Clearly the therapy needed maximisation and this was a case of severe-life threatening asthma as a result of a viral infection and smoking.

The advice obtained, based on evidence and guidance from UpToDate 15.1 and British Thoracic Guidelines was to:

  • Add beta-stimulant
  • Provide a high dose of steroid using a traditional steroid for asthma treatment such as methylprednisolone or hydrocortisone; not betamethasone that had been given.
  • Magnesium sulphate therapy (used to stabilise histamine containing cells)
  • Paralyze and formal mechanical ventilation (with a general anaesthetic) as this would reduce the work of breathing, and GA can have a bronchodilator effect e.g. isofluorane. I have also seen this effected with high dose propofol under mechanical ventilation.
In the UK, where intravenous salbutamol is available, I would advocate its use in this severe form of asthma and in addition, the use of nebulised atrovent with salbutamol (beta-stimulant) which together have a better effect on control of asthma than beta-stimulant alone. As I understand it, and cannot quite fathom why, ipratropium (atrovent) is not available in nebulised form in Japan, when this is a life-saving and relatively innocuous therapy useful in asthma and COPD.

I have talked of asthma before on this blog, but I have found that its management in Japan is not in keeping with other international guidance and there needs to be standardisation for provision of effective evidence based therapy.

Peak Flow measurement is extremely important and this patient could have possibly avoided this episode if he had been keep in the previous hospital on appropriate therapies and under close observation.

If you wish to know more, please check the British Thoracic Guidelines for asthma plus UpToDate 15.1.

Another problem I have encountered is the wrongful belief that it is correct not to treat atrial fibrillation and by treating the underlying cause it will somehow spontaneously resolve itself.

This kind of advice is NOT consistent with international therapy for AF.

Arrhythmias are not a normal occurrence and AF amongst other rhythm disturbances, can precipitate coronary ischaemia and make heart failure or underlying ischaemia far worse. Moreover, the longer that AF is left untreated, the more difficult it becomes to cardiovert the patient. Elderly patients who are affected by AF the most, may have other underlying diseases and a drop in perfusion due to fast AF can cause compromise to other organs.

Hence, it is important to treat AF promptly and not leave it to somehow get better by itself.

Dehydration in itself, is not an established cause of AF.

Patients should also receive some form of anticoagulation, unless contraindicated, to reduce the risk of stroke events which are approximately 2% per year but higher in cases where there is underlying mitral stenosis.

Fast AF with low BP should be treated by DC Cardioversion but if normotensive, it can be slowed with effective drugs such as Amiodarone, beta-blockers or Ca channel blockers or Class 1c drugs such as flecainide or propafenone acutely.

If there is heart failure and if it is not safe to give beta-blockers or calcium channel blockers e.g. with a low ejection fraction, then amiodarone or digoxin can be given.

Flecainide cannot be given if there is underlying ischaemic heart disease as it can be made worse by this drug and hence, is probably inadvisable in most instances as one of the commonest causes of chronic AF is ischaemic heart disease.

Flecainide and propafenone should not be given chronically as ironically they increase the risk of death from dysrrhythmias.

Even mild to moderate AF should be treated to slow the rate to less than 100 as the ventricles have more time to fill and hence, the ejection fraction and cardiac output can improve.

Of course, trying to establish the underlying cause of AF and treating that may help the AF to resolve e.g. thyroxicosis, sepsis, AMI, but rate-slowing therapy should NOT BE WITHHELD unless somehow contra-indicated.

I appreciate that this may be the view of some cardiologists to take the 'wait and see approach', but this is not consistent with international guidance.

Hence, in Japan, although the diagnosis can readily be established, the emergency treatment still needs to be effectively provided and based on current evidence and through step-by-step protocols that any level of doctor can follow.

Senior doctors need to maintain their knowledge base through paper reviews and using the most up-to-date of medical texts, as these days, therapeutics are rapidly changing and hence, so should the medical practices in Japan.

Teaching the junior doctors the right way through evidence based medicine is the only way to improve acute and continuing therapy and having seniors available who know how to effectively treat the patient by putting this knowledge into practise and guiding their junior physicians.

I reiterate again, that it is best to carry a PDA where quick access to electronic books can be effected such that stardardised medical therapy can be provided at the bed side with confidence that the junior doctor is doing the job correctly.

Wednesday, 11 April 2007

Fluid Balance, Drugs and Heart Failure

I have recently heard of some cases of worsening heart failure that have resulted from the underlying disease of heart failure but also due to under treatment with diuretics and over administration of fluid.

For example, a young female admitted to another hospital with acute oliguric renal failure from sepsis was being provided over 2.5 litres per day in IV fluid and she was unable to be extubated due to acute heart failure, bilateral effusions and type 1 respiratory failure.

She required daily haemofiltration to remove the excessive fluid but this was still insufficient to treat the problem.
It was clear that fluid balance needed to be controlled. In a usual healthy patient, daily 'insensible losses' e.g. fluid loss from breathing, sweating and loss in faeces is approximately 500ml in a stable condition. This will increase in pathological conditions e.g. fever, hot conditions, diarrhoea etc.

In the absence of urine production such as in acut
e oliguric renal failure, in order to attain the status quo, fluid input should match fluid output through considering insensible losses once euvolaemic. This may be quite difficult to acieve especially when intravenous drugs need to be given plus nutrition. However, it is of importance to help control acute heart failure and hypertension which are obvious problems.

Furosemide was also given by the attending physician in this setting but proved ineffective in stimulating urine output and this is in keeping with the observations that Furosemide is not associated with any significant clinical benefit in the pre
vention and treatment of acute renal failure in adults and with high doses being associated with ototoxicity. BMJ 2006;333:420-3.

After taking advice, the attending physician in reducing the fluid input and continuing daily haemofiltration, the acute heart failure with effusions reduced so that the patient could come off the ventilator.

An example at the other end of the spectrum, was in an elderly patient at another hospital with heart failure who had presented with 'asthma'. She had a history of heart failure and had been treated for asthma with steroids for one month but she developed recent worsening respiratory function which suggested that the cause was perhaps 'cardiac asthma' from her underlying heart failure.

She was using BIPAP and the Xray showed a mixture of CHF and infection. MRSA had been identifie
d in 3 out of six blood cultures. One concern was she was also receiving over 1 litre of intravenous fluid per day and daily furosemide dose was just 20mg/day with only an additional furosemide dose if the urine output decreased below 100ml/hour.

This is not standard treatment for heart failure as you either diurese a patient to reduce fluid or if dehydrated, given judicious fluids to maintain kidney function, but not both at the same time otherwise there will never be an accurate and continued fluid loss.

This is a bit like filling a container from the top but opening the tap from below and hoping to keep the fluid level the same. In other words, the heart failure will not be effectively treated.

When a patient is fluid overloaded with a background of cardiac failure, such patients need fluid restriction to approximately 500ml orally (see insensible losses above) per day to ensure that they go into a NEGATIVE fluid balance through diuresis, that we commonly refer to as 'drying out the patient'.

Patients should be weighed daily to ensure sustained weight loss and a general rule is to lose approximately 1kg per day in excess fluid unless renal dysfunction occurs in which case a slower diuresis can be effected.

Patients should also have no added salt in their diet. If IV fluids are to be given, they should not contain sodium, and hence, dextrose should be provided.
ACE inhibitor or ARB therapy should started and Spironolactone considered (to treat secondary hyperaldosteronism) if the patient has excess oedema and the CHF does not respond to the ACE-I/ARB alone.

Moreover, it is somewhat dangerous to have ACE-I/ARB plus Spironolactone used together as it may cause worsening renal dysfunction and HYPERKALAEMIA especially in the elderly who tend to suffer with heart failure the most. However, close monitoring of renal function should be instituted. Spironolactone reduces mortality from CHF so its use should be considered.

Patients commonly need intravenous furosemide at much higher doses than 20mg/day, and I am used to giving at least 40 to 160mg of furosemide per day to patients on a case-by-case basis to establish a controlled cardiac state. As oral bioavailability of furosemide is only about 50% and that this may be reduced further from gastric oedema in heart failure, it is always preferable to give intravenous furosemide in advanced heart failure.

A very good question was 'What about the patient having low blood pressure'.

Well, if one considers why the patient has low blood pressure, the answer can be simply made.
In heart failure with systolic compromise (rather than the diastolic compromise), the more the ventricle is over stretched, the less the muscle can contract (Starling Effect) and hence blood pressure may decrease despite rises in heart rate and central venous pressure. As there is a high output of aldosterone and catecholamines, a low blood pressure in the absence of another cause, suggests poor cardiac function.

Renal failure in CHF is contributed from the vasoconstrictive effect, and hence by reducing the ventricular filling and improving the ejection fraction in theory, the vasoconstrictive effect should be reduced leading to better renal perfusion and better diuresis.

In advanced heart failure, injection of furosemide causes a greater release of renin and plasma norepinephrine resulting in vasoconstriction but with an acute initial drop in ventricular function and rising filling pressures. However, blood pressure increases. This is an acute effect of furosemide injection seen in the first hour. Ann Intern Med 1985 Jul;103(1):1-6

In such cases of low blood pressure, counter-intuitively, furosemide causing diuresis, can aid in raising the blood pressure.
However, furosemide can also cause venodilatation, similar to the venous morphine-effect, and can drop the blood pressure further especially if blood pressure is dependent on heart rate and raised central venous pressure when there is poor ventricular function, and so using it alone may be problematic especially when it is not known which are the greater contributors to maintaining the blood pressure.

It is likely that there is an interplay between venodilatation, vasconstriction (from secondary hyperaldosteronism), diuresis and reduction in circulatory volume thereby reducing pre-load and after-load with the use of furosemide.

However, if patients have severe cardiac failure and low blood pressure (shock) they essentially have cardiogenic shock, and ionotropes can be used to support such patients in the short term such as Noradrenaline, Dobutamine or High Dose Dopamine.

It should be mentioned at this juncture that despite the beneficial blood pressure elevating effects of inotropes, they have not been shown to improve survival.

CPAP is also a good short term measure of aiding heart failure and improving oxygenation, BUT if patients have low blood pressure, such non-invasive ventilation can worsen BP control and hence such therapy may be relatively contra-indicated.

Providing renal dose dopamine to ensure continued renal perfusion is of
unproven benefit (Lancet 2000; 356: 2139-43) and the general opinion based on current evidence is not to use renal-dose dopamine in renal failure (UpToDate 15.1: Use of vasopressors and inotropes; Intensive Care Med 1996 Mar;22(3):213-9)

Hence, in this patient, the suggestion was to reduce daily fluid administration and to increase the daily amount of furosemide with the consideration to curtail unproven therapies such as renal-dose dopamine.

Monday, 9 April 2007

The Pain Relief Pyramid

In my career so far, I have noticed that patients on occasion have their pain relief poorly managed by junior physicians.

Patients in the UK and Japan all experience pain of some sort, depending upon their underlying condition. However, the expression of the pain can be different.

I have noticed that when patients complain of pain, the pain relief provided may sometimes be inadequate either because the pain is simply not appreciated by the doctor, the patient expresses their pain and their treatment wishes poorly and the doctor's knowledge and experience in treating pain may be limited.

In order to treat pain effectively, it must be understood what is actually causing the pain.

Is the pain organic or functional? Is it inflammatory (Sharp)? Is it bone pain (deep and aching)? Is it cardiac pain (central chest, severe and heavy)? Is the pain muscular? Is the pain like a lightning bolt? Does it come on at night and feel like burning and associated with 'pins and needles' (neuropathic)? Is the pain the result of a problem elsewhere (radiating pain)?

For example, inflammatory pains such as pleuritis and tenosynovitis are effectively treated with acetaminophen and NSAIDs.

However, ischaemic chest pain from an acute myocardial infarction is not going to be treated effectively from these mild analgesic agents and morphine is required in this setting.

I recently was teaching residents that pain relief must be given to patients suffering from an acute myocardial infarction rather than just calling the cardiologists and hoping the pain will just go away as the patient leaves the ER department (and out of your sight and responsibility) as they go to the catheter lab for PTCA and stenting ! When I mentioned using morphine or diamorphine, the residents looked astounded and said that this was only used in terminal disease. Well, the UK guidance for treating AMI is pain relief with morphine/diamorphine and from my experience, it is extremely effective and calms patients down as well, in an otherwise very painful and stressful situation.

Pain from cancer is again effectively treated with opioid or opiate therapy but some pains are also helped in combination with acetaminophen and / or NSAIDs and even neuropathic pain therapies (detailed later). Radiotherapy and bisphosphate use in bone pain conditions can also be very useful.

There are less strong opiate therapies such as codeine phosphate, which is an effective analgesic agent used in situations when acetaminophen and / or NSAIDs are still providing ineffective to suppress pain. However, they can cause constipation so are generally given with lactulose / senna or magnesium hydroxide.

In the UK, we generally use an analgesic pyramid for treating pain such that pain can be effectively treated. Hence, in severe pain of any type we use oral morphine or even intravenous diamorphine, unless contra-indicated, and not just for terminal cancer patients.

For example, a patient with pericarditis may have a sharp-type pain. Acetaminophen should be given first and if ineffective, a non-steroidal drug (NSAID) can be added or substituted. If however, the pain gets worse despite treatment, an opioid such as codeine phosphate can be added to the above regimen.

Another example is in myeloma with bone pain; if the pain got worse despite the above three drugs, the codeine could be stopped and oral morphine liquid could be given instead. The advantage of using morphine orally is that a total daily amount can be estimated which controls pain, and following this a dose of Morphine Sulfate (MST) can be estimated and given instead of the oral morphine. Lets say a patient requires 20mg of oral morphine per day to control their severe chronic back pain, an estimated daily dose of long acting MST can be given at 10mg twice daily as an initial starting dose and increased if the pain is still problematic.

Morphine naive patients can safely be given 5-10mg every 3-4 hours and those on long term doses may require larger amounts to control their pain (UpToDate 15.1)

Of course, if morphine sulfate doses escalate further, transdermal opiod patches can be used such as Fentanyl which provides a much smoother delivery of the drug and avoid having to take lots of MST tablets and are changes after 72 hours.

Pethidine which is a tablet, intramuscular and intravenous opioid therapy, can sometime be given for pain relief. Its main advantage is that it is not supposed to cause contraction of the duodenal papilla (Ampulla of Vater / Sphincter of Oddi) unlike morphine, and it is therefore useful in conditions such as biliary colic and pancreatitis.

The downside of such therapy in the long term is addiction and 'professional' patients in the UK sometimes ask specifically for pethidine if they get a return of their 'pain'. I have experienced such patients who do not have clinical pain but manufacture their condition in order to obtain pethidine or morphine like compounds to feed their physical and psychological addiction.

However, short term use (days) of opiate/opioid use, for example, in an acute MI will not lead to addiction, and chronic pain syndromes are likely to need such therapies in any case.

Buprenorphine is a partial agonist with a high binding affinity for opiate receptors and it is used in acute pain. It is excreted mainly in the faeces and some in the urine unchanged.

Non-Traditional Analgesic Therapies

Sometimes, Tricyclic antidepressant therapy can be used for chronic headache or neuropathic pain. Traditionally, amitryptilline 10mg as a starting dose has been used and incrementally increased until effective pain relief is achieved. However, tricyclic agents although having antidepressant properties, are fraught with side effects from their anti-histamine, anti-muscarinic blocking properties. These agents cannot treat acute pain as they are pain modulators and in fact, take several weeks before the patients experience a reduction in their pain.

Perhaps better therapies are Gabapentin or Pregabalin, which are effective therapies for neuropathic pain syndromes, and in the UK are typically used in Diabetic patients who can develop severe nocturnal pain due to diabetic neuropathy.

Another very new development is with the drug Duloxetine which is a dual SNRI anti-depressant which is effective in neuropathic pain syndromes and is also used in diabetic patients. In is approved in more than 70 countries for use in severe depression, but as I understand it, Japan will be marketing the drug for use in incontinence.

Of course, non-drug treatment of pain can be with TENS (Transcutaneous Electrical Nerve Stimulation) which can be effective for 'gating' pain and is used in pregnant patients and chronic back pain conditions in the UK. Basically, this consists of stick-on pads that deliver an electrical current onto the skin of the affected area thereby stimulating the local nerves and making them refractory to the conduction of painful stimuli from the area downstream causing the painful condition.

Salmon Calcitonin is an effective therapy used in the UK and USA for treating osteoporotic fractures. It is given subcutaneously until the pain level is reduced by approximately 50%. It is usually given for a week or thereabouts, but it is frequently associated with nausea and vomiting. However, it is an effective therapy for such bony conditions and is combined with oral bisphosphonate treatment and traditional analgesic agents.

Protecting Your Patients When Giving Analgesia

Always be very careful when prescribing NSAIDs. Adverse side effects include asthma in susceptible individuals, GI bleeding and renal failure to name but a few.

Always take a careful drug and allergy history to ensure that patients have not experienced adverse effects from these drugs in the past.

In the elderly, if you do consider NSAID therapy, please consider adding a Proton Pump Inhibitor (not H2 blocker) especially in the elderly as this is the most effective acid-suppressant therapy and this may prevent a patient developing an ulcer with prevention being better than cure!

Check BUN and Creatinine a few times a week to ensure that the patient does not develop renal failure. If the patient has underlying renal disease and / or is taking diuretic therapy or other potentially nephrotoxic agents, then be warned as NSAIDs reduce renal blood flow through abolition of vasodilatory prostaglandins and renal failure can ensue.

NSAIDs can be substituted by using the above combination of acetaminophen and codeine phosphate but please be careful in patients with liver dysfunction as codeine / morphine compounds require the liver ( and kidneys) to be eliminated. Remember, morphine has the addition of two glucuronic acid side chains (morphine diglucuronide) to be excreted in the bile / urine. Renal failure can slow the excretion of morphine as well, dependent on the creatinine clearance, so dose reductions for opioid/opiates may be necessary.

The elderly are also very sensitive to opiates / opioids in who may benefit the most from having their pain controlled and hence, a smaller starting dose may be necessary.

Specific major side effects include reduced respiratory rate, pin-point pupils, confusion, unconsciousness, hallucinations and the classical 'opiate twitch' seen in opiate toxicity. Luckily, the reversal agent is Naloxone (Narcan), given intravenously and intramuscularly or as a constant infusion and I have personally seen over-treated and unrousable patients suddenly start breathing and open their eyes after seconds of an injection of the anti-dote. Unfortunately, NSAID side effects cannot be reversed as easily! However, please remember that naloxone's effects are short lived and sometimes an infusion is necessary and hence, in patients with hepatic and/or renal failure this may need to be prolonged.


For a full analgesic explanation, side effect profile and indications and contra-indications, please refer to a pharmacology text before prescribing. Some major information on drugs can also be found in UpToDate 15.1

So, I hope that the above gives you a better idea of how to treat pain, and your patients will feel better as a result.

Please let me have your feedback.