Lasix for Acute Pulmonary Oedema?… An Overview

Just recently our ICU team was called to the wards to look at a 74 year old gentlemen with sudden shortness of breath and low peripheral saturations. He was known to suffer of hypertensive heart disease and now presented with acute pulmonary oedema. After giving oxygen over a non-rebreathing mask he was administered furosemide (Lasix) intravenously and brought to the unit for non-invasive ventilation.

​Interestingly a discussion started on whether giving Lasix as a first line agent in the acute setting of pulmonary oedema is beneficial or not.  A quick look into to current literature gave no clear answer and reading further into the topic revealed amazing properties of Lasix we hadn't been really aware of so far. We all use and love Lasix, but do we really know the drug?

The Beginning of Lasix

Furosemide (sometimes also called frusemide) was first developed by 'Farbwerke Hoechst AG' in Frankfurt am Main, Germany, a company that was founded back in the year 1863. Karl Stürm, Walter Siedel and Rüdi Weyer set the basis with the invention of N-substituted-3-Carboxy-6-Halo-Sulfanilamide and it's derivates, one of them being furosemide. The researchers soon noticed its saluretic (sodium Na, potassium K and chloride Cl) and diuretic effect in almost equivalent proportions. As these substances did not cause any acidosis nor alkalosis they suggested their future usage for the treatment of oedema and hypertension.

The Naming of Furosemide

Researchers soon noticed that the diuretic effect of furosemide lasted for about 6 hours... 'LAsts for SIX hours'... and therefore gave it the name: LASIX!

​What is Furosemide

​Furosemide is an organic anion from the group of loop diuretics (as are bumatenide and torasemide) and is sold under the brand name of Lasix©. It's indications are for the treatment of oedema due to heart or liver disease as well as kidney disease. It is also used for the treatment of mild or moderate hypertension. Furosemide has become one of the cornerstones in the treatment of heart failure.

How does it work?

Furosemide can be applied by oral intake as a tablet or as an intravenous injection. Once in the blood stream it is predominantly bound to proteins (>90%).

Loop diuretics do not undergo glomerular filtration. In fact they pass the glomerulus and are actively secreted across proximal tubular cells by organic anion transporters and the multidrug resistance associated protein 4 (area A). It is important to know that non-steroidal anti-inflammatory drugs (NSAID) and endogenous uremic anions compete with this loop diuretic secretion and can cause 'diuretic resistance'.

Once loop diuretics have reached the tubular system they bind to to sodium-potassium-chloride co-transporters (NKCC2) in the ascending limb of the loop of Henle and block the reabsorption of these ions directly (area B). Further down at the macula densa they inhibit the same co-transporter (area B) thereby stimulating renin secretion and inhibiting tubuloglomerular feedback. This results in preserved glomerular filtration despite increased salt delivery to the macula densa. All this finally results in the loss of sodium, chloride and potassium and therefor loss of water.
Other Effects

Furosemide also interacts with other sodium-potassium-chloride co-transporters (NKCC1) elsewhere in the body:
- Blocking NKCC1 in the ear probably explains the ototoxicity of loop diuretics
- Blocking NKCC1 in smooth muscle cells causes vasodilation
​- Blocking NKCC1 in the afferent arteriole and near the macula densa elevates renin secretion and the generation of angiotensin II

These complex interactions on haemodynamics explain that the net response in each patient might be different. On the one hand loop diuretics dilate blood vessels directly and increase the level of vasodilatory prostaglandins. On the other hand some of these effects counteract each other making it difficult to predict which effect will finally predominate.

Many studies have looked closer into the vasoactive properties of furosemide. Current evidence indicates that it has  systemic venodilator effect  which actually reduced preload acutely. The same investigators found a reduction in the right atrial pressure and the pulmonary capillary wedge pressure, presumably reflecting the systemic venodilator effect of furosemide.

While the acute venodilator effect may be beneficial to the failing heart its action on arteries might be detrimental. Several studies have shown that in patients with chronic heart failure furosemide causes arterial vasoconstriction. Also there is one study showing that pulmonary vascular resistance in healthy volunteers rose significantly. 

Francis GS et al described how the administration of furosemide actually led to decreased LV function, increased LV filling pressures, increases in MAP, SVR, plasma renin activity, and plasma noradrenaline levels.

Beneficial venodilator response predominates over arterial vasoconstriction in patients with (1) myocardial infarction and (2) salt depleted volunteers.

Venous relaxant effect has not been demonstrated in patients with chronic heart failure. In this setting detrimental arterial vasoconstriction seems to predominate.

Pardeep S et al. Br J Clin Pharmacol. 2000 Jul; 50(1): 9–13.

Francis GS et al. Ann Int Med 1985; 103(1): 1-6.

Pharmacological Properties

Administered orally furosemide has a limited and highly variable bioavailability. The diuretic effect starts within the first hour and the duration of action is around 6 hours (4-8 hours). Injected intravenously furosemide is approximately twice as potent on per-miligramm basis as oral doses. 

In acute decompensated heart failure sodium retention becomes more avid and higher peak levels might be required to become more effective. This can be achieved by giving furosemide intravenously.

Once a loop diuretic is administered, the excretion of sodium chloride is increased for several hours. This is then followed by a period of very low sodium excretion resulting in a so called 'post-diuretic retention'.

How to use Furosemide for Acute Decompensated Heart Failure (ADHF)

So far for the basics of furosemide, but what about it's usage for acutely decompensated heart failure? Should furosemide be given as soon as possible or not?

The 2013 ACCF/AHA guidelines for the management of patients with heart failure give diuretics a class I recommendation. The evidence behind these recommendations though is level B or level C only! So these recommendations are not really helpful to answer this question.

The authors in UpToDate® mention diuretics directly after the use of oxygen. For patients with evidence of volume overload their recommendation is to give loop diuretics immediately (Grad 1B) as there is evidence that in this setting this may improve outcomes. They also suggest that patients with ADHF usually are volume overloaded, therefor suggesting that most patients should receive diuretics ASAP.  
The only exception they mention where some delay in inducing diuresis might be required is in patients with severe hypotension or cardiogenic shock.

There is reasonable doubt that patients with ADHF are usually volume overloaded, as suggested by UpToDate®. Zile MR et al. demonstrated that while most patients with acute pulmonary oedema have increased filling pressures, most did not have significant increases from their dry weight on presentation! Fallick et al. actually argue that it isn't fluid gain but rather shift in fluids from other compartments, particularly shift from the splanchnic circulation, which is normally very compliant.

And as mentioned above, there is evidence that giving a straight shot of furosemide might actually influence haemodynamics negatively in different ways (decreased LV function, increased LV filling pressures, increases in MAP, SVR, plasma renin activity and plasma noradrenaline levels).

In conclsion there is no straight forward answer to this question but I would put it down as follows:

​- Furosemide should not be routinely used for the immediate treatment of acute decompensated heart failure (ADHF)/ acute pulmonary oedema

- However, in patients with evidence of volume overload the administration of early furosemide (preferentially given as an intravenous bolus) seems beneficial and  improves outcome. But beware, most patients are not volume overloaded!

- In urgent situations the focus should be on early non-invasive ventilation and the administration of nitroglycerin!

Identify a Pacer by Chest X-Ray

Clinicians are confronted every day with a growing number pacemakers (PMs), implantable cardioverter-defibrillators (ICDs) and implantable loop recorders (ILRs). Collectively these devices are sub summarized as cardiac rhythm management devices (CRMDs). Identification of these devices is simple as long a the patient can present an ID card or some other form of identification. This can become challenging especially in emergencies where such information might not be accessible and interrogation of the pacemaker becomes a problem.
Using the wrong manufacturer-specific device programmer causes delay in diagnostic and treatment and can be relevant in these situations.

Techniques to identify a CRMD are following:

- Patient's ID card

- Medical records

- Manufacturers' patient registries (All CRMD manufacturers keep their own in-house registry of patients implanted with their devices and provide 24-hour telephone technical support

- Device specific radiopaque alphanumeric codes (ANC)

All these identification techniques have their problems in clinical practice and so far no other technique or algorithm was available to help out in such a dilemma. Sony Jacob et al. have therefor developed and validated the so called

Cardiac Rhythm Device Identification Algorithm using X-rays (CaRDIA-X, see below)

The study participants using this algorithm showed an overall accuracy of 96.9%. This study was published in 2011 but only now caught our attention.

We have tried this algorithm on a few X-rays ourselves and came to the conclusion:

Using the chart is a little challenge itself, but very helpful in most cases! Certainly worth keeping in mind!

Jacob S et al. Heart Rhythm. 2011 Jun;8(6):915-22.

CT is the Key to Clear the Spine in the Intoxicated!

We just had the discussion again and finally found a good and solid answer to it:

A 19 year old male was transferred to our unit from casualty with a GCS of 10 (E2, V3, M5) secondary to a little bit of... to many drinks. As he was found lying on the ground with no company an unwitnessed fall was considered and a rigid collar applied by paramedics. A c-spine CT-scan in the hospital showed no abnormalities and the patient was transferred to ICU for further treatment... with the rigid collar still in place!

The question soon arose whether it is safe to remove a rigid collar in the intoxicated and dazed patient after a normal c-spine scan or not. Some argued that the patient should also be examined clinically once sober in order to safely evaluate and clear the spine. As always by the way: The rigid collar was removed in ICU and no further problems evolved. 

At that time we just knew it is safe to do so but now we seem to get some excellent evidence supporting this procedure.

Martin et al. have just published a 

prospective multicenter study at 17 centers

in which they analyzed

10191 trauma patients that underwent CT of the c-spine during their primary evaluation (67% male, 83% car accidents or falls, mean ISS 11)

They found that 

the intoxicated cohort had a lower incidence of c-spine injuries

and that

c-spine CT had a sensitivity of 94%, a specifity of 99.5% and a negative predicitve value of 99.9%!
In words this means that a negative CT-result for a patient gives us a very high confidence that this negative result is true!

The Bottom Line:

Clearing the c-spine by CT-scan in the intoxicated patient is definitely safe, especially when there are no other injuries or history of a high velocity trauma.

Martin MJ et al. J Trauma Acute Care Surg. 2017 Jul 19