A Mystery Rhythm, Explained by K. Wang's Ladder Diagram.

This was presented at the SMACC-Gold EKG workshop:

Can you figure it out?
See the answer below.

Here is a nice ladder diagram and explanation from K. Wang:

--The primary problem is irregular sinus bradycardia (sinus node dysfunction), with junctional escape beats (R1, 2, 3, 5, 6, 7,and 9, which occur with exactly the same interval) and two capture (conducted) beats (R4 and 8). 

--The patient also must have some degree of AV conduction problem both anterograde and retrograde. Otherwise, R2, 3, 6, and 7 would have resulted in retrograde P waves, or P2 and 5 would have conducted. 

--P3 and 6 occur with slightly longer RP interval than P2 or 5, which is the reason why they are conducted but still with a long PR interval.

--P1, 4, and 7 are completely assumed even though it is unusual for them to occur exactly within the QRS (too much of coincidence). Otherwise, P3P5 interval is too long not to have a P wave in between when P2P3 or P5P6 can occur.

Diffuse ST Elevation. What do you think?

What do you think of this ECG, without any clinical information?

There is inferior and lateral ST elevation and ST depression in V1 and V2, just what would be present in an infero-postero-lateral STEMI.  What other finding is there?

Answer:

An extremely long QTc is present, and this was even noted by the computer algorithm, which accurately measured it at 575 ms.  This strongly suggests stress cardiomyopathy (SCM).  This immediately caught my eye when shown to me and SCM immediately came to mind.

The patient presentation is of course critical to the diagnosis of SCM: this patient presented with altered mental status and a Na of 107 mEq/L.  She had presumably had a seizure.

An echocardiogram revealed multiple wall motion abnormalities, though not the typical "Takotsubo" Apical Ballooning.

Here are 5 other cases of Stress Cardiomyopathy

Here is a case of Reverse Takotsubo

When I saw this ECG, I also thought "hypokalemia,"  Why?  There is a "wavy" pattern in V2 which is caused by an inverted T-wave followed by a large U-wave.  See this annotated version: 

The lines show the "wavy" pattern and the arrow points to the large U-wave (arrow).  The wavy pattern could be mistaken for a down-up T-wave, which is common in Posterior MI, but in this case it would be a far too long QT interval for this to be T-wave..

Here are some more examples of the wavy pattern of hypokalemia.


Outcome:
Peak troponin I was 2.5 ng/mL.  ECG findings quickly resolved.  There was no angiogram.




How to suspect takotsubo stress cardiomyopathy from the presenting symptoms, signs and ECG

First, it is believed to by caused by diffuse small vessel ischemia due to catecholamines, and thus has the same electrophysiologic substrate as STEMI.  It affects the entire heart except the base, resulting in diffuse circumferential wall motion abnormalities that only spare the base (top) of the heart.  These diffuse wall motion abnormalities (lateral, posterior, inferior, septal, anterior, apical) result in systolic "apical ballooning" which looks like a Japanese octopus trap (a takotsubo).

Of course, the clinical presentation can help to suspect this: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3214344/
It is most common in postmenopausal women and is associated with severe emotional upset (stress) or severe physiologic stressors such as respiratory failure. 

Stress Cardiomyopathy (Apical Ballooning syndrome, or Takotsubo cardiomyopathy) only presents with ST elevation in about 1/3 of cases, but when it does, it is one of the most difficult mimics of anterior STEMI, and often the only way to tell the difference is to do an angiogram. 

ECG Differentiation of SCM from STEMI

First, a very long QT is quite specific for SCM, but not sensitive.  In this study, the mean QTc for SCM was 567 (+/- 81) ms vs. 489 (+/- 61) ms for anterior STEMI.

A review and analysis of the literature in ECG differentiation of the two entities (1-6) reveals that an analysis of ST elevation vector is a good predictor of anterior STEMI vs. stress cardiomyopathy.  In anterior STEMI, whether proximal, mid, or distal LAD occlusion, there is ST elevation in V1 (1 mm measured at 80 ms after the J-point) in about 80% of cases, whereas this is present in 20% of cases of SCM.  SCM also has a negative ST segment in aVR and is more likely to have ST elevation in inferior leads, or at least absence of ST depression in inferior leads (however, 40% of anterior STEMI lack inferior ST depression). Finally, precordial ST elevation in SCM is more pronounced in V3-V5 vs. V2-V4.

Putting these all together, it is apparent that the ST vector in anterior STEMI is more commonly anterior and superior (V1-V4), without STE in inferior leads, whereas in SCM the ST Vector it is more inferior and lateral (V2-V5, with STE in inferior leads and ST depression in aVR).  This correlates with the location of wall motion abnormalities in SCM (diffuse and toward the apex, similar to pericarditis, including inferior and lateral walls) vs. anterior STEMI (anterior as well as septal-apical). 

In this very interesting study by Kosuge et al., the combination of the presence of ST-segment depression in lead aVR and the absence of ST-segment elevation in lead V₁ identified SCM (vs. anterior STEMI) with 91% sensitivity, 96% specificity, and 95% predictive accuracy, which was superior to any other electrocardiographic findings.

1.     Tamura A et al.  A New Electrocardiographic Criterion to Differentiate Between Takotsubo Cardiomyopathy and Anterior Wall ST-Segment Elevation Acute Myocardial Infarction.  Am J Cardiol Sept 2011; 108(5):630-633.

2.    Ogura R, et al. Specific findings of the standard 12-lead ECG in patients with “takotsubo” cardiomyopathy: comparison with the findings of acute anterior myocardial infarction. Circ J 2003;67:687– 690.

3.    Inoue M, et al. Differentiation between patients with takotsubo cardiomyopathy and those with

anterior acute myocardial infarction. Circ J 2005;69:89 –94.

4. Bybee KA, et al.  Electrocardiography cannot reliably differentiate transient left ventricular

apical ballooning syndrome from anterior ST-segment elevation myocardial infarction. J Electrocardiol 2007;40:38.e1–38.e6.

5. Jim MH, et al. A new ECG criterion to identify takotsubo cardiomyopathy from anterior

myocardial infarction: role of inferior leads. Heart Vessels 2009;24:124–130.

6. Kosuge M, et al.   Simple and accurate electrocardiographic criteria to differentiate takotsubo

cardiomyopathy from anterior acute myocardial infarction.  J Am Coll Cardiol 2010;55:2514 –2516.

http://content.onlinejacc.org/article.aspx?articleid=1142882

7. Kosuge M, et al.  Similar abstract from 2012: http://content.onlinejacc.org/article.aspx?articleid=1204510

Prolonged (63 minutes) Ventricular Fibrillation, Followed by Shock. What's going on?

A middle-aged patient presented in continued ventricular fibrillation after 5 minutes of down time and 45 minutes of prehospital resuscitation by medics, using King Airway, LUCAS, Inspiratory Threshold Device (ITD, ResQPod), defibrillation 4 times, and epinephrine x 3 through an intraosseous line.  The patient had continued to swallow and breathe while being resuscitated (suggesting effective chest compressions).

In the ED, we found that ventilations were effective with the King airway.  LUCAS compressions were continued, and end-tidal CO2 was 26 mm Hg (supporting evidence that chest compressions were effective and supporting the possibility of a good neurologic prognosis). 

We administered ventilations slowly at 10 per minute, following the indicator light on the ITD.  After 300 mg of amiodarone, 100 mg of lidocaine, and 500 mcg/kg of esmolol + 50 mcg/kg/min drip, plus more epinephrine and also bicarbonate, and another defibrillation, a rhythm check at 18 minutes after arrival revealed an organized, mostly narrow complex, but slow, rhythm.  We could not feel a pulse.  A bedside cardiac ultrasound, subcostal view, showed the following:

This is reverse orientation: ventricles are right upper and atria left lower.  The RV is closest to the transducer and is very small (essentially excluding pulmonary embolism as etiology).  The LV has extremely thick walls and a very small LV chamber (there is very little blood to pump)


I  interpreted this as hypertrophic cardiomyopathy (HOCM), and was suspicious of HOCM as the etiology of arrest, as it is well known to cause ventricular fibrillation.


I put the vascular transducer on the right carotid artery, with power Doppler, and this showed good flow in the carotid, corresponding to the cardiac contractions.


An ECG was recorded:

The first 5 seconds appears to be an irregular wide complex tachycardia, with multiform QRS.  However, there are many beats which are clearly narrow complex but only appear to be wide due to ST segment shifts.  This is best seen in lead II across the bottom.
The next 5 seconds appear to be an irregularly irregular, polymorphic wide complex tachycardia.  This is reminiscent of Atrial Fib with WPW, except that the rate is not as fast as is usually seen with that entity.

The exact rhythm here is uncertain.

It is not unusual to have very bizarre ECGs immediately after resuscitation, especially if there is underlying cardiomyopathy, as suspected here.

Case continued:

The patient remained very hypotensive.  Due to the very small LV volume and the need for volume loading in patients with very thick-walled ventricles and slit-like LV [as one sees in HOCM (See this very instructive case)], we began volume loading.

Another ECG was recorded 5 minutes after the first:

There is an uncertain supraventricular rhythm, sinus vs. accelerated junctional, with a narrow QRS.  There appear to be delta waves.  There is bizarre ST elevation in V1-V3 and aVR that does not look like STEMI

My opinion was that this was not a STEMI and we did not activate the cath lab.  

As the patient was bradycardic and hypotensive, we gave the patient push dose epinephrine, and a norepinephrine drip was started.   The esmolol was stopped.  Fluids were continued.  The BP and pulse rose.

The venous pH was 7.16, pCO2 48, bicarb 17, and lactate 6.8.  K = 3.6 mEq/L.  

The King airway was removed and he was endotracheally intubated.  A third ECG was recorded another 20 minutes later:

Now there is clearly sinus tachycardia.  There is an incomplete RBBB.  There is unusual ST elevation in V1-V3 which does not look like STEMI.
Lead V3 looks simile to a spiked helmet sign

No charts had yet been found.  At this point in time, the cardiologist was called and he recognized the patient and stated that he has HOCM.  He was in favor of assessing the coronary arteries, and so the cath lab was activated.

The patient became more hemodynamically stable.  Another bedside echo was done:


This is a parasternal short axis, and shows very thick concentric hypertrophy, but better LV filling now, with much more effective cardiac output

Here is the parasternal long axis view:



An arterial line was placed, and the BP by arterial line was 190/120, with a heart rate of 130.  O2 saturations fell and the chest x-ray revealed pulmonary edema.  Fluids were stopped and esmolol was rebolused and the infusion restarted.  The BP improved at 130/80 with a pulse of 90-120

As access for a cooling catheter was difficult, it was decided to delay targeted temperature management until after the angiogram.

Shortly before transfer to the cath lab, this ECG was recorded:

Sinus tachycardia with narrow complex, with delta waves.  ST elevation largely resolved.

It was learned that the patient had a history of HOCM and WPW, and also a history of severe embolic ischemic stroke due to paroxysmal atrial fibrillation, with hemorrhagic transformation.  Because of this bleeding danger, and also because the physician did not believe that the patient was having a acute coronary syndrome, no aspirin or Plavix or heparin was given.  The possibility was also considered that this was all initiated by a cerebral hemorrhage that caused stress cardiomyopathy.  He therefore underwent a CT scan of the head prior to angiography. This had no new findings, only the previous ischemic stroke (encephalomalacia).

The angiogram showed normal coronaries.  

Peak troponin I was 51 ng/mL (large Type 2 MI)

Formal echo showed HOCM with no outflow obstruction.

Cooling: The patient underwent targeted temperature management.

By 72 hours, the patient showed no signs of awakening, but by 96 hours was intermittently following commands.  By 7 days, the patient was "very interactive."


Learning Points:

1.   With excellent CPR technique, patients in ventricular fibrillation can be resuscitated even after a very long down time.  In this case, even with a left ventricle that could barely fill, the CPR was effective enough to have adequate perfusion.  Good chest compressions, at the right rate (at least 100) and depth (at least 5 cm, or 2 inches), decompression, ITD (ResQPod), slow ventilations (10/min), are among the many critical interventions that may lead to successful resuscitation.  Whether co-incidental or not in this case, we have had good rates of conversion of VF when esmolol is given.  

See this case of 68 minutes of cardiac arrest in a paramedic, plus recommendation from a 5 member expert panel on CPR.

2.  Not all cardiac arrest, even with pathologic ST elevation, is due to STEMI.   Cardiomyopathies, combined with cardiac arrest, can result in bizarre ECGs.  Stress cardiomyopathy may cause VF and ST elevation, and other PseudoSTEMI patterns may be present but unrelated to the VF.

3.   ECGs may be very bizarre immediately after defibrillation. Give a few minutes to record another before coming to conclusions.

4.  Bedside ultrasound is incredibly valuable in cardiac arrest, both for assessing cardiac function and for assessing carotid blood flow.

5.  Pulses may be absent when there is good perfusion through the carotid.  Use Doppler carotid ultrasound to assess carotid flow.  To my knowledge, there is no human literature on this.

6.  End Tidal CO2 is a good indicator of effectiveness of chest compressions. 
--By this systematic review in Resuscitation 2013, a value less than 10 mmHg (1.33 kPa) is associated with a very low return of spontaneous circulation.    
--In this systematic review from J Int Care Med 2014, the mean etCO2 in patients with return of spontaneous circulation (ROSC) was 26 mm Hg (3.5 kPa)

7.  Do not do any adverse neurologic prognostication prior to 72 hours after arrest, and it is preferable to wait even longer.  Here is one article from 2014 on this topic by Keith Lurie's group from HCMC and the U of Minnesota, and another (on which I am a co-author) from HCMC this summer of 2014.

8.  When a cardiac arrest victim has a history of "clots" and is on coumadin, one must entertain the diagnosis of pulmonary embolism.  However, ventricular fibrillation is an unusual presenting rhythm in pulmonary embolism:
--In this study, 5% of VF arrest was due to PE: V fib is initial rhythm in PE in 3 of 60 cases.  On the other hand, if the presenting rhythm is PEA, then pulmonary embolism is likely.  When there is VF in PE, it is not the initial rhythm, but occurs after prolonged PEA renders the myocardium ischemic.

--Another study by Courtney and Kline found that, of cases of arrest that had autopsy and found that a presenting rhythm of VF/VT had an odds ratio of 0.02 for massive pulmonary embolism as the etiology, vs 41.9 for PEA.      

===================================

MY Comment by KEN GRAUER, MD (6/27/2020):

===================================

As I reviewed the above series of 4 tracings in active search for insightful commentary about the various cardiac rhythms — I found myself continually returning to Dr. Smith’s 3rd Learning Point cited above = “ECGs may be very bizarre immediately after defibrillation. Give it a few minutes to record another before drawing conclusions.” As motivated as I was to devise some new, definitive interpretation for the rhythms in this case — it didn’t happen for me. Instead — I’ll simply add this 9th Learning Point:

• Accept that your peri-resuscitation patient may not show you an easy-to-interpret tracing. When this happens — Be content with the basics. VFib and malignant VT rhythms need to be shocked. In contrast — rhythms such as seen in the 2nd tracing above do not need to be shocked — because even though there is much I can’t explain on this 2nd ECG — the rhythm is regular (at ~70/minute) — with a distinct supraventricular look to the tracing (albeit P waves are not to be seen).

Rhythms such as seen in the 1st tracing above may defy interpretation. For example, the initial part of the QRS complex is narrow and irregularly irregular during the first half of this 1st tracing. This looks like rapid AFib. But as per Dr. Smith — the widened, much more amorphous and irregularly irregular QRS complexes in the second half of this 1st tracing look much more like PMVT (PolyMorphic VT). If this rhythm that we see in the second half of this 1st tracing were to sustain and be accompanied by hemodynamic instability — then it would become “a rhythm to be shocked”.

• NOTE: Osborn waves are not only seen with hypothermia. They may also be seen during cardiac arrest from VFib (See My Comment in the November 22, 2019 post). I believe the notching we see in lead V3 (and possibly in V2) in the 2nd and 3rd tracings above may be the result of Osborn waves — that may contribute to the bizarre ECG appearance.
• Finally — serial tracings obtained during resuscitation (and ideally finding a prior tracing on the patient for comparison) — can go a long way toward putting together a cohesive picture. In this case — learning that this patient in cardiac arrest did have a history of hypertrophic cardiomyopathy and WPW, was instrumental in clarifying some of the changes in QRS morphology being seen. For example, sinus tachycardia is definitely seen in the 3rd tracing above. With regard to this 3rd, and then the 4th tracing that follows it — looking at these 2 ECGs in succession reveals as the main change, a new initial slurring of the QRS complex in multiple leads in the 4th tracing that was not seen in the 3rd tracing. This initial slurring in multiple leads can now be recognized as representing delta waves in this patient who we have learned has WPW (even though the PR interval does not look as short in many leads as it is usually does with WPW).

BOTTOM LINE: Through superb efforts by the resuscitation team — this patient was saved despite less than definitive arrhythmia diagnosis. Definitive arrhythmia diagnosis simply wasn't possible early on during resuscitation — but it wasn't needed, because the patient was saved. ECGs may look bizarre for a while after defibrillation ...

  

Two (apparent wide complex) Rhythms in One Patient: First is at rate of 300, second at Rate of 180

A middle-aged patient with no known significant past medical history had sudden onset of  palpitations, diaphoresis, dyspnea. This lasted for roughly 30 seconds.  EMS was called and he had palpitations again and had this monitor strip (labeled as leads I, II, and III):

There is a wide complex tachycardia at a rate of 302.  There is a narrow spike at the top of each wave, suggesting rapid conduction to the ventricle.  Perhaps it is actually a narrow complex?

He was awake with a normal blood pressure and no shock.

A rate of 302 is very fast for any tachycardia in an adult, but is particularly fast for ventricular tachycardia.  The narrow spike at the beginning of each QRS suggests that the ventricle is activated through the fast conducting Purkinje system, and is probably a supraventricular rhythm.  One typical SVT that occurs at a rate of 300 is atrial flutter.  It is unusual, however, for the AV node to conduct at this rate.

No matter what the source, it is very fast.

Before this could be electrically cardioverted, the patient spontaneously converted to sinus rhythm (again, leads I, II, and III):

This shows sinus rhythm.  There is a wide complex with a deep S-wave in lead I, strongly suggesting right bundle branch block.

He arrived in the ED and had this 12-lead ECG:

Again, sinus rhythm, and with confirmation of RBBB.  No ischemia.

That the patient tolerated his rhythm of 300 is very re-assuring and makes this rhythm much less life-threatening than if he had been syncopal, hypotensive, or in shock.  It also suggests a structurally normal heart.  A patient with cardiomyopathy would not tolerate this rate.  He remained stable in the ED.

K was 3.6 mEq/L.  Mg was 1.6 mEq/L.

Thinking the patient had suffered from VT, he was started on amiodarone.

Because of worry about primary ischemia as the underlying etiology, he went to the cath lab and coronaries were normal.

An echocardiogram showed normal anatomy and function.

While in the hospital, he again had symptoms and had another ECG recorded:

This is very different from the first. 
It shows a regular wide complex tachycardia, with a left bundle branch block pattern and an inferior axis.  The rate is 180.  There are no P-waves.  The QRS duration is only 120 ms, which is quite narrow for VT.

Considerations in the diagnosis:

The electrophysiologist noted A-V dissociation in lead-II (which is nearly diagnostic of ventricular tachycardia).  I am unable to recognize it in this tracing.

An LBBB pattern by itself strongly suggests an SVT with LBBB-type aberrancy, as does the QRS duration of 120 ms.  Most typical VT (but certainly not all) has a QRS duration of  > 140.  Few typical (i.e., not fascicular) VT have a QRS as short as 120 ms.

However, the fact that the patient has RBBB at baseline, and this ECG has LBBB, makes SVT (sinus, PSVT, flutter) with LBBB-aberrancy virtually impossible.

So now we know that it is wide, LBBB, not SVT with aberrancy, and not a typical VT.  The ultrasound showing a structurally normal heart also makes typical VT unlikely. 

If you can see A-V dissociaton as the electrophysiologist did, that clinches the diagnosis of VT.  

This leaves us with the "idiopathic" ventricular tachycardias: probably fascicular VT or right ventricular outflow tract VT.  These are "idiopathic"  VT's which occur in an otherwise normal heart, and are, compared to typical VT, relatively narrow.  See these cases for a more detailed explanation of fascicular VT.

Subsequent events;

For the second rhythm, the electrophysiologist suspected right bundle branch fascicular re-entry (I had not heard of it before) because of the presence of baseline RBBB when in sinus.  

For the first rhythm, he suspected atrial flutter with 1:1 conduction.

At EP study, he was right on both counts, and underwent ablation of fascicular VT as well as cavo-tricuspid isthmus ablation to eliminate the atrial flutter loop.

The patient did very well.

Final Diagnosis:

1. Atrial Flutter at rate of 302 with 1:1 conduction and ventricular rate of 302 with RBBB.
2. Right Bundle Fascicular Re-entrant Tachycardia.

Massive Excessively Discordant Anterior ST Elevation in a Paced Rhythm

This patient has a standard DDD pacer, with RV pacing (not biventricular pacing), severe chronic nonischemic cardiomyopathy with EF of 10% (partly due to many years of having an RV pacemaker), severe systolic dysfunction, 3rd degree heart block from penetrating trauma, mild to moderated aortic stensosis, multiple LV thrombi, and a standard RV pacemaker.  He has had previous angiograms showing "large vessels" and "no significant coronary disease." 

He presented with chest pain, not relieved by nitro, pain reproducible on exam and centered around the pacemaker insertion site.  Here is his ED ECG

There is RV Pacing.  There is a very large amount of ST elevation in leads V1-V6.  It is out of proportion to the preceding S-wave, with a maximum ratio in leads V3 and V4 of 10/33 =  0.30.   

In LBBB, a ratio of greater than 0.25 is very specific for STEMI, and there is some evidence, as well as rationale, that a paced rhythm behaves similarly.
Here is one case of anterior STEMI in a paced rhythm.
Here is a case of lateral STEMI in a paced rhythm.

Here is his ECG one month prior, on admission for chest pain at that time also:

Similar ratios.  LV Ejection Fraction at the time of this hospitalization was 10%.

At that previous visit, he had had some mildly elevated troponins, but mostly had severe heart failure from very poor systolic function and aortic stenosis.

There was an ECG from 2 months prior as well, at which time the EF was 30%.  Here it is:

Here the maximum ratio is in lead V3 and is 7/42 = 0.167 (normal ratio).

Thus, the top two ECGs with excessively discordant ST elevation are false positives. During both presentations, the patient was fluid overloaded, and had decompensated heart failure with a very low ejection fraction.  It is likely that severe cardiomyopathy and loading conditions result in false positives.

How could you suspect that this is false positive?  
1) there was a previous ECG to compare with
2) there was a recent normal angiogram
3) the chest pain was fully reproducible
4) decompensated heart failure can affect the ECG.

In both presentations, the treating physicians were not fooled by the excessive ST elevation, though they did not comment on it.

Lesson:

1. There are false positives in every situation, whether normal conduction, LBBB, or pacing, or other.  Use all the information at your disposal to assess the situation. 
2. Severe decompensated cardiomyopathy likely can exaggerate the ST elevation associated with paced rhythm, and probably also LBBB.

Intravenous Nitroglycerine in STEMI, with data: Avoid its use if giving tPA

If you are giving tPA to patients with STEMI, it is wise to avoid IV nitroglycerine.  I am revisiting this topic because of a recent case I posted in which a patient who was on IV nitro received tPA.  This patient was very hypertensive, and thus needed something to control BP. But I would advise against nitroglycerine.

This is data that very few cardiologists are aware of

Background: 

First, know that, in the reperfusion era, there is absolutely no data to support the use of nitroglycerine in STEMI.  See the ACC/AHA recommendation below that puts the level of evidence at “C”.  I have pasted below the ACC/AHA guideline.  There are a total of 4 references provided.   Three are from the pre-reperfusion era (1 shows is a pooled analysis showing decrease in mortality from 7.7% to 7.4%); 1 uses transdermal nitrates.

There is data showing worse outcome with nitroglycerine when tPA is used (see 3 abstracts pasted below, one is a randomized human study, though small).  This data is far better than that referenced in the guidelines, and actually also includes rationale and lab confirmation (tPA levels are much lower with, than without, nitro drips).

The reason for this is that Nitro apparently increases hepatic blood flow and tPA metabolism, lowering tPA blood levels.

Some have argued that GISSI-3 proved nitro to be efficacious.  This simply shows a bias towards nitro and away from any data about it.  GISSI-3 studied transdermal nitrates, given all day for 6 weeks.  Furthermore, and I quote from the article: “the systematic administration of transdermal GTN did not show any independent effect on the outcome measures (0.94 [0.84-1.05] and 0.94 [0.87-1.02]).”

The application of literature that is prior to the thrombolytic and even aspirin era to the reperfusion era of today is not rational. 

With the evidence below, and at least one other study (White CM.  Pharmacotherapy 20(4):380-2, April 2000) confirming decrease in tPA levels with use of nitro, it would be very unwise to give nitrates and expect tPA to work.

Even with HTN or pulmonary edema, I would use another drug if I were giving tPA and expecting reperfusion.  Exactly which medication would be better, however, is uncertain.  Beta blockers probably do not have this effect on tPA, but some other vasodilators (if beta blockade does not sufficiently lower the BP) might also have this effect.  IV enalapril is one possibility, but can have irreversible hypotensive effects.  Nitroprusside is great to lower BP, but does it also lower tPA levels?  In any case, I would try beta blockade first if there are no absolute contraindications.  The BP must be less than 185/110 in order to give tPA and avoid catastrophic intracranial bleeding.

Finally, the dose used that interrupted reperfusion was high (100 mcg/min), but any efficacious dose of nitro would have to be high (many physicians forget that sublingual nitro q 5 minutes is equal to 80 mcg/min).

tPA and Nitroglycerine: an Annotated Bibliography:

Concurrent nitroglycerine therapy impairs tissue-type plasminogen activator-induced thrombolysis in patients with acute myocardial infarction.¹

Nitroglycerin given with tissue-type plasminogen activator (t-PA) has been shown to decrease the thrombolytic effect of t-PA in animal models of coronary artery thrombosis. The present study was conducted to determine whether such an interaction between nitroglycerin and t-PA occurs in patients with acute myocardial infarction undergoing thrombolytic treatment. Patients with acute myocardial infarction were treated with t-PA plus saline solution (group 1; n = 11) or t-PA plus nitroglycerin (group 2; n = 36). Stable coronary artery reperfusion assessed by continuous ST-segment monitoring in 2 electrocardiographic leads, and release of creatine kinase occurred in 91% of group 1 patients and in 44% of group 2 patients (95% confidence interval, 14% to 82%; p < 0.02). Plasma levels of t-PA antigen were consistently (p < 0.005) higher in group 1 than in group 2 patients up to 6 hours after t-PA infusion. Conversely, plasminogen activator inhibitor-1 (PAI-1) levels were slightly higher in group 2 than in group 1 patients. These observations indicate that nitroglycerin given with t-PA significantly decreases the plasma t-PA antigen concentrations and impairs the thrombolytic effect of t-PA in patients with acute myocardial infarction.

Concurrent nitroglycerine administration decreases thrombolytic potential of tissue-type plasminogen activator.²

Dynamic coronary vasoconstriction may play a role in coronary artery reocclusion after successful thrombolysis. The effect of nitroglycerin on the thrombolytic effects of recombinant tissue-type plasminogen activator (rt-PA) was examined in dogs with an electrically induced occlusive coronary artery thrombus. Eleven dogs were randomly given rt-PA alone and seven rt-PA with nitroglycerin. The dose of rt-PA was 0.75 mg/kg body weight given over 20 min and the dose of nitroglycerin was 125 micrograms/min for 40 min. The reperfusion rate in the dogs given rt-PA alone was 73% (8 of 11 dogs) and that in the rt-PA plus nitroglycerin group was 57% (four of seven dogs) (p = NS). The time to thrombolysis (or reperfusion) in dogs receiving rt-PA plus nitroglycerin was 70% greater than in those receiving rt-PA alone (means +/- SD/29.8 +/- 9.9 versus 17.6 +/- 5.9 min, p less than 0.02), and the duration of reperfusion much shorter (11 +/- 17 versus 42 +/- 16 min, p less than 0.02). Peak coronary blood flow after reperfusion in dogs receiving rt-PA plus nitroglycerin was also less than in those receiving rt-PA alone (36 +/- 52 versus 63 +/- 20 ml/min, p less than 0.02). Reocclusion occurred in all dogs given rt-PA with nitroglycerin and in six of eight given rt-PA alone (p = NS). Plasma concentrations of rt-PA were lower when nitroglycerin was given with rt-PA alone (427 +/- 279 versus 1,471 +/- 600 ng/ml, p less than 0.01).  In addition, whole blood platelet aggregation decreased significantly with administration of rt-PA alone, but not with administration of rt-PA with nitroglycerin (0.23 ± 0.57 and 5.26 ± 6.23, respectively, p less than 0.02). Peripheral blood platelet count decreased during thrombus formation in all dogs; with administration of rt-PA alone, platelet counts stabilized but continued to decrease with concurrent administration of nitroglycerin with rt-PA (mean platelet counts at the end of rt-PA infusion 7.23 ± 1.68 and 4.78 ± 3.00 × 10⁸/ml, respectively, p less than 0.02), suggesting continued sequestration of platelets in the intracoronary thrombus. In four additional dogs nitroglycerin was given after rt-PA-induced thrombolysis, but nitroglycerin failed to sustain coronary artery reperfusion.This study shows that 1) nitroglycerin given concurrently with rt-PA may have a detrimental effect on the thrombolytic potential of rt-PA, probably because of the reduction in plasma t-PA concentrations, and 2) nitroglycerin given after rt-PA-induced thrombolysis does not prevent coronary artery reocclusion.

Concurrent nitroglycerin administration reduces the efficacy of recombinant tissue-type plasminogen activator in patients with acute anterior wall myocardial infarction.³

The aim of this study was to evaluate the impact of concurrent nitroglycerin administration on the thrombolytic efficacy of recombinant tissue-type plasminogen activator (rTPA) in patients with acute anterior myocardial infarction (AMI). Sixty patients (53 men, 7 women; mean age 54 +/- 7 years) with AMI entered the study. Thirty-three patients were randomized to receive rTPA alone (100 mg in 3 hours) (group A) and 27 to receive rTPA plus nitroglycerin (100 micrograms/min) (group B). Time from the onset of chest pain and delivery of rTPA was similar in the two groups of patients. Patients in group A had signs of reperfusion more often than the patients in group B (25 of 33 or 75.7% vs 15 of 27 or 55.5%, p less than 0.05). Time to reperfusion was also shorter in group A than in group B (19.6 +/- 9.4 minutes vs 37.8 +/- 5.9 minutes, p less than 0.05). Group B had a greater incidence of in-hospital adverse events (9 of 27 vs 5 of 33, p less than 0.05) and a higher incidence of coronary artery reocclusion (8 of 15 or 53.3% vs 6 of 25 or 24%, p less than 0.05). Peak plasma levels of rTPA antigen were higher in group A compared with group B (1427 +/- 679 vs 512 +/- 312 ng/ml, p less than 0.01). In conclusion, concurrent nitroglycerin administration reduces the thrombolytic efficacy of rTPA in patients with AMI probably by lowering the plasma levels of rTPA antigen. The diminished efficacy of rTPA is associated with an adverse outcome.

References

1.         Nicolini FA, Ferrini D, Ottani F, et al. Concurrent nitroglycerine therapy impairs tissue-type plasminogen activator-induced thrombolysis in patients with acute myocardial infarction. Am J Cardiol 1994; 74:662-666.

2.         Mehta JL, Nicolini FA, Nichols WW, Saldeen TG. Concurrent nitroglycerine administration decreases thrombolytic potential of tissue-type plasminogen activator. J Am Coll Cardiol 1991; 17:805-811.  Full text: http://content.onlinejacc.org/article.aspx?articleID=1117488

3.         Romeo F, Rosano GM, Martuscelli E, et al. Concurrent nitroglycerin administration reduces the efficacy of recombinant tissue-type plasminogen activator in patients with acute anterior wall myocardial infarction. Am Heart J 1995; 130:692-697.

From ACC/AHA Guidelines
Class I

1. Patients with ongoing ischemic discomfort should receive sublingual nitroglycerin (0.4 mg) every 5  minutes for a total of 3 doses, after which an assessment should be made about the need for intravenous nitroglycerin.

(Level of Evidence: C)

2. Intravenous nitroglycerin is indicated for relief of ongoing ischemic discomfort, control of hypertension, or management of pulmonary congestion. (Level of

Evidence: C)

Class III

1. Nitrates should not be administered to patients with systolic blood pressure less than 90 mm Hg or greater than or equal to 30 mm Hg below baseline, severe bradycardia (less than 50 beats per minute [bpm]), tachycardia (more than 100 bpm), or suspected RV infarction. (Level of Evidence: C)

2. Nitrates should not be administered to patients who have received a phosphodiesterase inhibitor for erectile dysfunction within the last 24 hours (48 hours for tadalafil). (Level of Evidence: B)

The physiological effects of nitrates include reducing preload and afterload through peripheral arterial and venous

dilation, relaxation of epicardial coronary arteries to improve coronary flow, and dilation of collateral vessels, potentially creating a more favorable subendocardial to epicardial flow ratio (252-254). Vasodilation of the coronary arteries, especially at or adjacent to sites of recent plaque disruption, may be particularly beneficial for the patient with acute infarction. Nitrate-induced vasodilatation may also have particular utility in those rare patients with coronary spasm presenting as STEMI.

Clinical trial results have suggested only a modest benefit from nitroglycerin used acutely in STEMI and continued

subsequently. A pooled analysis of more than 80 000 patients treated with nitrate-like preparations intravenously or orally in 22 trials revealed a mortality rate of 7.7% in the control group, which was reduced to 7.4% in the nitrate group. These data are consistent with a possible small treatment effect of nitrates on mortality such that 3 to 4 fewer deaths would occur for every 1000 patients treated (152). Nitroglycerin may be administered to relieve ischemic pain and is clearly indicated as a vasodilator in patients with STEMI associated with LV failure. Nitrates in all forms should be avoided in patients with initial systolic blood pressures less than 90 mm Hg or greater than or equal to 30 mm Hg below and treatment with aspirin, beta-blockers, and ACE inhibitors. Nevertheless, any patient with a risk from the intervention that exceeds their STEMI risk reduction will, on average, do better without that treatment. This group will generally include patients with a higher risk from the intervention or a lower absolute risk reduction (generally because f a low absolute STEMI risk). This issue may be particularly important for younger patients, who tend to have a lower absolute risk of mortality (245), and for the elderly, who tend to have a higher risk from interventions, particularly with respect to fibrinolytic therapy (246). Precise estimates of risks and benefits are useful because the low STEMI risk in younger patients is often accompanied by a lower risk of interventions. In contrast, in the elderly, the higher intervention risk is accompanied by a higher STEMI risk (and thus a larger absolute reduction in risk with the intervention) (247). The use of any risk assessment tool should not contribute to any delay in providing the time-sensitive assessment and treatment strategies that patients with STEMI require. Further research is necessary to determine how these tools may best contribute to optimizing patient outcomes.

152. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. Lancet1995;345:669-85.

252. Abrams J. Hemodynamic effects of nitroglycerin and long-acting nitrates. Am Heart J 1985;110:216-24. 253. Winbury MM. Redistribution of left ventricular blood flow produced by nitroglycerin: an example of integration of the macroand microcirculation. Circ  Res 1971;28(Suppl 1):140-7.

254. Gorman MW, Sparks HV. Nitroglycerin causes vasodilatation within ischaemic myocardium. Cardiovasc Res 1980;14:515-21.