COMMENTARY

Three Lessons From a Sudden Death Not Caused by Caffeine

John Mandrola, MD

Disclosures

June 05, 2017

It's sad when a young person dies suddenly. Not learning from the event only adds to the tragedy.

When young people die without an obvious cause, we should try to understand why and how it happened.

After Davis Allen Cripe, age 16, collapsed and died in his South Carolina high school classroom, the coroner attributed his death to a "caffeine-induced cardiac event causing a probable arrhythmia."

But caffeine alone was not likely the culprit. In this review, I will discuss three learning points from this event.

1. Caffeine Was Not the Likely Cause of Death

Mr Cripe was said to have consumed a McDonald's latte, a diet soft drink, and an energy drink over a 2-hour period before his death. The exact dose of caffeine is hard to calculate, but upper estimates have it as no more than 626 mg—or six cups of coffee.

That's enough caffeine to cause side effects, jitteriness, increased heartbeat, nausea, anxiety, diaphoresis, etc, but it's well below the generally accepted lethal dose of 10 g daily (100 cups of coffee).[1,2]

By email, Dr David Juurlink (University of Toronto, ON) wrote: "Something is fishy about this case. I agree that the dose seems too low. I'd have expected significant caffeinism but not fatal toxicity. I'm guessing either a) the dose was greater than estimated or b) he had some sort of unrecognized predisposition to the arrhythmogenic effects of caffeine."

It's Juurlink's latter point that strikes me as most notable and most probable. If the caffeine from six cups of coffee could kill young people, we would see many more of these deaths.

2. The Molecular Autopsy

I believe that Mr. Cripe had an unrecognized predisposition to the effects of caffeine. His unexplained death would have been an excellent opportunity for a molecular autopsy. In recent years, the enhanced ability to sequence DNA can point to genetic causes of death when a standard autopsy shows no obvious abnormalities.

In a review paper, Dr Chris Semsarian (University of Sydney) and colleagues reported the proportion of sudden unexplained death in young people with negative autopsies range from 17% to 29%.[3] That is a lot of unexplained death.

In 2012, a Mayo Clinic team reported results of DNA sequencing in 173 cases of autopsy-negative sudden deaths. They found possible mutations in genes for long-QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT) in 45 cases (26%).[4]

Before 2016, the molecular autopsy targeted only genes for the most common inherited diseases, such as long-QT syndrome, Brugada syndrome, and CPVT. Recent advances in sequencing have allowed a more comprehensive and cost-effective molecular search.[3]

In 2016, researchers reported in the New England Journal of Medicine on a 3-year series of 490 cases of sudden death in children and young adults in Australia and New Zealand. They found a clinically relevant cardiac gene mutation in 31 of 113 cases (27%) that had genetic testing. A clinical diagnosis of an inherited cardiac disease was identified in 13% of the families in which an unexplained sudden cardiac death occurred.[5]

Similarly, a team from the Scripps Institute in San Diego used exome sequencing on blood or tissue from deceased young people (n=25) and found a likely or plausible cause of death in 40% of cases.[6] Notably, seven of 10 cases of likely or plausible pathogenic mutations were inherited from relatives who did not die suddenly.

A molecular autopsy helps manage risk in surviving family members. For instance, if the death had a possible genetic cause, parental testing can tell whether the mutation was inherited or de novo. If it's de novo, then family members can be reassured. If the mutation is inherited, then at-risk family members can be screened for the same mutation.[7]

3. Caffeine Misinformation

After the coroner's report of Mr Cripe's death, many news outlets ran stories vilifying caffeine. Although this case involved a high dose, and toxicity turns on dose, the published literature on caffeine runs counter to the widely held opinion (and guideline statements) suggesting the substance causes arrhythmia or other adverse health outcomes.[8,9]

Caffeine and Ectopy. Using longitudinal data, a team led by the University of California, San Francisco group studied the relationship between chronic use of caffeinated products (coffee, tea, chocolate) and cardiac ectopy.[2] Nearly 850 individuals in the study consumed one or more caffeinated products daily. The researchers found no differences in premature atrial or ventricular beats across levels of coffee, tea, and chocolate intake.

Caffeine and AF. Caffeine also does not associate with an increased risk of incident AF and may even be protective at low doses.

In a 2013 systematic review and meta-analysis of seven observational studies (>115K individuals), researchers from the University of Lisbon found no overall association of caffeine exposure and AF.[10] In fact, the point estimates trended toward a protective effect of caffeine (odds ratio 0.92; 95% CI 0.82–1.04). When the authors looked only at higher-quality studies, caffeine exposure associated with a decrease in the risk of AF by 13% (OR 0.87, 95% CI 0.80–0.94).

A year later, researchers from the Peking Union Medical College in Beijing confirmed these findings in another meta-analysis looking at caffeine dose-response and AF that included more than 228,000 individuals.[11] Similarly, caffeine exposure trended toward a reduced risk of AF (RR 0.90, 95% CI 0.81–1.01; P=0.07).

Caffeine and Overall Cardiovascular Health. A massive systematic review and dose-response meta-analysis, which included 36 studies of more than 1.2 million individuals, reported a nonlinear association of coffee consumption and CV risk.[12] Namely, moderate coffee intake was inversely associated with CV risk and the lowest risk occurred in the three- to  five-cups/day category. Even heavy coffee consumption did not associate with higher CV risk.

Caffeine's Lack of Acute Electrical Effects. Canadian researchers enrolled 80 patients who were to have catheter ablation of supraventricular tachycardia (SVT) in a clinical trial of caffeine exposure.[13] Half the group received caffeine tablets (5 mg/kg) and the other half received placebo 1 hour before the procedure. Caffeine intake mildly increased average systolic BP (143 vs 132 mm Hg) but it did not affect electrical properties of the atrium or ventricle.

Caffeine Safety in Patients With Heart Failure. Brazilian researchers used a randomized trial to assess the short-term effects of high-dose caffeine in patients with heart failure due to systolic dysfunction (mean LVEF 29%).[14] In a double-blinded fashion they gave 500 mg of oral caffeine or placebo to 51 patients and then measured the burden of atrial or ventricular premature beats. Despite the presence of severe underlying heart disease, caffeine ingestion did not cause ectopic beats.

Caffeine Safety in Pregnant Women. The bar for safety is higher in pregnancy. This given makes one of (the many) findings from a 2017 systematic review of more than 10,000 caffeine-related papers so remarkable.[15] The authors concluded that caffeine consumed in moderate doses (≤300 mg daily) during a healthy pregnancy was "generally" not associated with adverse reproductive or developmental effects.

Conclusions

The most obvious message of this sad story is that we should learn as much as possible when a young person dies for unknown reasons. When standard autopsies are negative, molecular techniques may reveal important genetic causes of death.

The second message is that we need to unlearn much of the dogma surrounding caffeine. The observational evidence is remarkably consistent: the intake of reasonable amounts of natural caffeine products, such as coffee, chocolate, and tea, does not associate with adverse health outcomes. The absence of acute cardiac effects from small randomized trials lends credence to the observational data. And . . . the possible protective effective of caffeine for incident AF is highly curious.

This reversal on caffeine is not trivial. When clinicians fuss about nonharmful substances, they distract patients from important things—weight loss, exercise, reduction of alcohol intake, and stress management, for instance.

I purposely left three caveats for the closing.

First, it's reasonable to be skeptical of observational evidence surrounding caffeine. Self-selection is a possible confounding variable: if coffee once caused palpitations, it's unlikely that person becomes a habitual coffee drinker.

Second, exposing the lack of evidence for prohibiting caffeine does not mean I condone the use of sugar- or alcohol-containing energy drinks. These drinks are the antithesis of naturally occurring. They often contain high doses of caffeine in combination with unhealthy doses of sugar or alcohol.

Finally, I acknowledge that individuals may have specific sensitivities to caffeine. If a patient ingests caffeine and experiences adverse effects, the obvious recommendation is to avoid caffeine.

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