Ketamine and Hypertension - What matters to Patients?
Ketamine produces a sympathomimetic response, typically leading to tachycardia and hypertension. Most often this elevation is modest, in keeping with light exercise. Concerns have been raised that ketamine therapy should be denied to those with hypertension, or those with cardiovascular risk factors. Some physicians advocate for the emergent treatment of ketamine associated hypertension (KIH) when it occurs during Ketamine Assisted Therapy (KAT).
Fundamental to evidence based medicine are the concepts of patient oriented outcomes versus disease oriented outcomes. Patient oriented outcomes are the things that matter to people; mortality, loss of a limb, hospitalizations, days sick. Disease oriented outcomes are surrogate markers that may correlate to clinical outcomes, such as cholesterol levels predicting heart attacks or uric acid for gout. However, disease oriented outcomes are often of less importance to patients than patient oriented outcomes – a drug that lowers cholesterol numbers but leads to painful leg cramps is unlikely to be acceptable.
Returning to hypertension, the initial recommended treatment is diuretics or ace inhibitors, medications that have both been shown to reduce blood pressure, and more importantly, to decrease long term mortality. Beta blockers are used only later in therapy, because despite being very effective in lowering blood pressure, they produce little to no effect on mortality. This represents a problem when a disease oriented outcome (blood pressure number) does not correlate with a primary patient oriented outcome (mortality). We have long realized that there is little point in treating a number if there is no benefit to the patient.
Another Epidemiology Moment
Number needed to treat (NNT) – Simply put, this is the inverse of the number of people who got better out of the number given the medication or treatment. A very effective medication is dexamethasone, which has an NNT of 7 in the treatment of croup; for every 7 children treated, one gets better. On the other hand, antibiotics for sinusitis are not recommended because the NNT for benefit is 17, higher than the NNH of 8 for harms, which means that one in eight had significant side effects, while only one in 17 was helped.
The treatment of hypertension has a surprisingly high NNT. In 125 people who take blood pressure medication for five years, one fewer will die. Even when taking blood pressure medication to prevent stroke, 67 people must take medication for five years to avert 1 stroke. The difficulty in treating hypertension is managing the side effects which are much more common than the benefits, with an NNT of 10 for harms or stopping medication. While the benefits to the individual are relatively low, we know that by treating people on a population basis, we can avert significant numbers of heart attacks and strokes. But, it is important to understand that the majority of people taking these medications are not helped.
Hypertension and end-organ damage
The reason for treating hypertension is that over the long term, years to decades, persistent elevated blood pressure produces damage to blood vessels and increases the risk of heart attack, stroke, and other cardiovascular diseases. End organ damage is the term used for the pathology caused by persistent elevated blood pressure and is manifested as retinopathy and vision loss, kidney failure, heart failure, atherosclerosis, and cerebral ischemia. However, all of these take considerable time to develop. A Canadian study followed over 30,000 people who presented with asymptomatic high blood pressure for 2 years and found that there was no increased risk for cardiovascular outcomes, even in the group that presented with BP >180/110.
From exercise physiology, it is also understood that transient increases in blood pressure do not result in adverse outcomes by themselves. Under heavy resistance, athletes can generate systolic blood pressure greater than 300 mm Hg with no adverse effects.
This evidence suggests that transiently acutely elevated blood pressure without end organ damage is a very poor surrogate marker for acute events.
A hypertensive emergency is defined as significantly elevated blood pressure accompanied by signs of end organ damage, such as confusion, chest pain, shortness of breath or visual loss. Hypertensive emergency is very rare, while asymptomatic hypertension (AHT) is very common. In the absence of end organ damage, the American College of Emergency Physicians recommends that patients who present with AHT be discharged, with or without treatment, to be seen by their primary care provider. For AHT, acute treatment with antihypertensive medication is discouraged as this can lead to acute harms.
The American College of Cardiology notes that recreational drugs such as cocaine, amphetamine and “bath salts” have the potential to increase blood pressure. They do not recommend acute treatment with hypertensives in the absence of end organ damage, but rather waiting until the effects of these substances wear off. This is consistent with general practice in the emergency room, where the elevated blood pressure is a recognized side effect of these substances, rather than representing pathology.
While blood pressure is recognized as a vital sign, low blood pressure is more highly associated with acute pathology than high blood pressure.
In order to calculate the number needed to harm (NNH) from elevated blood pressure due to ketamine, we would need to express this as the number of acute harms associated with acute ketamine administration over the number of patients who have received ketamine (this could be in any setting, including the emergency department). The harms should be patient oriented rather than disease oriented, particularly in that we have shown that transient AHT is a poor surrogate for acute disease. In a recent systematic review of side effects associated with the use of ketamine depression, there were no reports of myocardial infarction or stroke in 60 studies of almost 900 patients. While it is likely that there could be some unreported episodes of bad cardiovascular outcomes from ketamine therapy, based on the evidence, the NNH is a very large number, approaching infinity.
Although it makes sense to avoid ketamine use in those with poor cardiac reserve (i.e. unable to climb two flights of stairs), mistaking elevated blood pressure for a bad outcome is likely to unnecessarily limit access to ketamine therapy. More concerning are protocols for the treatment of elevated blood pressure due to ketamine; these are likely to outlast the effects of the ketamine and rapid lowering of blood pressure is associated with bad outcomes in a way that acute elevations of blood pressure are not.