Blood pressure safety of subanesthetic ketamine for depression: A report on 684 infusions

This retrospective open-label study (n=66) assessed the blood pressure safety profile of subanesthetic ketamine (35mg/70kg) infusion for patients with depression. Although hypertensive patients had higher blood pressure peaks during the infusions, the overall changes in blood pressure were small, well-tolerated, and clinically insignificant.

Abstract

“Background: The dissociative anesthetic agent ketamine is increasingly being utilized to treat depression, despite not having FDA (Food and Drug Administration) approval for this indication. There are many questions about the potential risks of this treatment and hence the proper setting and degree of monitoring required to ensure patient safety. There is limited data about the cardiovascular safety of ketamine when administered at subanesthetic doses to treat depression.

Methods: 66 patients in the Department of Psychiatry at Emory University received a total of 684 ketamine infusions between 2014 and 2016. Ketamine was dosed at 0.5 mg/kg body weight and infused over 40 min. Blood pressure was measured every 10 min during the infusions and every 15 min thereafter.

Results: Mean age of the patients was 56.7 years, 87.9% had unipolar depression and 36.1% had essential hypertension. No infusions were discontinued due to instability of vital signs, adverse physiological consequences or acute psychotomimetic effects. The biggest increases in blood pressure were measured at 30 min (systolic 3.28 mmHg, diastolic 3.17 mmHg). Hypertensive patients had higher blood pressure peaks during the infusions. Blood pressures returned to baseline during post-infusion monitoring. There was no development of tolerance to the blood pressure elevating effects of ketamine between the first and sixth infusions.

Limitations: This is a single site, retrospective analysis, of patients who were spontaneously seeking clinical care.

Conclusions: The blood pressure changes observed when ketamine is administered over 40 min at 0.5 mg/kg for the treatment of depression are small, well tolerated and clinically insignificant.”

Authors: Patricio Riva-Posse, Collin M.Reiff, Johnathan A.Edwards, Gregory P.Job, Gail C.Galendez, Steven J.Garlow, Tammy C.Saah, Boadie W.Dunlop, William M. McDonald

Summary

Ketamine, a dissociative anesthetic agent, is increasingly being utilized to treat depression, despite not having FDA approval for this indication.

1. Introduction

Ketamine, a dissociative anesthetic medication, was originally developed as an anesthetic agent, but is now being used in psychiatry for treatment-resistant depression. It causes an increase in heart rate, blood pressure, and cardiac output, and is used in the induction of general anesthesia.

Ketamine is being used off-label to treat mood disorders, but there is limited data on the safety and long-term risks of this agent. Some studies have shown that ketamine increases blood pressure, and some subjects required antihypertensive medications to treat the elevation.

Ketamine is used in psychiatry for the treatment of depression and suicidality. The protocols for its use are different from those used in general anesthesia or pain management.

2. Methods

All patients were evaluated in the Treatment Resistant Depression (TRD) Clinic at Emory University, and were given ketamine infusions as part of regular clinical care. The data collection and retrospective analysis presented in this report was authorized by the Emory University Institutional Review Board.

2.1. Data source

This report is based on the medical records of 66 sequential patients evaluated in the TRD clinic at Emory and recommended to receive ketamine treatment for depression. All patients were older than 18 years of age and had signed informed consent for the clinical use of ketamine for depression.

2.2. Medication preparation and administration

Racemic ketamine was administered by continuous IV infusion using an electronic infusion pump. Patients were required to fast at least 8 hours before drug administration and up until 2 hours after the start of infusion.

2.3. Vital sign monitoring

Patients were monitored with cardiac monitors with continuous heart rate and oxygen saturation. A baseline blood pressure of 160 mmHg, DBP 100 mmHg was required for patients to receive each ketamine infusion.

2.4. Clinical assessments

Before each infusion, patients completed the QIDS-SR16 and the CGI-S and CGI-I. They were monitored for cognitive, psychiatric, or urinary side effects.

2.5. Frequency of administration

The standard protocol started with biweekly infusions for the first three weeks, and then continued with once a week to once a month infusions depending on the duration of the antidepressant effect.

2.6. Statistical analysis

Initial exploratory analysis was completed using Minitab 17 (State College, PA), and full analyses were completed using R v3.4.1 (Vienna, Austria). Paired t-tests were used for within subject analyses and Student’s t-tests were used for comparisons between subgroups.

66 patients received a total of 684 infusions of ketamine, with the majority having major depressive disorder and 8 subjects having bipolar depression. All infusions were tolerated, and no patients required pharmacological intervention to treat elevated blood pressure.

3.2. Cardiovascular assessment

At the start of the infusion, average blood pressure was 105.27 mmHg, diastolic pressure was 71.81 mmHg and mean arterial pressure was 82.96 mmHg. Blood pressure increased by 3.28 mmHg, 3.17 mmHg and 3.21 mmHg, respectively, at 30 and 40 min, respectively.

3.3. Differences by groups (Table 3, Fig. 2)

Analyses were performed in patients with essential hypertension, patients who received lorazepam prior to infusion, and patients younger or older than 60 years old.

Patients with essential hypertension had higher SBP and lower DBP at the start of the infusion, and a higher peak systolic elevation at 30 min compared to normotensive patients. Patients who received pre-infusion lorazepam had higher systolic pressures and higher diastolic pressures at 30 and 40 min, respectively. Patients 60 years and older had higher systolic pressure and MAP throughout the infusions and the post-infusions, but lower diastolic pressures. Older patients had slightly higher increases in the systolic pressure at 30 min, and younger patients had peak systolic pressures at 40 min.

3.4. Clinically relevant increases in blood pressure

Sixty-three infusions were followed by a clinically significant increase in blood pressure, and fifty (79.5%) were elevations in diastolic blood pressure. Seventy-eight percent of the significantly elevated readings occurred at the 30- or 40-min marks.

3.5. Ketamine dose

All patients received 0.5 mg/kg of ketamine. Patients who received the largest dosage had the greatest increase in DBP during the first infusion.

4. Discussion

This study included patients with severe depression, who had tried several medications, half of them had previously received ECT, and the sample included both young and older adults.

Ketamine causes small average increases in blood pressures of approximately 3.2 mmHg in SBP, DBP, and MAP, but these changes are not clinically relevant.

Hypertensive patients have higher baseline systolic blood pressure and statistically significant increases in systolic blood pressure during ketamine infusion, but these differences resolve at the end of monitoring.

Lorazepam was initially used to manage distressing dissociative effects of ketamine. It was phased out after it was noticed that patients tolerated the infusion without requiring a sedative, and the patients who received lorazepam had consistently lower blood pressure readings.

Patients age 60 and over had larger increases in systolic blood pressure and smaller increases in diastolic blood pressure compared to patients under age 60, but no increased risk of adverse cardiac events.

Ketamine caused no tolerance in the subjects’ blood pressure. Some subjects had blood pressure elevations, but they were sporadic and did not reoccur.

This study was a retrospective analysis of clinical data abstracted from the charts of patients treated with ketamine for depression. It had several limitations, including the inability to correlate blood pressure changes with clinical outcome. Treatment resistant depression is predominantly reported in Caucasian populations, perhaps due to racial disparities in access to specialized care and cultural factors that impact minorities acceptance of treatment for severe mood disorders.

Ketamine, infused over 40 min at 0.5 mg/kg, is safe and well tolerated in the acute setting for the treatment of depression. More research is needed on the long-term effects of subanesthetic ketamine on the cardiovascular system, cognition, genitourinary system, hepatic toxicity and abuse liability.

Author statement

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