Ketamine for continuous sedation of mechanically ventilated patients.

CONTEXT: Long-term sedation with midazolam or propofol has been demonstrated to have serious adverse side effects, such as toxic accumulation or propofol infusion syndrome. Ketamine remains a viable alternative for continuous sedation as it is inexpensive and widely available, however, there are few analyses regarding its safety in this clinical setting.
OBJECTIVE: To review the data related to safety and efficacy of ketamine as a potential sedative agent in mechanically ventilated patients admitted to the intensive care unit (ICU).
MATERIALS AND METHODS: This was a single-center retrospective study from September 2011 to March 2012 of patients who required sedation for greater than 24 hours, in whom ketamine was selected as the primary sedative agent. All patients greater than 18 years of age, regardless of admitting diagnosis, were eligible for inclusion. Patients that received ketamine for continuous infusion but died prior to receiving it for 24 hours were not included.
RESULTS: Thirty patients received ketamine for continuous sedation. In four patients, ketamine was switched to another sedative agent due to possible adverse side effects. Of these, two patients had tachydysrhythmias, both with new onset atrial fibrillation and two patients had agitation believed to be caused by ketamine. The adverse event rate in our patient population was 13% (4/30).
CONCLUSIONS: Among ICU patients receiving prolonged mechanical ventilation, the use of ketamine appeared to have a frequency of adverse events similar to more common sedative agents, like propofol and benzodiazepines.

INTRODUCTION

Background

Continuous infusion of sedatives are often necessary in critically ill patients requiring mechanical ventilation to manage their anxiety, decrease excessive oxygen consumption, and facilitate care.[1] However, long-term sedation has been associated with a number of adverse effects including: Longer intensive care unit (ICU) stays,[2] higher costs[2], and increased mortality. Midazolam may produce acute withdrawal syndrome comprising of severe agitation, confusion, paranoid delusions, and hallucinations.[3] Propofol at high doses may cause propofol infusion syndrome (PRIS), consisting of metabolic acidosis, rhabdomyolysis, hyperlipidemia, and enlarged or fatty liver.[4] Newer agents like dexmedetomidine have been suggested as alternatives; nevertheless, they are expensive and may be associated with complications like hypotension, hypertension, nausea, bradycardia, atrial fibrillation, and hypoxia.[5] The current national drug shortage of benzodiazepines and propofol[6], has led to the use of other agents for long-term sedation in mechanically ventilated patients in many centers. At our institution, ketamine hydrochloride is generally used for continuous sedation in hypotensive patients requiring mechanical ventilation, with propofol being the agent of choice in the normotensive patient. Ketamine is a dissociative agent that works by effectively disconnecting the central nervous system from external stimuli.[7] It produces sedation, amnesia and analgesia, while preserving respiratory effort, cardiovascular stability and airway reflexes.[8] These qualities, in addition to low cost, wide availability, and a large therapeutic window, have made ketamine the anesthetic of choice for painful emergency department (ED) procedures in children.[9] Although ketamine's use in mechanically ventilated patients has not been well studied despite common use for this purpose in many developing countries, the above characteristics suggest its use will be favorable in many patients requiring ventilation.

Importance

In a pilot study assessing the hemodynamic and bronchodilator effects of continuous sedation with ketamine compared to fentanyl in ICU patients; it was reported that the ketamine group exhibited a higher mean arterial pressure (MAP), fewer vasopressor requirements, and were less likely to be found in a shock state.[8] Another study by Huber et al., demonstrated a two-thirds reduction in airway resistance compared to pretreatment values, following injection of ketamine in patients with moderate to severe bronchospasm.[10]

Goal of this investigation

We sought to determine the incidence of adverse events of ketamine as a sedative agent in patients who require mechanical ventilation for greater than 24 hours. We hypothesized that the rate of adverse events would be similar to more commonly utilized agents.

MATERIALS AND METHODS

Study design and setting

This was a single-center retrospective study of the use of ketamine for continuous sedation of mechanically ventilated patients greater than twenty-four hours between September 2011 and March 2012. These dates were chosen as they coincided with the peak shortage of traditional agents, and the greatest use of ketamine as the alternative. Ketamine was selected as the primary sedative agent, as determined by the treating physician. The study was performed at a tertiary-care suburban community Level 1 trauma center with an annual ED census of almost 101,000 patients. The study was approved by the hospital's Institutional Review Board with a waiver of informed consent.

Selection of participants

Consecutive patients admitted from the ED to the ICU receiving continuous sedation with ketamine were enrolled. All patients were intubated and mechanically ventilated. Inclusion criteria were the following:

Adult patients (age > 18 years); and

A need for light to moderate sedation using ketamine with infusion greater than 24 hours.

Additionally, patients included in our study had varying degrees of blood pressure and not all were hypotensive. Patients were excluded if they were pregnant, age <18 years, and received ketamine for less than 24 hours. Patients that received ketamine for continuous infusion but died prior to receiving it for 24 hours were excluded.

Interventions

Patients were mechanically ventilated according to standard practice in our ED. All patients received continuous sedation using ketamine started at 0.5 mg/kg/hr and titrated up to achieve appropriate sedation. No bolus was given.

Data collection and processing

Data was collected on multiple variables, including demographics, adverse events, ventilator days, ICU days, and mortality. Patient demographic data included patient name, age, medical record number, date of admit, and diagnosis. From the medication administration record, we collected data on the maximum dose of ketamine used, concurrent use of a fentanyl drip for additional analgesia, vasopressor use and number of vasopressors used. Also, we collected hemodynamic data that included the initial lactate and lactate after 24 hours of ketamine use, the average MAP in first 24 hours of ketamine use and the average heart rate in first 24 hours of ketamine use. To assess the adequacy of sedation, we collected data on the Motor Activity Assessment Score (MAAS) and reported the average MAAS in the first 24 hours. The goal MAAS was 2.0. The MAAS was charted by the nursing staff every 2 hours while in the ICU.

Adverse events were assessed by reviewing the nursing progress notes, which were updated every shift. Specifically, the onset of adverse events that are attributed to ketamine use were recorded, including tachyarrhythmias (new onset atrial fibrillation/flutter with rapid ventricular response (greater than 130 beats/minute), supraventricular tachycardia, ventricular tachycardia, ventricular fibrillation, or sinus tachycardia not thought to be related to underlying illness), hypersalivation requiring treatment with scopolamine or atropine, agitation, defined as the addition of another sedating agent or the discontinuation of ketamine for patients where adequate sedation could not be maintained. Additional measures that were recorded included ICU length of stay, total number of days on mechanical ventilation, and mortality.

Outcome measures

The primary outcome of this study was to determine the incidence of adverse events as defined above.

Secondary outcomes included, average MAAS score in the first 24 hours, average heart rate and mean arterial blood pressure in the first 24 hours, ICU Length of stay (LOS), mechanical ventilation days, vasopressor use, number of vasopressors required, and the use of concurrent opiates for additional sedation.

Primary data analysis

Descriptive statistics were used to analyze and report our data. Specifically, we report means and ranges of ketamine doses and duration of sedation, point estimates of adverse event rates, and confidence intervals using the exact method.

RESULTS

Characteristics of study patients

A total of 30 patients received continuous sedation with ketamine while mechanically ventilated for greater than 24 hours during our 6-month study period. Patient demographics are listed in Table 1.

Table 1

Patient demographics

Main results

The average dose of ketamine administered was 2.0 ± 0.98 mg/kg/hr, with a range of 0.5-4 mg/kg/hr. The median dose of ketamine administered was 2.0 mg/kg/hr (IQR, 1.1-2.5). The average dose in patients with adverse events was 2.4 ± 1.25 mg/kg/hr. The median dose of ketamine in patients with adverse events was 2.25 mg/kg/hr (interquartile range, IQR, 2-2.9). The mean duration of sedation with ketamine was 59.6 hours. In four patients ketamine was switched to another sedative agent due to possible adverse side effects. Of these, two patients (6.7%) (95% CI, 2%-21%) had tachydysrhythmias, both with new onset atrial fibrillation. Another two patients (6.7%) (95% cumulative incidence, CI, 2-21%) had agitation believed to becaused by ketamine. One of the patients with atrial fibrillation presented with pneumonia and sepsis while the other had a perforated colon and peritonitis. Both patients were maintained on one vasopressor, which was started prior to the development of atrial fibrillation. One of the patients with agitation presented with a history of heroin overdose and was maintained on a fentanyl drip while the other had pneumonia and sepsis. The adverse event rate in our patient population was 13% (4/30; 95% CI, 5%-30%). Additionally, none of our patients developed hypersalivation requiring the use of either atropine or a scopolamine patch (both of which are generally reserved for patients with significant hypersalivation at our institution). The average sedation score using the MAAS recorded from nursing notes was 1.9. Fifteen patients had fentanyl drips concurrently running with the ketamine infusion, which was a decision made by the treating team and not explained in the notes. None of the patients received propofol, dexmedetomidine, or benzodiazepines. Summary of adverse events and description of MAAS is listed in Tables 2 and 3, respectively.

Table 2

Summary of adverse events

Table 3

Motor activity assessment scale (MAAS)

Limitations

This is a single center, small study, with no comparison group. In comparing side effects to other studies, there is clinically significant difference between the events seen in our study and others. For example, there is considerable distinction between an adverse event of nausea/vomiting (often seen with narcotics) versus atrial fibrillation (which was seen in our study), or between general tachycardia and atrial fibrillation. Furthermore, agitation from withdrawal of narcotic/benzodiazepine is different from agitation occurring while ketamine is being administered. Some adverse events are more serious than others, and unless comparing similar patient populations and specifically defined adverse events across studies, it is difficult to make strong conclusions about comparisons. Additionally, retrospective chart review limits the ability to offer firm conclusions about the safety and efficacy of ketamine as a continuous sedative agent in mechanically ventilated patients greater than 24 hours. The MAAS recorded is not used as frequently as the Richmond Agitation Sedation Scale (RASS), therefore limiting the generalizability of our results. Lastly, one has to take into consideration the lack of proper adherence to guidelines for conducting a retrospective chart review as this can result in; incomplete or missing documentation, poorly recorded, and absent information.

DISCUSSION

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist, with a potent anesthetic effect.[11] It has traditionally been used to facilitate painful ED procedures in children. Overall, the use of ketamine for continuous sedation has been limited to a second line agent likely because of its perceived side effect profile and the unfamiliarity with its use. Although side effects are always a concern, several studies have shown that serious adverse events are rare[9] and likely occur at similar rates of other medication used for sedation. This study represents a retrospective review to examine the safety and efficacy of ketamine as a continuous sedative agent.

We found ketamine to be efficacious, with a frequency of adverse events similar to more common sedative agents, such as propofol and benzodiazepines. Ketamine appeared to have a favorable safety profile without significant effects on hemodynamics or agitation in our patient population.

As elucidated by Delvin et al., motor activity assessment scale score is a valid and reliable sedation scale for mechanically ventilated patients in the ICU.[12] Ketamine was able to produce adequate sedation, resulting in an average motor activity assessment score of 1.9 in our patients. Our target sedation score was between 0-2, with sedation ranging from unresponsive to responsive only to touch or name. This suggests efficacy of ketamine as a continuous agent helping to achieve appropriate sedation in mechanically ventilated patients.

In this study, adverse effects with ketamine occurred at a rate of 13%, affecting four out of our thirty patients, who had to be switched to another sedative agent. This rate is comparable to other sedatives as seen in a study by Dahaba et al., looking at remifentanil versus morphine analgesia and sedation for mechanically ventilated critically ill patients. In that study, the overall rate of adverse events was 8/20 or 40% in the remifentanil group, and 6/20 or 30% in the morphine group.[13] Adverse events included; nausea, vomiting, diaphoresis, depression, hypotension (MAP < 50 mm hg), tachycardia (Heart rate (HR) > 120 beats/min), hypertension (MAP > 120 mm hg), and dysrhythmia.[13] This can also be seen in another study by Riker et al., evaluating dexmedetomidine vs midazolam for sedation of critically ill patients. In this study, the dexmedetomidine treated group had an adverse event rate related to treatment of 40.6%, while the midazolam group had a rate of 28.7%.[14] Adverse events included; bradycardia, tachycardia, hypotension, hypertension, metabolic (hyperglycemia), infections (urinary tract infection and hospital acquired pneumonia), and 30-day mortality.[14]

Of the four patients with adverse effects, 2 or 7% had tachydysrhythmias, both with new onset atrial fibrillation. A similar rate was also seen in Dahaba et al., with 5% of patients in remifentanil and morphine group reporting tachycardia anddysrhythmia respectively.[13] Additionally, in Riker et al., tachycardia was present in 25.4% of the patients in the dexmedetomidine group and 44.3% of patients in the midazolam group.[14]

Of the four patients in our study with adverse effects, 2 (7%) had agitation requiring switching to another sedative agent. This rate is significantly lower as compared to that seen in an observational study by Katz et al., of 23 children receiving continuous fentanyl infusion. Withdrawal with agitation or delirium after cessation of fentanyl, was seen in 13 (57%).[15] Similarly, in two retrospective data collections on children who received sedation with midazolam for mechanical ventilation, 7.5% and 35%, respectively had withdrawal symptoms of agitation.[1617]

CONCLUSION

In summary, among ICU patients receiving prolonged mechanical ventilation, the use of ketamine appeared to have a frequency of adverse effects similar or lower to that of common sedatives like, propofol and benzodiazepines. Additionally, ketamine appeared to have a favorable safety profile in our patient population without significant effects on hemodynamics and agitation. Its efficacy as a sedative agent along with its low incidence of adverse effects, suggest it may be a reasonable alternative for patients requiring mechanical ventilation.