Ketamine PCA led to lower cumulative opioid consumption and lower oxygen supplementation requirements, though hallucinations occurred more frequently with use of ketamine. Additional studies are needed to investigate the tolerability of ketamine as an alternative to traditional opioid-based PCA.

Twenty subjects were randomized. There was no difference in median daily breakthrough opioid use (10 [0.63-19.38] mg versus 10 [4.38-22.5] mg, P = 0.55). Subjects in the ketamine group had lower median cumulative opioid use on therapy day 1 than the hydromorphone group (4.6 [2.5-15] mg versus 41.8 [31.8-50] mg, P < 0.001), as well as in the first 48 h (10 [3.3-15] mg versus 48.5 [32.1-67.5] mg, P < 0.001) and first 72 h (10 [4.2-15] mg versus 42.5 [31.7-65.2] mg, P < 0.001) of therapy. Daily oxygen supplementation requirements were lower in the ketamine group (0.5 [0-1.5] L/min versus 2 [0.5-3] L/min, P = 0.020). Hallucinations occurred more frequently in the ketamine group (40% versus 0%, P = 0.090).

This is an investigator-initiated, single-center, double-blinded, randomized, pilot trial conducted from 2014 to 2016 at a level 1 trauma center. Nonintubated trauma patients in intensive care, who were receiving PCA, were randomized to ketamine or hydromorphone PCA plus opioid analgesics for breakthrough pain.

It is unknown whether ketamine administered via patient-controlled analgesia (PCA) provides adequate analgesia while reducing opioid consumption in the traumatically injured patient. Differences in opioid consumption, pain scores, and adverse effects between ketamine and hydromorphone PCA were studied.

This pilot study aimed to assess the efficacy of ketamine PCA compared with hydromorphone PCA for baseline analgesia in nonintubated trauma patients with acute pain initially treated in the intensive care unit (ICU). It was hypothesized that ketamine PCA would lead to decreased breakthrough opioid use and similar pain scores compared with hydromorphone PCA in traumatically injured patients.

Ketamine is an N-methyl-D-aspartate antagonist approved for use in induction and maintenance of general anesthesia. Ketamine has also been effective as a primary or adjunctive analgesic agent in postoperative patients.Analgesia from ketamine occurs via noncompetitive blockade of glutamate, resulting in modulation of central sensation and hyperalgesia as well as direct activity on kappa, delta, and mu-1 receptors.Potential side effects of ketamine include hypertension, tachycardia, hallucinatory effects, and laryngospasm.Notably, ketamine lacks the dose-limiting side effects of central nervous system and respiratory depression, key features distinguishing it from opioids.As such, ketamine has gained interest as an alternative or adjunctive analgesic for acute pain management in military and civilian medicine.Ketamine has been studied in PCA devices in combination with opioid agents, but no published studies have evaluated ketamine-only PCA in trauma patients.

Opioids administered via continuous infusion, epidural infusion, intermittent intravenous (IV) push or orally, or via patient-controlled analgesia (PCA) device are the preferred analgesia for severely injured patients in the acute phase of care.Although opioids provide effective analgesia, untoward effects such as respiratory depression are dose-limiting which may result in the inability to achieve adequate pain relief in some patients.Acute and chronic opioid use has also come under scrutiny related to the current abuse epidemic in the United States as prescription opioid use may lead to increased risk of prescription and illicit drug abuse.The rate of overdose deaths involving opioids has increased by 200% since the year 2000.Prescription opioid and heroin abuse led to a record high death rate due to overdose in 2014, a 14% increase from 2013.Alternative analgesic agents may help patients achieve acceptable pain control and decrease opioid use in the acute post-traumatic and postoperative setting and curtail the need for postacute and chronic opioid therapy.

Opioids and the management of chronic severe pain in the elderly: consensus statement of an International Expert Panel with focus on the six clinically most often used World Health Organization step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone).

Given the pilot nature of this study, it was planned to enroll a total of 30 patients (15 in the ketamine group and 15 in the hydromorphone group). This sample size would provide 80% power with an alpha level of 0.05 to detect at least 10 ± 10 mg absolute difference in total daily breakthrough IV morphine equivalents between the groups.

Data were analyzed using SAS, version 9.4 (SAS Institute; Cary, NC). An intention-to-treat model was used for data analysis. Nominal data were reported using frequencies of occurrence and proportions as appropriate. Ordinal and continuous data were reported using medians and interquartile ranges. Hypothesis testing was two-sided and was performed using the Fisher's exact test or chi-square test as appropriate based on sample size. Ordinal and nonparametric continuous data were compared using a Wilcoxon rank-sum test. A P-value < 0.05 was considered statistically significant.

The primary outcome was daily breakthrough opioid requirements between the two groups; total daily opioid requirement was assessed as a secondary outcome. Median daily pain scores measured via the NRS were also evaluated. All opioid requirements were measured in mg of IV morphine equivalents. Other outcomes included oxygen desaturation frequency (oxygen saturation less than 92%), incidence of nausea and vomiting, incidence of bowel movements, and incidence of hallucinations and delirium. Delirium was assessed by nurses caring for the patient using the Confusion Assessment Method for the ICU score; all nurses were trained on use of the Confusion Assessment Method for the ICU score as part of standard care for patients in the unit.Hospital length of stay, ICU-free days, and incidence of use of opioids on first follow-up appointment after hospital discharge were also assessed.

Lorazepam 0.5-1 mg IV was available for treatment of potential patient-reported hallucinations. If hallucinations occurred, subjects received lorazepam 0.5 mg IV. If symptoms of hallucinations did not resolve in 20 min, they were eligible to receive an additional 0.5 mg of lorazepam. Subjects continued randomized therapy until transfer or discharge from the ICU, or if they were transitioned off of PCA therapy to oral analgesia per the trauma physician while in the ICU. Once study treatment was stopped, analgesic therapy was at the discretion of the trauma physician.

Participants underwent randomization to either ketamine or hydromorphone PCA. Randomization was performed using the computerized Wichmann-Hill random number generator in blocks of 10. Participants were assigned to interventions using the random number generator by the local investigational drug services, and study personnel were not involved in randomization or treatment group assignments. Participants, caretakers, and study personnel were blinded to the treatment groups. To maintain blinding, the concentrations of ketamine and hydromorphone in the dispensed PCA syringes were set for the study so that each dosage setting (standard, minimum, or maximum) would deliver the same volume of drug whether the PCA contained ketamine or hydromorphone. Pain scores were measured using the Numeric Rating Scale (NRS) by nurses caring for the subjects who were trained on the use of the NRS. The NRS ranges from 0 to 10, where 0 was no pain and 10 was the worst possible pain.PCA settings allowed for doses of ketamine 1.5-6 mg IV bolus with a lockout of 6 min or hydromorphone 0.1-0.4 mg IV bolus with a lockout of 6 min ( Fig. 1 ). No hourly limits were set, and basal infusions were reserved for subjects with persistent severe pain at highest intermittent dose and PCA mode. Both groups could receive breakthrough opioid analgesia outside of the PCA as hydromorphone 0.5 mg IV push every 2 h as needed for pain scores with NRS of 4-6 or hydromorphone 1 mg IV push every 2 h as needed for pain scores with NRS of 7-10. Pain scores were assessed by nursing per ICU standard of care every 2 h using the NRS.

Nonintubated trauma surgery patients admitted to the surgical ICU were evaluated for inclusion in the study from April 2014 through August 2016. Patients were included if they (i) were adults aged ≥ 18 y, (ii) had a total injury severity scoreof greater than 9, (iii) were planned to receive or were using a PCA for delivery of analgesic therapy, (iv) were able to effectively use a PCA device as assessed by a physician, and (v) had at least one major orthopedic injury, defined as an upper or lower extremity fracture with an Abbreviated Injury Scale of greater than or equal to 2.Due to challenges encountered with a low number of patients meeting these criteria, the inclusion criterion for orthopedic injury was removed 14 mo after the trial commenced. Patients were excluded for (i) body mass index greater than 35 kilograms per meter squared (kg/m), (ii) history of bipolar disorder or schizophrenia, (iii) acute kidney injury (defined as serum creatinine increase of 2-3 times baseline or a glomerular filtration rate decrease of greater than 50%),(iv) history of chronic kidney disease, (v) history of liver failure, (vi) history of heart failure or coronary artery disease, (vii) opioid use as outpatient maintenance therapy, (viii) need of treatment of acute withdrawal as indicated by an order for active monitoring of alcohol withdrawal by the treating physician, (ix) Glasgow Coma Scale (GCS) score < 13 or a motor sub-score below six at the time of enrollment, (x) allergy to any medications used in the study (i.e., ketamine, hydromorphone, or lorazepam), (xi) pregnancy, or (xii) actively incarcerated. Cognitive function was assessed for continuation in the study by using the GCS every 6 h. Participants were deemed cognitively impaired and ineligible for continuation if they had a GCS score < 13.

This study was an investigator-initiated, single-center, randomized, patient- and caregiver-blinded, controlled study. The methodology was approved by the University of Cincinnati and the Wright–Patterson Air Force Base Institutional Review Boards. Informed consent was obtained for all subjects at the time of enrollment.

There were also no differences in the rates of nausea and vomiting, pruritus, oxygen desaturation events, and spontaneous bowel movements between the two groups ( Table 3 ). Daily oxygen supplementation requirements, however, were lower in the ketamine PCA group than the hydromorphone PCA group (0.5 [0-1.5] L/min versus 2 [0.5-3] L/min, P = 0.02).

Hemodynamic effects between the two groups were similar, with the exception of maximum daily mean arterial pressure in millimeters of mercury (mm Hg) which was significantly higher in the ketamine group than the hydromorphone group (107 [104-113] mm Hg versus 95 [87-104] mm Hg, P = 0.01, Fig. 3 ). No difference was noted in minimum daily mean arterial pressures (79 [69-85] mm Hg versus 70 [65-78] mm Hg, P = 0.19). Study subjects’ daily minimum and maximum heart rates were recorded, but no difference was noted between the groups.

More participants in the ketamine group experienced hallucinations compared with the hydromorphone group, but this did not reach statistical significance ( Table 3 ). There was no difference in the number of lorazepam doses administered between the two groups for management of hallucinations or other indications ( Table 3 ). There was no difference in the incidence of ICU delirium.

Hospital length of stay, ICU length of stay, and ICU-free days in the ketamine versus hydromorphone group were similar ( Table 2 ). All participants who had a documented follow-up visit in the trauma clinic after discharge from the hospital (six subjects in the ketamine group and nine subjects in the hydromorphone group) reported continued use of opioid analgesics. Median time to follow-up after hospital discharge was 10 d.

Total opioid use was significantly lower in the ketamine group in the first 48 h (10 mg versus 48.5 mg, P < 0.001) and first 72 h (10 mg versus 42.5 mg, P < 0.001) of the study. In addition, the total amount of opioid that a subject received per day of therapy was significantly lower in the ketamine group than the hydromorphone group (9.2 mg versus 45 mg, P = 0.02). NRS values were not statistically different between the two groups for each day of therapy ( Table 2 ). There were no differences noted in the adjunctive analgesic therapies used between the two groups ( Table 3 ).

Opioid use in the two groups is listed in Table 2 . There was no difference in breakthrough opioid use between the ketamine and hydromorphone groups at any time point in the study or in daily median breakthrough opioid use over the course of treatment (10 mg [0.63-19.38 mg] versus 10 mg [4.38-22.5 mg], P = 0.55). In addition, subjects received a similar median number of breakthrough opioid doses/d between the two groups. Subjects in the ketamine group had a lower median total opioid use on day 1 of therapy than the hydromorphone group ( Table 2 ).

Participants enrolled in the study largely remained on the standard starting dose of PCA therapy, with the exception of the following four subjects. Two participants in the hydromorphone group moved to the maximum delivered PCA dose because of uncontrolled pain, one after 17 h of therapy and one after 24 h of therapy. No patients required use of the basal rate of study drug to be administered. One participant in each group moved to the minimum dose of PCA therapy due to excessive somnolence. There were no statistically significant differences in transition of PCA doses between the two groups.

Due to unanticipated barriers to enrollment, including a lower than expected number of eligible patients meeting inclusion criteria, study enrollment was suspended before reaching the planned 30 patients. A total of 330 patients met the inclusion criteria for enrollment between April 2014 and August 2016, and 266 patients met one or more exclusion criteria ( Fig. 2 ). Forty-five patients met the inclusion criteria, but were excluded for various reasons outside of exclusion criteria ( Fig. 2 ). Twenty participants were enrolled in the study, underwent randomization, and were included in the intention-to-treat analysis. Four subjects in the ketamine group withdrew from the study after initiating treatment (study days 1, 4, 1, and 3, respectively), and one subject in the hydromorphone group withdrew from the study after initiating treatment (study day 1) (P = 0.30). No statistically significant differences in demographics were noted between the ketamine group and the hydromorphone group ( Table 1 ).

Discussion

The objective of this pilot study was to compare opioid use and pain scores between nonintubated trauma patients in the ICU receiving ketamine PCA or hydromorphone PCA. Breakthrough opioid use was not found to be different between the two groups, but cumulative opioid use was lower in the ketamine PCA group than the hydromorphone PCA group. Higher cumulative opioid use in the hydromorphone PCA group was not unexpected, as those patients were receiving opioid through their PCA and the ketamine PCA group was not. Despite ketamine patients receiving significantly less total opioid, pain scores were not significantly different between the two groups. Lengths of stay in the ICU and hospital were not different between the two groups. These results indicate that ketamine delivered via a PCA is a useful adjunctive agent for acute analgesia for trauma patients in the ICU setting. All subjects in the study with a documented follow-up visit reported continued use of opioid medications on first follow-up appointment. Median time to follow-up was 10 d, and so the clinical meaning of this data is difficult to interpret given that first follow-up encounter was relatively soon after hospital discharge.

It is possible that differences in patient demographics including race, sex, age, and injury patterns may be associated with differing responses to analgesic agents; however, we are unable to assess this given the pilot nature and size of this trial. The protocol for inclusion of patients was altered 14 mo after the study commenced due to low enrollment in the initial study period. Patients with orthopedic injury had initially been an inclusion criterion to attempt to standardize injury and pain patterns from a civilian trauma population to those seen in military blast-type injuries without traumatic brain injury. Total and abbreviated injury severity scores were similar between the groups, and so this likely accounts for any differences in injury type or location between the ketamine and hydromorphone groups.

1 Barr J.

Fraser G.L.

Puntillo K.

et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. , 2 Malchow R.J.

Black I.H. The evolution of pain management in the critically ill trauma patient: emerging concepts from the global war on terrorism. 1 Barr J.

Fraser G.L.

Puntillo K.

et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. 1 Barr J.

Fraser G.L.

Puntillo K.

et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Consequences of uncontrolled pain in critically ill postoperative patients include exhaustion due to lack of sleep, disorientation, agitation, stress response, and post-traumatic stress disorder.Patients recall pain as a major source of stress during their ICU stays.Use of opioid medications for the treatment of acute pain in critically ill trauma patients is a standard of care, but the adverse effect profile of these agents may limit optimal efficacy, particularly hypotension, bradycardia, central nervous system depression, decreased gastrointestinal motility, and respiratory depression.Notably, the ketamine group in this pilot study had lower oxygen supplementation requirements than the hydromorphone group, which could be an indicator of improved respiratory function in the ketamine group and lower rates of respiratory depression.

3 Smythe M. Patient-controlled analgesia: a review. 21 Erstad B.L.

Patanwala A.E. Ketamine for analgosedation in critically ill patients. 21 Erstad B.L.

Patanwala A.E. Ketamine for analgosedation in critically ill patients. 22 Lilburn J.K.

Dundee J.W.

Nair S.G.

et al. Ketamine sequelae. Evaluation of the ability of various premedicants to attenuate its psychic actions. Administering analgesia via a PCA device allows patients to deliver analgesic doses when required and can prevent overuse by implementing a lockout for dose administration, allowing baseline analgesia to be achieved without over-sedation or undertreatment.The primary mechanism of action for ketamine is through N-methyl-D-aspartate antagonism, although the drug may exhibit additional receptor activity including opioid receptor antagonism and gamma aminobutyric acid antagonism.When administered intravenously, ketamine has an immediate onset of action, with a dose-dependent duration of action of 5-20 minThis short onset and duration of action may be advantageous for PCA. The adverse effect profile of ketamine differs from opioids that are traditionally used by PCA. Ketamine is less likely to depress respiratory protective reflexes and to cause respiratory depression compared with opioids. Ketamine can cause both excitatory and depressive effects in the central nervous system, whereas opioids cause only depressive effects. Ketamine may cause hallucinations or other psycho-mimetic reactions, and these anticipated effects can be treated with use of intermittent benzodiazepines.

Hallucinations occurred in 40% of subjects in the ketamine PCA group in this study compared with none in the hydromorphone PCA group. These results may be important in considering the tolerability of ketamine PCA. In addition, differences in hallucination rates could have potentially impacted resources utilized in the ICU, including need for additional patient observation or monitoring or replacement of medical devices inadvertently removed by the patient, or ICU and hospital lengths of stay. Differences in resources used were not collected in this study, but the study did find that ICU and hospital lengths of stay were similar between the two groups. However, hallucinations may be a reasonable short- and long-term tradeoff compared to effects and consequences of opioid use. If the role of ketamine in analgesic therapy—including via PCA delivery—can be further established in future studies, it may become an important tool considering the current climate of the opioid abuse crisis in the United States.

21 Erstad B.L.

Patanwala A.E. Ketamine for analgosedation in critically ill patients. The effects of ketamine on the cardiovascular system differ from opioids and other sedative agents through inhibiting catecholamine reuptake leading to increased heart rate and blood pressure. Conversely, opioid use may lead to reduced heart rate and blood pressure.No differences in hemodynamic effects were observed between the two groups, with the exception of higher maximum daily mean arterial pressure in the ketamine group compared with the hydromorphone group. This was expected based on anticipated effects of ketamine on the cardiovascular system listed previously.

5 Dowell D.

Haegerich T.M.

Chou R. CDC guideline for prescribing opioids for chronic pain–United States 2016. 23 Guillou N.

Tanguy M.

Seguin P.

et al. The effects of small-dose ketamine on morphine consumption in surgical intensive care unit patients after major abdominal surgery. Studies have shown that ketamine provides analgesia when administered at subdissociative doses (bolus doses < 500 mcg/kg).One trial evaluated the analgesic effects of postoperative small-dose ketamine continuous infusion of 2 mcg/kg/min compared to placebo on morphine consumption in 101 patients receiving morphine PCA after major abdominal surgery. Cumulative 4-h morphine doses were significantly lower in the ketamine group than the placebo group. Mean morphine consumption over 48 h was also significantly lower in the ketamine group than the placebo group (58 ± 35 mg versus 80 ± 37 mg, P < 0.05). The mean ketamine consumption over 48 h was 367 ± 37 mg. No significant differences in adverse effects between the two groups were observed, though this could be due to the fact that the study did not meet target enrollment.Although supportive of ketamine as an adjunctive therapy, use as a continuous infusion may have limited practicality across inpatient environments.

8 Dickenson A.H. NMDA receptor antagonists: interactions with opioids. , 24 Wang L.

Johnston B.

Kaushal A.

et al. Ketamine added to morphine or hydromorphone patient-controlled analgesia for acute postoperative pain in adults: a systematic review and meta-analysis of randomized trials. 9 Adriaenssens G.

Vermeyen K.M.

Hoffman V.L.

et al. Postoperative analgesia with i.v. patient-controlled morphine: effect of adding ketamine. , 10 Javery K.B.

Ussery T.W.

Steger H.G.

Colclough G.W. Comparison of morphine and morphine with ketamine for postoperative analgesia. , 11 Chazan S.

Buda I.

Nesher N.

et al. Low-dose ketamine via intravenous patient-controlled analgesia device after various transthoracic procedures improves analgesia and patient and family satisfaction. , 12 Nesher N.

Ekstein M.P.

Paz Y.

et al. Morphine with adjuvant ketamine vs higher dose of morphine alone for immediate postthoracotomy analgesia. 25 Sveticic G.

Farzanegan F.

Zmoos P.

et al. Is the combination of morphine with ketamine better than morphine alone for postoperative intravenous patient-controlled analgesia?. , 26 Reeves M.

Lindholm D.E.

Myles P.S.

et al. Adding ketamine to morphine for patient-controlled analgesia after major abdominal surgery: a double-blinded, randomized controlled trial. 27 Cohen S.P.

DeJesus M. Ketamine patient-controlled analgesia for dysesthetic central pain. 28 Mion G.

Tourtier J.P.

Rousseau J.M. Ketamine in PCA: what is the effective dose?. Other studies have evaluated the combination of opioids plus ketamine PCA compared to opioids alone.These studies have wide variability in bolus PCA doses, lockouts, and limits on the PCA pumps. Many trials have shown improved pain control and opioid-sparing effects of this strategy with no differences in adverse events.However, other studies show no advantage to the combination of morphine and ketamine in PCAs compared to morphine alone.One case report describes the use of ketamine alone in a PCA device for a patient experiencing intractable central pain. The settings on the PCA device were a basal rate of ketamine delivered at 2.7 mg/h with a 2.7-mg bolus demand dose. The lockout was 15 min with no 4-h limit. Ketamine was a viable treatment option to control pain in this report.From these studies, intermittent ketamine PCA doses between 2 and 5 mg have been suggested.

A limitation of the pain assessments for this study is that all pain scores were combined and not collected at different times when patient activity may have varied. Pain scores may vary when a patient is at rest versus with activity, as well as before and after breakthrough analgesics are administered, and this was not recorded and reported in this study.

The major limitation of the present study was unforeseen low enrollment rate. Many patients were ineligible because they met exclusion criteria set to mitigate potential confounders given the pilot nature of the trial. Also, a higher than anticipated number of patients declined to participate in the study after being deemed eligible. In addition, there was a relatively high withdrawal rate from the study. Five patients withdrew after receiving treatment: three due to experiencing the effects of hallucinations, a well-known effect of ketamine, and two due to a perception of inadequate analgesia. Although “as needed” lorazepam was available for intermittent treatment of hallucinations, scheduled low-dose benzodiazepine may have better addressed this adverse effect. The decision to not use a scheduled frequency for lorazepam in this study was to avoid additional risk in the hydromorphone subjects given additive adverse effects of combination therapy. The study was stopped early by the investigators due to the high dropout rate and challenges with enrollment, which may cause the study to be underpowered to find statistically significant differences where they exist. This also may speak to a limited feasibility of the use of ketamine PCA in a general trauma population at doses used in this study. Alternative or lower ketamine doses, or PCA lock-out settings, may provide a different effect and should be further investigated. Future investigations of ketamine-only PCA should note these challenges in awake patients receiving randomized therapy.