Introduction

Procedures performed under sedation are very common, but have the same incidence of severe morbidity and mortality as procedures performed under general anaesthesia.1–3 The demand for anaesthesia care outside the operating room has substantially increased and it poses major risks to those patients concerned.4 Respiratory depression has been commonly identified as the main risk to patients undergoing procedures under sedation.5–7 Adverse clinical events associated with hypercapnia include hypertension, tachycardia, cardiac arrhythmias and seizures.8,9 This situation is compounded by the fact that the pulse oximeter is not sensitive enough to detect hypoventilation in patients receiving supplemental oxygen until very late.10

Ketamine is an anaesthetic with an established role in perioperative analgesia, but its effects on clinical intraoperative hypoventilation in humans have not been examined.11,12 Other investigators have also suggested a beneficial effect of ketamine on airway patency and ventilation in patients undergoing sedation,13,14 but those investigations were limited by the lack of an objective measurement of clinical hypoventilation. It remains unknown whether the beneficial respiratory properties of ketamine can translate to a lower incidence and severity of hypoventilation in patients undergoing surgery under deep sedation.

The primary objective of the current investigation was to examine the effect of ketamine, when added to midazolam and propofol, on the duration and severity of hypoventilation as assessed by hypercapnia, in patients undergoing deep sedation. We hypothesised that ketamine would reduce the duration and severity of hypoventilation compared with isotonic saline.

Methods

This study was a prospective, randomised, double-blind placebo-controlled trial. Clinical trial registration for this study can be found at ClinicalTrial.gov; url:http://www.clinicaltrials.gov; registration identified: NCT01535976. Study approval was obtained from the Northwestern University Institutional Review Board, and written informed consent was obtained from all the study participants.

Eligible participants were women, American Society of Anesthesiologists’ Physical Status class one or two undergoing outpatient breast lumpectomy under monitored anaesthesia care and deep sedation. Patients with a history of allergy to ketamine or propofol, chronic use of an opioid analgesic or benzodiazepine drugs, and pregnant patients were not enrolled. Reasons for exclusion from the study following study drug administration were conversion from sedation to a general anaesthetic requiring the use of laryngeal mask airway or endotracheal tube.

Participants were allocated randomly using a computer-generated table of random numbers to one of two groups to receive ketamine (0.5 mg kg−1 bolus followed by 1.5 μg kg−1 min−1 infused until the end of the case) or a similar volume of isotonic saline. The ketamine dose chosen is similar to the one used by studies evaluating analgesic and anti-shivering effects of perioperative ketamine.15–17 Group assignments were sealed in sequentially numbered opaque envelopes that were opened by an investigator not involved with patient care. The study drug was prepared in syringes labelled ‘study drug’ to blind the anaesthesia provider (certified registered nurse anaesthetist) managing the patient and a research nurse responsible for data collection.

In the preoperative holding area, participants were asked to complete the Berlin questionnaire to assess sleep disorder breathing and the risk of sleep apnoea.18,19 All participants received 2 mg intravenous (i.v.) midazolam as a coinduction agent. In the operating room, monitors were applied according to American Society of Anesthesiologists’ standards. A transcutaneous carbon dioxide (TCO 2 ) monitor (TOSCA 500; Radiometer Inc., Westlake, Ohio, USA) was also applied to each participant's earlobe after calibration following the manufacturer's guidelines. TCO 2 data were collected electronically every 12 s for the duration of the study. The monitor display was not visible to the anaesthesia provider and was not used to support clinical decisions or airway manoeuvres. Supplemental oxygen was administered through a nasal cannula at 4 l min−1. A propofol infusion was started at 100 μg kg−1 min−1 and the anaesthesia provider was instructed to titrate this by 25 μg kg−1 min−1 every 5 min in order to produce a level of sedation on the Observer's Assessment of Sedation Scale (OASS) between 2 and 3 (0 = does not respond to pain, 1 = does not respond to mild prodding or shaking, 2 = responds after minor prodding or shaking, 3 = responds after calling loudly and repeatedly, 4 = responds slowly to voice with normal tone, 5 = responds readily to voice with normal tone).20 The study drug bolus and infusion were administered immediately after the propofol infusion was started. No opioids were administered intraoperatively. The OASS was assessed and recorded every minute for the duration of the procedure. In cases of upper airway obstruction and S a O 2 below 95%, a chin lift was performed. Before the surgical incision, local infiltration of 2% lidocaine was administered by the surgeon and the total volume was recorded.

As ketamine has been previously associated with the development of psychomimetic effects,21 the subjective psychomimetic effects of ketamine were evaluated before hospital discharge using a set of true/false questions from the lysergic acid diethylamine (LSD) short form of the Addiction Research Center Inventory (ARCI).22 The LSD ARCI has been validated and used to examine the psychomimetic effect of ketamine.23 One of the investigators (PF) blinded to group allocation was responsible for collecting other study data, including participants’ characteristics, details of the surgical procedure, number of airway interventions, postoperative pain scores, incidence of nausea and vomiting and time to hospital discharge.

The primary outcome for the study was the percentage of the sedation time that the participant's TCO 2 was greater than 6.7 kPa. The data used in the calculation for the primary outcome were electronically collected every 12 s by the device, downloaded to a spreadsheet and evaluated for the total duration of TCO 2 above the cut-off by a second investigator (PF). A second research assistant re-extracted the data to confirm accuracy. The level of TCO 2 (6.7 kPa) has been previously demonstrated to be equivalent to hypoventilation (P a CO 2 >6.0 kPa) detected by carbon dioxide measured in arterial blood in patients receiving deep sedation.24 Sedation time was calculated from the start of the propofol infusion until the patient demonstrated an OASS of at least 4 following discontinuation of the infusion at the end of surgery. Secondary analysis included the percentage time that the patients’ TCO 2 was above 8.0 kPa, which is consistent with the development of respiratory acidosis,24 the number of patients who did not exceed a TCO 2 more than 8.0 kPa during sedation, the number of airway manoeuvres performed, time to hospital discharge, the association between the percentage of sedation time more than 6.7 kPa and discharge time, and the incidence of psychomimetic side-effects.

Based on pilot data from 20 participants, the ketamine group had a median (SD) percentage duration of hypoventilation (TCO 2 >6.7 kPa) during sedation of 19 (29) compared with 48 (31) in the isotonic saline group. A sample size analysis determined that 23 participants per group would be required to achieve 90% power to detect a difference using a two-tailed Mann–Whitney test and α 0.05. The sample size calculation was made using PASS version 8.0.15 release date 14 January 2010 (NCSS, LLC, Kaysville, Utah, USA).

Non-normally distributed interval and ordinal data are reported as median (interquartile range) and were compared between groups using the Wilcoxon exact test. Categorical variables were evaluated using the Fisher's exact test. An α <0.005 was set to adjust for multiple comparisons in respiratory rates, TCO 2 values and OASS scores at intervals during the procedure. All reported P values are two-tailed. Statistical analysis was performed using R version 2.15.1, release date 6/12/2012 (The R Foundation for Statistical Computing, www.r-project.org).

Results

A Consort flow diagram is presented in Fig. 1. Fifty-four participants were enrolled and two participants were excluded after randomisation. One in the placebo group was unable to tolerate the procedure under sedation, which was converted to general anaesthesia. One participant in the ketamine group was excluded from the analysis because the monitor was not calibrated. Personal characteristics and surgical details were similar between the study groups (Table 1).

Fig. 1: Consort flow diagram describing recruitment, allocation, follow-up and analysis. Table 1: Personal and surgical characteristics and postoperative outcomes

The propofol dose (mg kg−1) and the dose in μg kg−1 min−1 are shown in Fig. 2. Respiratory rates, TCO 2 levels and sedation scores for 60 min of sedation in 5-min intervals from before the start of sedation are shown in Fig. 3. Respiratory rates were lower in the isotonic saline group at all intervals from 5 to 45 min. Median TCO 2 values were greater in the intervals between 20 and 40 min. There were no significant differences in OASS scores at any time. Heart rate, SBP and DBP at the same intervals are shown in Fig. 4. There were no significant differences in heart rate, SBP or DBP at any time.

Fig. 2: Box plot of propofol dose (mg kg−1) and dose in μg kg−1 min−1 for the study groups. Median total propofol in the isotonic saline group 6.0 mg kg−1 (95% confidence interval, CI 4.8 to 7.6) compared with 6.5 mg kg−1 (95% CI 5.6 to 9.7) in the ketamine group (P = 0.06). The propofol doses per min of sedation were 100 μg kg−1 min−1 (95% CI 85 to 114) and 110 μg kg−1 min (95% CI 98 to 120) for the isotonic saline and ketamine groups, respectively (P = 0.24). Median response is represented by the horizontal bar and the interquartile range (IQR) is depicted by the boxes. Whiskers represent the 10th and 90th percentiles of the data and circles represent the outliers. Fig. 3: Box plots of respiratory rate, transcutaneous carbon dioxide (TCO2) and Observer's Assessment of Sedation Scale scores (OASS) at 5 min intervals from the time just prior to the administration of the study drug. † = difference between isotonic saline and ketamine group (P < 0.005). Median response is represented by the horizontal bar and the interquartile range (IQR) is depicted by the boxes. Whiskers represent the 10th and 90th percentiles of the data and circles represent the 5th and 95th percentiles. Fig. 4: Box plot of heart rate, SBP and DBP at 5 min intervals from the time just prior to the administration of the study drug. There are no significant differences between groups at any time. Median response is represented by the horizontal bar and the interquartile range (IQR) is depicted by the boxes. Whiskers represent the 10th and 90th percentiles of the data and circles represent the 5th and 95th percentiles.

Participants in the ketamine group spent less of the total sedation time with a TCO 2 above 6.7 kPa, median 1.2% (95% confidence interval, CI, 0 to 83) of the total surgical time compared with the isotonic saline group, median 65.1% (95% CI, 0 to 88) (P = 0.01; Fig. 5). Participants in the ketamine group also demonstrated less severe hypoventilation (TCO 2 >8.0 kPa), median 0% (95% CI, 0 to 11.7) compared with a median of 28% (95% CI, 0 to 79.3; P = 0.0002) for the isotonic saline group. The number of participants who did not exceed a TCO 2 of 8.0 kPa during sedation was greater in the ketamine group, 19 of 26 compared with the isotonic saline group, six of 26 (P = 0.012). The ketamine group required fewer airway manoeuvres, median 0 (95% CI, 0 to 3) to maintain S a O 2 greater than 95% compared with a median of 3 (95% CI, 0 to 16) for the isotonic saline group (P = 0.004).

Fig. 5: Box plot of the percentage of the total sedation time with a TCO2 higher than 6.7 kPa, median 1.2% (95% confidence interval, CI, 0 to 83) of the total surgical time for the ketamine group compared with 65.1% (95% CI, 0 to 88) of the time in the isotonic saline group (P = 0.01). Median response is represented by the horizontal bar and the interquartile range (IQR) is depicted by the boxes. Whiskers represent the 10th and 90th percentiles of the data and circles represent the 5th and 95th percentiles.

There was no significant difference in verbal rating score for pain at 30 min or in the incidence of nausea or vomiting prior to hospital discharge. The median (95% CI) time to hospital discharge was shorter in the ketamine [75 (60 to 150) min] compared with the isotonic saline group, [110 (55 to 150) min] (P = 0.01). The incidence of psychomimetic side-effects was rare and did not differ significantly between the study groups (Table 2).

Table 2: Lysergic acid diethylamine Addiction Research Center Inventory questionnaire

Discussion

Several important findings have emerged from the current investigation. Participants who received subanaesthetic doses of ketamine in addition to propofol and midazolam for deep sedation spent less time with TCO 2 above 6.7 kPa than participants who received solely propofol and midazolam. In addition, the number of participants who did not exceed a TCO 2 value of 8.0 kPa and the fractional time with a TCO 2 more than 8.0 kPa was substantially reduced by the addition of ketamine. The need for airway rescue manoeuvres to maintain S a O 2 was also reduced. Taken together, our data suggest that the addition of ketamine is an effective strategy for reducing the duration and severity of intraoperative hypoventilation in patients undergoing surgery requiring deep levels of sedation.

Our findings have important clinical implications as hypoventilation has been identified as the major cause of morbidity and mortality in closed claim analysis of individuals undergoing surgery with sedation and monitored anaesthesia care.3 The current trend in clinical practice towards less invasive procedures, and more performed in an office-based setting using sedation, further increases the clinical importance of our findings.4 Future studies examining a possible effect of ketamine in reducing morbidity and mortality associated with intraoperative hypoventilation and hypercapnia are needed.

It was also interesting to note that patients in the ketamine group received similar doses of propofol compared with the isotonic saline group. Beneficial respiratory properties of the use of ketamine during sedation have been attributed to a propofol-sparing effect of the drug.25 The lack of a difference in propofol requirement in the current study may reflect longer procedure durations requiring deeper levels of sedation and the use of extensive field infiltration of local anaesthetic. Another possible explanation is a direct respiratory stimulating effect of ketamine,26 or a combination of both mechanisms could be responsible for the beneficial properties of ketamine in reducing hypoventilation in deeply sedated patients.

Other clinical studies have suggested that adding ketamine to propofol has beneficial effects on respiratory variables.21,27 Some studies have used indirect and less reliable measurements of hypoventilation such as end-tidal carbon dioxide, oxygen saturation and observed respiratory rate. In the current study, we measured hypoventilation continuously using a TCO 2 probe with data collected electronically every 12 s. Our group has previously demonstrated that the TCO 2 but not end-tidal carbon dioxide is a reliable method for detecting hypoventilation in deeply sedated patients.24

Another important finding of the current study was the shorter time to hospital discharge in patients receiving ketamine compared with isotonic saline. This finding has important clinical implications for the reduction of the economic burden of prolonged hospital stays after outpatient surgery.28,29 Even more interesting to note was a possible association between the duration of hypoventilation and time to hospital discharge. It is possible that hypercapnia can modulate common factors associated with delayed hospital discharge such as postoperative pain and nausea, although the current study was underpowered to detect these differences.

We did not observe any significant differences in regard of potential psychomimetic side-effects of ketamine in this study. However, it is important to note that we used an analgesic dose rather than an anaesthetic dose. Higher doses of ketamine have been shown to produce psychomimetic effects in patients undergoing sedation.30 It seems that lower doses of ketamine are effective in preventing hypoventilation without producing side-effects.

We have only studied healthy individuals and did not observe any significant haemodynamic adverse event in those receiving ketamine. It is, however, important to note that Olofsen et al.31 have observed a detrimental effect on cardiac output measurements in healthy volunteers receiving subanaesthetic doses of ketamine. In addition, as gender plays an important role in anaesthetic effect and recovery and we only studied female participants, future studies examining the role of ketamine on intraoperative hypoventilation including male participants are warranted.32

The administration of ketamine has been associated with hypersalivation, which is undesirable in deeply sedated patients without a protected airway. We did not pretreat our participants with an anticholinergic agent and did not observe clinically significant airway complications associated with hypersalivation. Brown et al.33 examined over 1000 children receiving ketamine administration for procedural sedation and reported that hypersalivation incidents were rare. The administration of an anticholinergic drug did not show benefit.

Our study should be considered in the context of its limitations. We targeted our sedation protocol to an observer assessment instead of using a depth of anaesthesia monitor such as the bispectral index monitor. We did not attempt to standardise the level of sedation using a depth of anaesthesia monitor because correlating the output of processed EEG monitors and the clinical levels of sedation using ketamine is controversial.34,35 We also examined patients requiring high doses of propofol for sedation and it is possible that we would not have observed the beneficial effects of ketamine if we had used a more superficial level of sedation. Patients requiring greater depth of sedation are at higher risk of hypoventilation and have the greatest need for interventions to reduce morbidity associated with severe hypercapnia. We did not use opioids as part of our study protocol and future studies examining the effect of ketamine on hypoventilation in clinical protocols that include opioids are warranted.

We only studied healthy patients and the number evaluated is too small to assess the risk of serious side-effects such as regurgitation and aspiration.36,37 In addition, the potential for cardiovascular side-effects in higher risk patients with hypertensive or ischaemic heart disease needs to be further evaluated before they are given ketamine.38–40

In summary, ketamine reduces the incidence and severity of hypoventilation in patients undergoing surgical procedures under deep sedation with propofol and midazolam. Patients receiving ketamine required fewer airway interventions to maintain adequate oxygenation. The low dose of ketamine used did not lead to a higher incidence of psychomimetic side-effects. As hypoventilation is the major factor responsible for major morbidity and mortality in patients undergoing sedation, ketamine should be considered in this setting to reduce the incidence and severity of hypercapnia.

Acknowledgements relating to this article

Assistance with the study: none.

Financial support and sponsorship: support was provided solely from institutional and/or departmental sources. Radiometer America Inc. provided devices and disposable equipment for the study. Radiometer America Inc. was not involved in any aspect of the study design, study conduct or article preparation.

Conflicts of interest: none.

Presentation: none.