Anesthesiology Research and Practice

Anesthesiology Research and Practice / 2020 / Article

Review Article | Open Access

Volume 2020 |Article ID 9637412 | https://doi.org/10.1155/2020/9637412

Nathan J. Smischney, Mohamed O. Seisa, Allison S. Morrow, Oscar J. Ponce, Zhen Wang, Muayad Alzuabi, Katherine J. Heise, Mohammad H. Murad, "Effect of Ketamine/Propofol Admixture on Peri-Induction Hemodynamics: A Systematic Review and Meta-Analysis", Anesthesiology Research and Practice, vol. 2020, Article ID 9637412, 15 pages, 2020. https://doi.org/10.1155/2020/9637412

Effect of Ketamine/Propofol Admixture on Peri-Induction Hemodynamics: A Systematic Review and Meta-Analysis

Academic Editor: Enrico Camporesi
Received17 Feb 2020
Accepted15 Apr 2020
Published08 May 2020

Abstract

To evaluate the effectiveness of an admixture of ketamine and propofol on peri-induction hemodynamics during airway manipulation, we searched electronic databases of randomized controlled trials from January 1, 2000, to October 17, 2018. Trial screening, selection, and data extraction were done independently by two reviewers with outcomes pooled across included trials using the random-effects model. We included 10 randomized trials (722 patients, mean age of 53.99 years, 39.96% female). American Society of Anesthesiologists physical status was reported in 9 trials with classes I and II representing the majority. Ketamine/propofol admixture was associated with a nonsignificant increase in heart rate (weighted mean difference, 3.36 beats per minute (95% CI, −0.88, 7.60), I2 = 88.6%), a statistically significant increase in systolic blood pressure (weighted mean difference, 9.67 mmHg (95% CI, 1.48, 17.86), I2 = 87.2%), a nonsignificant increase in diastolic blood pressure (weighted mean difference, 2.18 mmHg (95% CI, −2.82, 7.19), I2 = 73.1%), and a nonsignificant increase in mean arterial pressure (weighted mean difference, 3.28 mmHg (95% CI, −0.94, 7.49), I2 = 69.9%) compared to other agents. The risk of bias was high and the certainty of evidence was low. In conclusion, among patients undergoing airway manipulation and needing sedation, the use of a ketamine/propofol admixture may be associated with better hemodynamics compared to nonketamine/propofol sedation. This trial is registered with CRD42019125725.

1. Introduction

Peri-intubation hypotension, defined by either systolic blood pressure or mean arterial pressure (MAP) below a certain threshold (i.e., <90 mmHg or <65 mmHg) or the introduction of vasopressors, has been recognized as a potential target area for research given its association with patient-centered outcomes. For example, peri-intubation hypotension has been associated with both increased length of stay and mortality [13]. Furthermore, this association has been identified not only in the critically ill but also in elective surgical patients [4, 5]. Several studies indicate that the frequency with which peri-intubation hypotension occurs is fairly high, with one report indicating an incidence of greater than 80% [1, 2, 5, 6]. However, the data presented on the frequency is dependent on definitions currently used in the literature for which no standard consensus exists. Perhaps, the best evidence for peri-intubation hypotension incidence in the critically ill comes from Green and colleagues [7]. They performed a systematic review of emergent intubations performed outside the operating room and found that the incidence of peri-intubation hypotension ranged from 5 to 440 cases per 1,000 intubations (0.5–44%) with a pooled estimate of 110 cases per 1,000 intubations (11%) [7]. Thus, peri-intubation hypotension is not uncommon, and given the associations observed in the literature, prevention of peri-intubation hypotension is likely to improve patient-centered outcomes.

Several putative risk factors have been implicated in the pathway to peri-intubation hypotension. Age, illness severity, and preintubation hemodynamic derangement have consistently been implicated in the development of peri-intubation hypotension [2, 3, 8, 9]. One modifiable risk factor potentially leading to peri-intubation hypotension is the choice of intravenous anesthetics with some anesthetics (i.e., propofol and barbiturates) more likely to lead to peri-intubation hypotension than others (i.e., etomidate and ketamine) [10]. Lately, a novel intravenous anesthetic admixture has gained popularity based on potential hemodynamic preservation postadministration [1113]. The admixture involves the combination of propofol with its vasodilatory effects balanced by the vasoconstricting properties of ketamine [10].

The majority of studies on ketamine/propofol admixture have evaluated critically ill patients in the emergency department with the evidence demonstrating a potential sparing effect on hemodynamics along with improved pain relief and sedation quality. These studies have evaluated ketamine/propofol admixture from the standpoint of a continuous infusion for procedural sedation and analgesia [1416]. There have been a couple of systematic reviews on ketamine/propofol admixture sedation, demonstrating that ketamine/propofol admixture appears safe and efficacious for procedural sedation and analgesia and is possibly better than propofol only at reducing cardiorespiratory problems [17, 18]. The wealth of the evidence above has mainly focused on ketamine/propofol admixture use in terms of infusions for procedural sedation and analgesia. There are limited studies addressing the potential hemodynamic preservation effects of the admixture when administered as an induction agent for endotracheal intubation. Given the above associations between peri-intubation hypotension and increased patient morbidity and mortality, and the mounting evidence with ketamine/propofol admixture as an agent that allows potential maintenance of hemodynamics when administered for endotracheal intubation, our aim was to perform a systematic review and meta-analysis on the hemodynamic effects of ketamine/propofol admixture when administered as an induction agent for airway manipulation such as endotracheal intubation.

2. Methods

We used the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2015 statement to report the trial [1922]. All reviews were conducted by two independent reviewers (MS and AM). Data collection was performed from January 1, 2000, to October 17, 2018. A formal protocol does not exist for this systematic review and meta-analysis. The review was registered with the International Prospective Register of Systematic Reviews (CRD42019125725).

2.1. Eligibility Criteria

Randomized controlled trials published in peer-reviewed journals and written in English were eligible if they included the following: (1) adult patients who received ketamine/propofol admixture as an induction agent in procedural areas and underwent airway manipulation such as endotracheal intubation or supraglottic device placement; (2) a comparison to other induction agents including propofol, ketamine, etomidate, and sodium thiopental or any other combination; and (3) a report of hemodynamic effects (heart rate, systolic and diastolic blood pressure, and MAP) during the first 10 minutes after the induction of general anesthesia in American Society of Anesthesiologists I II, III, and IV patients. The intervention must have equal or similar doses (e.g., ketamine/propofol admixture 1 : 1 or 1 : 2 ratios). No restrictions were placed on trial location, clinical procedure, or patient severity. We excluded pediatric patients, patients who did not undergo induction of anesthesia, or patients who did not undergo airway manipulation. We also excluded observational studies, review articles, erratum, letters, and notes.

2.2. Data Sources and Search Strategies

A comprehensive search of several databases was conducted by a medical reference librarian. The databases included Ovid MEDLINE, Epub Ahead of Print, Ovid Medline In-Process and Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus. Controlled vocabulary supplemented with keywords was used to search for the trials. We limited our search from January 1, 2000, to October 17, 2018. The search strategy is listed in Table 1.


SearchesResults

1exp Propofol/66561
2exp Ketamine/42453
31 and 26807
4exp Anesthetics, combined/232731
5exp Drug Therapy, Combination/496978
63 and (4 or 5)5984
7((ketamine adj2 propofol) or ketofol).ti,ab,hw,kw.2372
8From 6 keep 5441–5620180
97 or 82519
10exp evidence based medicine/1070204
11exp meta analysis/242451
12exp Meta-Analysisas topic/55758
13exp “systematic review”/178680
14exp controlled study/6264333
15exp Randomized Controlled Trial/971579
16exp triple blind procedure/194
17exp Double-Blind Method/420309
18exp Single-Blind Method/76722
19exp latin square design/353
20exp Placebos/342744
21exp Placebo Effect/10767
22exp Cohort Studies/2330769
23exp retrospective study/1404531
24exp prospective study/1038291
25((evidence adj based) or (meta adj analys) or (systematic adj3 review) or (control adj3 study) or (control adj3 trial) or (randomized adj3 study) or (randomized adj3 trial) or (randomised adj3 study) or (randomised adj3 trial) or “pragmatic clinical trial” or (random adj1 allocat) or (doubl adj blind) or (doubl adj mask) or (singl adj blind) or (singl adj mask) or (tripl adj blind) or (tripl adj mask) or (trebl adj blind) or (trebl adj mask) or “Latin square” or placebo or nocebo or cohort or retrospectiv or prospectiv or (random and (trial or study))).mp,pt.12961593
26or/10–2513401432
279 and 261493
28limit 27 to (editorial or erratum or letter or note or addresses or autobiography or bibliography or biography or blogs or comment or dictionary or directory or interactive tutorial or interview or lectures or legal cases or legislation or news or newspaper article or overall or patient education handout or periodical index or portraits or published erratum or video-audio media or webcasts) (limit not valid in Embase, CCTR,CDSR, Ovid MEDLINE(R), Ovid MEDLINE(R) Daily Update, OvidMEDLINE(R) In-Process, Ovid MEDLINE(R) Publisher; records were retained)13
29From 28 keep 111
30(27 not 28) or 291481
31limit 30 to yr = “2000-Current”1296
32Remove duplicates from 31817
Database(s): Embase 1988 to 2018 Week 42, EBM Reviews-Cochrane Central Register of Controlled Trials September 2018, EBM Reviews-Cochrane Database of Systematic Reviews 2005 to October 11, 2018, Ovid MEDLINE(R) and Epub Ahead of Print, In-Process and Other Non-Indexed Citations and Daily 1946 to October 16, 2018
Scopus
1TITLE-ABS-KEY((ketamine W/2 propofol) OR ketofol)
2TITLE-ABS-KEY((evidence W/1 based) OR (meta W/1 analys) OR (systematic W/3 review) OR (control W/3 study) OR (control W/3 trial) OR (randomized W/3 study) OR (randomized W/3 trial) OR (randomised W/3 study) OR (randomised W/3 trial) OR “pragmatic clinical trial” OR (random W/1 allocat) OR (doubl W/1 blind) OR (doubl W/1 mask) OR (singl W/1 blind) OR (singl W/1 mask) OR (tripl W/1 blind) OR (tripl W/1 mask) OR (trebl W/1 blind) OR (trebl W/1 mask) OR “Latin square” OR placebo OR nocebo OR cohort OR retrospectiv OR prospectiv OR (random and (trial or study)))
3PUBYEAR AFT 1999 4 1 and 2 and 3
5DOCTYPE(le) OR DOCTYPE(ed) OR DOCTYPE(bk) OR DOCTYPE(er) OR DOCTYPE(no) OR DOCTYPE(sh) 6 4 and not 5
7PMID(0) OR PMID(1) OR PMID(2) OR PMID(3) OR PMID(4) OR PMID(5) OR PMID(6) OR PMID(7) OR PMID(8) OR PMID(9) 8 6 and not 7

2.3. Trial Selection

Reviewers, working independently, screened abstracts and titles for eligibility using the above inclusion and exclusion criteria. Full-text articles were then further screened using the same criteria. At the level of full-text screening, any disagreements were resolved by consensus between the two reviewers (MS and AM) or by consulting a third reviewer (NJS).

2.4. Outcomes

The primary outcomes were hemodynamics (heart rate, systolic and diastolic blood pressure, and MAP) at 5 and 10 minutes following intravenous anesthetic administration. The secondary outcome of interest was pain score as assessed by the visual analog scale (VAS) during the 24 hours postdrug administration.

2.5. Methodological Quality and Certainty of Evidence

The risk of bias was assessed using the Cochrane Collaboration’s tool for randomized clinical trials. We assessed random sequence generation, allocation concealment, blinding of providers, outcome assessors, and patients, incomplete outcome data, selective outcome reporting (based on the availability of protocol and inclusion of all prespecified outcomes), and other sources of bias (conflict of interest, source funding, risk of bias due to deviations from the intended interventions, etc.). Disagreements were resolved by consensus between two reviewers (MS and AM). The overall certainty across trials for each outcome was appraised by discussion between the two reviewers using the grading of recommendations assessment, development, and evaluation (GRADE) approach. Using the grading of recommendations assessment, development, and evaluation approach, randomized trials, as in this systematic review, would provide a starting level of certainty that is high. This level can be downgraded based on the risk of bias of the individual trials, inconsistency in the results, indirectness, imprecision, and other considerations to provide a global assessment of the certainty warranted by the body of evidence [23].

2.6. Data Extraction

Two reviewers (MS and AM) independently extracted the following information from each trial: author, publication year, patient characteristics, intervention, comparison, and outcomes.

2.7. Data Synthesis and Statistical Analysis

We extracted or calculated the weighted mean difference (WMD) for continuous outcomes and relative risk for binary outcomes with associated 95% confidence intervals (CIs) from the included studies. Outcomes without measures of variations (e.g., standard deviation, standard error, and CI) were not included in the meta-analysis. The DerSimonian and Laird random-effects models were used to generate combined effects [24]. A two-sided value of less than or equal to 0.05 was used to determine significance for the secondary outcome. To evaluate heterogeneity, we calculated the I2 statistic [25, 26] and heterogeneity values, where I2 more than 50% or a value of less than 0.05 suggests high heterogeneity. All statistical analyses were performed using Stata, version 15.0 (StataCorp 2017, College Station, Texas, United States).

3. Results

3.1. Trial Inclusion

The searches identified 820 trials. After excluding the irrelevant trials, 33 full-text articles were assessed for eligibility, of which 10 randomized controlled trials (30%) met all criteria and were included in data analysis (n = 722) (Figure 1). All the trials were reported in full-length journal articles.

3.2. Trial Characteristics

There were a total of 10 trials with 722 patients included. The number of patients in each trial ranged from 40 to 100 (mean, 72.22) with a mean age of 53.99 years. The proportion of participants who were female ranged from 0 to 100% (mean, 39.96%). The American Society of Anesthesiologists physiologic status among participants ranged from I to III. Publication dates ranged from 2000 to 2018 (median, 2011 (all trials published after 2000)). The included trials were conducted in several different countries (four trials in Turkey, three trials in Iran, and one trial from India, Japan, Egypt, and United States). The characteristics of the included trials with dosing are summarized in Table 2.


Author, yearIntervention
-other adjuncts
Dose descriptionPatientsFemale, (%)Age, years (mean ± SD)Weight, kg (mean ± SD) or median (range)Care locationASA class (%)

Abdalla, 2015 [27]Ketamine/propofol admixture
-Atracurium
Ketamine: 1 mg/kg
Propofol: 2 mg/kg
3046.638 ± 10.761.8 ± 9.7Procedural suiteII: 80
III: 20
Dexmedetomidine + propofol
-Atracurium
Dexmedetomidine: 1 mcg/kg
Propofol: 2 mg/kg
3033.342.7 ± 8.760.7 ± 8.5Procedural suiteII: 86
III: 14

Aghdaii, 2015 [28]Ketamine/propofol admixture
-Sufentanil
-Cisatracurium
Ketamine: 1 mg/kg
Propofol: 1 mg/kg
503057.36 ± 5.572.06 ± 8.7ORII: 60
III: 40
Etomidate + midazolam
-Sufentanil
-Cisatracurium
Etomidate: 0.2 mg/kg
Midazolam: 0.06 mg/kg
503457.16 ± 5.671.28 ± 11.2ORII: 66
III: 34

Aydogan, 2014 [29]Ketamine/propofol admixtureKetamine: 100 mg
Propofol: 100 mg
205570 ± 65.8367 (50–100)ORI: 45
II: 55
PropofolPropofol: 200 mg205069 ± 65.8368 (50–102)ORI: 50
II: 50

Baradari, 2017 [30]Ketamine/propofol admixture
-Fentanyl
-Midazolam -Atracurium
Ketamine: 1 mg/kg
Propofol: 1.5 mg/kg
4139.0258.71 ± 9.2BMI: 26.85 ± 3.89ORI: 35
II: 65
Etomidate + placebo
-Fentanyl
-Midazolam
-Atracurium
Etomidate: 0.2 mg/kg
Placebo: normal saline
403062.23 ± 6.3BMI: 25.23 ± 4.02ORI: 49
II: 51

Erdogan, 2013 [31]Ketamine/propofol admixture
-Fentanyl
Ketamine: 0.75 mg/kg
Propofol: 0.75 mg/kg
40071.67 ± 7.171.05 ± 9.37ORI: 30
II: 70
Propofol
-Fentanyl
Propofol: 0.15 ml/kg (10 mg/ml)40070.85 ± 5.9571.32 ± 9.58ORI: 35
II: 65

Hosseinzadeh, 2013 [32]Ketamine/propofol admixture
-Fentanyl
-Midazolam
-Atracurium
Ketamine: 0.75 mg/kg
Propofol: 1 mg/kg
3046.765.97 ± 9.3173.48 ± 8.98ORI: 20
II:73.3
III: 6.7
Etomidate + propofol
-Fentanyl
-Midazolam
-Atracurium
Etomidate: 0.2 mg/kg
Propofol: 1 mg/kg
3234.463.91 ± 10.0572.00 ± 10.73ORI: 12.5
II: 68.8
III: 18.7

Iwata, 2009 [33]Propofol + placebo
-Fentanyl
-Atropine
-Vecuronium
Propofol: 2.0 mg/kg
Placebo: normal saline
1546.668 ± 1058 ± 11ORN/R
Ketamine/propofol admixture 0.5
-Fentanyl
-Atropine
-Vecuronium
Ketamine: 0.5 mg/kg
Propofol: 2 mg/kg
1546.669 ± 556 ± 10ORN/R
Ketamine/propofol admixture 1.0
-Fentanyl
-Atropine
-Vecuronium
Ketamine: 1 mg/kg
Propofol: 2 mg/kg
1533.366 ± 1056 ± 10ORN/R

Ozgul, 2013 [34]Ketamine/propofol admixture
-Remifentanil
Ketamine: 0.2 ml/kg (5 mg/ml)
Propofol: 0.2 ml/kg (5 mg/ml)
404537.75 ± 9.670.35 ± 12.42ORN/R
Propofol
-Remifentanil
Propofol: 0.2 ml/kg (10 mg/ml)4057.541.47 ± 12.8673.52 ± 12.61ORN/R

Smischney, 2012 [11]Ketamine/propofol admixture
-Fentanyl
-Midazolam
Ketamine: 0.75 mg/kg
Propofol: 1.5 mg/kg
416542 ± 1268.9 ± 11.2ORI: 35
II: 65
Propofol
-Fentanyl
-Midazolam
Propofol: 2 mg/kg436543 ± 1169.2 ± 11.7ORI: 49
II: 51

Vora, 2005 [35]Ketamine/propofol admixture
-Fentanyl
-Midazolam
Ketamine: 50 mg
Propofol: 100 mg
3033.342 ± 7.0549.4 ± 11.7Procedural suiteI-II: 100
Propofol + thiopentone
-Fentanyl
-Midazolam
Propofol: 100 mg
Thiopentone: 125 mg
3043.340.05 ± 9.2853.6 ± 10.4Procedural suite
Propofol + lignocaine
-Fentanyl
-Midazolam
Propofol: 190 mg
Lignocaine: 20 mg
303039.6 ± 11.951 ± 9.52Procedural suite

ASA: American Society of Anesthesiologists; BMI: body mass index; kg: kilograms; mcg: micrograms; mg: milligrams; ml: milliliters; N/R: not reported; OR: operating room; SD: standard deviation.
3.3. Risk of Bias

Overall, the risk of bias of included trials was high due to inadequate allocation concealment (7/10, 70%), partial blinding of outcome assessor (4/10, 40%), and selective reporting (9/10, 90%). The risk of summary bias is provided in Table 3.


TrialRandom sequence generationAllocation concealmentParticipant/personnel blindingBlinding of outcome assessmentIncomplete outcome data, % loss to follow-upSelective reportingOther sources of biasOverall risk

Abdalla, 2015Low riskUnclearLow riskUnclearLow risk, 0%UnclearUnclearHigh
Aghdaii, 2015Low riskUnclearUnclearLow riskUnclear, N/RUnclearUnclearHigh
Aydogan, 2014Low riskLow riskLow riskLow riskLow risk, 0%UnclearLow riskLow
Baradari, 2017High riskLow riskLow riskLow riskLow risk, 3.5%Low riskLow riskLow
Erdogan, 2013Low riskUnclearLow riskUnclearLow risk, 0%UnclearUnclearHigh
Hosseinzadeh, 2013Low riskUnclearLow riskLow riskUnclear, N/RUnclearLow riskModerate
Iwata, 2009Low riskUnclearUnclearLow riskUnclear, N/RUnclearUnclearHigh
Ozgul, 2013Low riskUnclearLow riskUnclearUnclear, N/RUnclearUnclearHigh
Smischney, 2012Low riskLow riskLow riskLow riskLow risk, 0%UnclearLow riskLow
Vora, 2005UnclearUnclearLow riskUnclearUnclear, N/RHigh riskUnclearHigh

N/R: not reported.
3.4. Heart Rate

Heart rate at 5 minutes was reported in six trials (n = 465) [11, 2831, 34], and three trials (n = 244) [11, 31, 34] reported heart rate at 10 minutes. All trials assessed ketamine/propofol admixture, four compared to propofol and two compared to etomidate at 5 minutes and three compared to propofol at 10 minutes. Patients in the ketamine/propofol admixture group had a nonsignificant increase in heart rate at 5 minutes (WMD, 3.36 beats per minute (95% CI, −0.88 to 7.60), I2 = 88.6%) and 10 minutes (WMD, 0.36 beats per minute (95% CI, −2.57 to 3.29), I2 = 69.9%) compared to patients in the nonketamine/propofol admixture group (Table 4 and Figures 2(a) and 2(b)).


InterventionOutcomeConclusionStudy design/sample sizeCertainty of evidence

Ketamine/propofol admixture vs. nonketamine/propofol admixtureHR 5 minWMD, 3.36 mmHg (95% CI, −0.88 to 7.60), I2 = 88.6%Six RCTs (n = 465) 11, 27–31Very low due to risk of bias, imprecision, and inconsistency
HR 10 minWMD, 0.36 mmHg (95% CI, −2.57 to 3.29), I2 = 69.9%Three RCTs (n = 244) 11, 27, 29Very low due to risk of bias, imprecision, and inconsistency
SBP 5 minWMD, 9.67 mmHg (95% CI, 1.48 to 17.86), I2 = 87.2%Five RCTs (n = 385) 11, 27–28, 30–31Low due to risk of bias and inconsistency
SBP 10 minWMD, 4.56 mmHg (95% CI, −1.09 to 10.20), I2 = 0.0%Two RCTs (n = 164) 11, 27Low due to risk of bias and imprecision
DBP 5 minWMD, 2.18 mmHg (95% CI, −2.82 to 7.19), I2 = 73.1%Four RCTs (n = 305) 11, 28, 30–31Very low due to risk of bias, inconsistency, and imprecision
DBP 10 minWMD, 4.80 mmHg (95% CI, 0.24 to 9.36), I2 = N/AOne RCT (n = 84) 11Low due to risk of bias and imprecision
MAP 5 minWMD, 3.28 mmHg (95% CI, −0.94 to 7.49), I2 = 69.9%Four RCTs (n = 345) 11, 29–31Very low due to risk of bias, imprecision, and inconsistency
MAP 10 minWMD, 4.08 mmHg (95% CI, −0.22 to 8.39), I2 = 41.4Two RCTs (n = 164) 11, 29Low due to risk of bias and imprecision

CI: confidence interval; HR: heart rate; WMD: weighted mean difference; RCT: randomized controlled trial; SBP: systolic blood pressure; DBP: diastolic blood pressure; MAP: mean arterial pressure; N/A: not applicable.
3.5. Systolic Blood Pressure

Systolic blood pressure at 5 minutes was reported in five trials (n = 385) [11, 2831] and two trials (n = 164) [11, 31] reported systolic blood pressure at 10 minutes. All trials assessed ketamine/propofol admixture, three compared to propofol and two compared to etomidate at 5 minutes and two compared to propofol at 10 minutes. Ketamine/propofol admixture was associated with a statistically significant increase in systolic blood pressure at 5 minutes when compared to nonketamine/propofol admixture intravenous anesthetics (WMD, 9.67 mmHg (95% CI, 1.48 to 17.86), I2 = 87.2%). At 10 minutes, patients in the ketamine/propofol admixture group had a nonsignificant increase in systolic blood pressure compared to patients in the nonketamine/propofol admixture group (WMD, 4.56 mmHg (95% CI, −1.09 to 10.20), I2 = 0.0%) (Table 4 and Figures 3(a) and 3(b)).

3.6. Diastolic Blood Pressure

Diastolic blood pressure at 5 minutes was reported in four trials (n = 305) [11, 2830] and one trial (n = 84) [11] reported diastolic blood pressure at 10 minutes. All trials assessed ketamine/propofol admixture, two compared to propofol and two compared to etomidate at 5 minutes and one trial compared to propofol at 10 minutes. Patients in the ketamine/propofol admixture group had a nonsignificant increase in diastolic blood pressure at 5 minutes (WMD, 2.18 mmHg (95% CI, −2.82 to 7.19), I2 = 73.1%) compared to patients in the nonketamine/propofol admixture group. At 10 minutes, there was a statistically significant increase in diastolic blood pressure in the ketamine/propofol admixture group compared to the nonketamine/propofol admixture group (WMD, 4.80 mmHg (95% CI, 0.24 to 9.36), I2 = not applicable) (Table 4 and Figures 4(a) and 4(b)).

3.7. Mean Arterial Pressure

Mean arterial pressure at 5 minutes was reported in four trials (n = 345) [11, 28, 30, 34] and 2 trials (n = 164) [11, 34] reported MAP at 10 minutes. All trials assessed ketamine/propofol admixture, two compared to propofol and two compared to etomidate at 5 minutes and two compared to propofol at 10 minutes. Patients in the ketamine/propofol admixture group had a nonsignificant increase in MAP at 5 minutes (WMD, 3.28 mmHg (95% CI, −0.94 to 7.49), I2 = 69.9%) and 10 minutes (WMD, 4.08 mmHg (95% CI, −0.22 to 8.39), I2 = 41.4%) compared to patients in the nonketamine/propofol admixture group (Table 4 and Figures 5(a) and 5(b)).

3.8. Pain

Only one trial assessed postprocedural pain by VAS (n = 60) [27]. Twenty-six patients in the propofol plus dexmedetomidine group and all patients in the ketamine/propofol admixture group (30 patients) had VAS 1-2 (difference between groups, ). Four patients in the propofol plus dexmedetomidine group had higher pain scores (VAS 3–5) whereas no patients in the ketamine/propofol admixture group had high pain scores (VAS 3–5, difference between groups, ).

4. Discussion

The present systematic review and meta-analysis demonstrate that ketamine/propofol admixture results in a potentially better hemodynamic profile as compared to other agents used for induction of anesthesia. In particular, systolic blood pressure was significantly higher with ketamine/propofol admixture sedation as compared to nonketamine/propofol admixture sedation when induction of anesthesia is required for airway manipulation. Although not statistically significant, heart rate, diastolic blood pressure, and MAP were higher when ketamine/propofol admixture-based sedation was employed versus nonketamine/propofol admixture based-sedation for induction of anesthesia. Furthermore, one study indicated a possible beneficial effect on pain scores in the immediate 24 hours postdrug administration [27].

Evidence has demonstrated that maintaining hemodynamics around the time of airway instrumentation such as endotracheal intubation is vitally important, in both the critically ill and noncritically ill. For example, in the critically ill, peri-intubation hypotension was associated with increased odds of dying (39% peri-intubation hypotension versus 30% no peri-intubation hypotension, ) and increased odds of experiencing intensive care unit length of stay greater than 14 days, duration of mechanical ventilation longer than 7 days, and requiring renal replacement therapy (odds ratio 2.0, 95% CI: 1.30–3.07, ) [1]. These observations have been demonstrated in other populations of critically ill patients [36]. In noncritically ill patients undergoing noncardiac surgery, a significant fraction of all hypotensive events occurred before skin incision and, therefore, due to anesthetic management as demonstrated in one study. In addition, this study revealed that the odds of developing acute kidney injury increased with MAP less than 65 mmHg (odds ratio 1.02, 95% CI: 1.01–1.04, ) [37]. Moreover, patients undergoing noncardiac surgery who experienced intraoperative hypotension defined as MAP less than 65 mmHg or a MAP decrease of 20% from baseline had increased odds of developing both myocardial and kidney injury [38]. Likewise, patients who developed greater than a 30% decrease in MAP from baseline intraoperatively had increased odds of developing postoperative stroke (odds ratio 1.013/min hypotension, 99.9% CI: 1.000–1.025, ) [39].

A recent systematic review suggested poor outcomes with increased end-organ injury in patients undergoing noncardiac surgery who experience MAP decreases <80 mm Hg for ≥10 minutes [40]. By the same token, elevated MAP thresholds have been postulated to be beneficial in the critically ill population. For example, one study demonstrated improved microcirculation in septic shock patients with previous hypertension when MAP was increased above a threshold of 65 mmHg [41]. Furthermore, others have shown that maintaining MAP well above 65 mmHg (i.e., 85 mmHg) in septic, critically ill patients may result in less myocardial and kidney injury as well as decreasing overall mortality [42].

Given that periprocedure (i.e., endotracheal intubation) hemodynamics are influenced by sedation and the preponderance of evidence demonstrating that preventing hypotensive episodes, especially with MAPs less than 65 mmHg or SBPs less than 90 mmHg, and maintaining perfusion pressure near baseline improves outcomes, the selection of an intravenous anesthetic agent during a procedure (i.e., endotracheal intubation) ought to have this goal in mind. To this end, a recent editorial questioned the current blood pressure parameter of MAP 65 mmHg in the intensive care unit, which largely comes from two retrospective studies [43]. The authors suggested that perhaps mean perfusion pressure, which is defined by MAP minus central venous pressure, may be a better parameter to use as compared to the current parameter of MAP. While we did not look at long-term outcomes in our current study, we demonstrated that induction with ketamine/propofol admixture rather than other intravenous anesthetic agents resulted in better hemodynamics. Therefore, it is possible that this may translate into improved patient-centered outcomes. Although elevated perfusion pressures may be advantageous in the general sense, this has to be individually tailored to each patient as high pressure/heart rate may be harmful to some. For example, ketamine may exacerbate myocardial ischemia in noncompensated coronary artery disease or hypertension through its effects on central nervous system stimulation and inhibition of norepinephrine reuptake (i.e., cardiac population) [10].

The current systematic review and meta-analysis are consistent with prior reviews of ketamine/propofol admixture administration for procedural sedation. Prior reviews have demonstrated better hemodynamics with ketamine/propofol admixture-based procedural sedation than with nonketamine/propofol admixture-based procedural sedation. For example, a recent review demonstrated that ketamine/propofol admixture-based procedural sedation was effective in reducing cardiovascular complications (relative risk for hypotension 0.11, 95% CI: 0.17–0.97, ; relative risk for bradycardia 0.47, 95% CI: 0.28–0.72, ). The authors also demonstrated similar rates of psychotomimetic complications and nausea-vomiting when compared to propofol [18]. A second review assessed adverse respiratory events and recovery times with ketamine/propofol admixture-based procedural sedation as compared to propofol-based procedural sedation. The authors noted that adverse respiratory events were significantly reduced with ketamine/propofol admixture as compared to propofol (risk ratio 0.82, 95% CI: 0.68–0.99, ); however, recovery times were similar in both groups. Hemodynamic thresholds were not assessed in this review [44]. Although the above reviews point towards the safety of this combination, the admixture can, by its very nature, lead to some undesired effects. Apart from the use of ketamine in the cardiac population (discussed above), ketamine causes initial release of glutamate through nicotinamide adenine dinucleotide phosphate hydrogen oxidase 2 leading to emergence delirium with eventual blockade of glutamate’s effects through N-methyl-D-aspartate antagonism. Emergence delirium could be devastating to patients with underlying mental illnesses such as schizophrenia, bipolar disorder, or posttraumatic stress disorder to name a few. This emergence delirium is dose dependent and also affected by cointerventions such as benzodiazepine administration. Interestingly, propofol has been shown to blunt glutamate’s effects through gamma-aminobutyric acidA agonist activity [10]. This may explain the findings in the literature demonstrating a reduced rate of emergence delirium with the admixture (∼30% with ketamine only vs. <5%) [1012, 14, 31].

Our study has several benefits. First, we focused on a theoretical advantage of ketamine/propofol admixture over other agents used for induction of anesthesia during procedures such as endotracheal intubation, namely, hemodynamic preservation. Furthermore, we extracted hemodynamic data in the immediate period after drug administration, thereby limiting the effects of other cointerventions. Second, we extracted data on all drug comparisons to ketamine/propofol admixture. Third, we included trials that had either similar or near equivalent dosing of ketamine/propofol admixture.

4.1. Limitations

Similar to other systematic reviews and meta-analyses, our results are limited by clinical trial quality. Although our search strategy was comprehensive, we included only English-language articles and published articles after 2000 and thus may have missed trials not published in English or published before the year 2000. Hemodynamic data were not recorded similarly in all trials nor was the frequency of hemodynamic data collected. Furthermore, 5 and 10 minutes may be an oversimplification of hemodynamic representation as intravenous anesthetics used for induction of anesthesia have a short initial elimination half-life and, therefore, collecting hemodynamic data every minute would have been ideal [10]. Moreover, we did not calculate MAP from trials reporting systolic and diastolic blood pressure because individual patient data were not reported. Three studies met our inclusion criteria and were included in the systematic review. However, we did not include these studies in the meta-analysis as we were unable to extract measures of variation [32, 33, 35]. Data on vasoactive medications which could alter hemodynamics and affect our estimates were not reported in the majority of included trials. We do not report subgroup meta-analyses for the different patient populations or interventions studied due to the limited number of studies in each meta-analysis (only 1 meta-analysis included 3 studies and the remainder had 2 studies). Thus, any subgroup and sensitivity analyses would reduce the number further with only 1 study, which is already presented well in the forest plots. Lastly, our systematic review illustrated moderate to high heterogeneity in the analyses and high risk of bias of the included studies. With such small numbers of studies in the meta-analysis, advanced bias evaluations were not appropriate. Thus, our results should be interpreted with caution.

5. Conclusions

We demonstrated a potentially better hemodynamic profile with ketamine/propofol admixture-based induction of anesthesia versus nonketamine/propofol admixture-based induction of anesthesia for procedures requiring airway manipulation such as endotracheal intubation. However, given moderate to high heterogeneity of trials included in the current meta-analysis, our results should be interpreted with caution.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

This work was supported by funding from the Department of Anesthesiology and Perioperative Medicine and the Critical Care Independent Multidisciplinary Practice at Mayo Clinic Rochester, Minnesota.

References

  1. R. S. Green, A. F. Turgeon, L. A. McIntyre et al., “Postintubation hypotension in intensive care unit patients: a multicenter cohort study,” Journal of Critical Care, vol. 30, no. 5, pp. 1055–1060, 2015. View at: Publisher Site | Google Scholar
  2. N. J. Smischney, O. Demirci, D. A. Diedrich et al., “Incidence of and risk factors for post-intubation hypotension in the critically ill,” Medical Science Monitor, vol. 22, pp. 346–355, 2016. View at: Publisher Site | Google Scholar
  3. A. C. Heffner, D. S. Swords, M. L. Nussbaum, J. A. Kline, and A. E. Jones, “Predictors of the complication of postintubation hypotension during emergency airway management,” Journal of Critical Care, vol. 27, no. 6, pp. 587–593, 2012. View at: Publisher Site | Google Scholar
  4. T. G. Monk, M. R. Bronsert, W. G. Henderson et al., “Association between intraoperative hypotension and hypertension and 30-day postoperative mortality in noncardiac surgery,” Anesthesiology, vol. 123, no. 2, pp. 307–319, 2015. View at: Publisher Site | Google Scholar
  5. R. S. Green and M. B. Butler, “Postintubation hypotension in general anesthesia,” Journal of Intensive Care Medicine, vol. 31, no. 10, pp. 667–675, 2016. View at: Publisher Site | Google Scholar
  6. J. B. Bijker, W. A. van Klei, T. H. Kappen, L. van Wolfswinkel, K. G. M. Moons, and C. J. Kalkman, “Incidence of intraoperative hypotension as a function of the chosen definition,” Anesthesiology, vol. 107, no. 2, pp. 213–220, 2007. View at: Publisher Site | Google Scholar
  7. R. Green, B. Hutton, J. Lorette, D. Bleskie, L. Mclntyre, and D. Fergusson, “Incidence of postintubation hemodynamic instability associated with emergent intubations performed outside the operating room: a systematic review,” CJEM, vol. 16, no. 1, pp. 69–79, 2014. View at: Publisher Site | Google Scholar
  8. N. J. Smischney, M. O. Seisa, K. J. Heise et al., “Predictors of hemodynamic derangement during intubation in the critically ill: a nested case-control study of hemodynamic management-Part II,” Journal of Critical Care, vol. 44, pp. 179–184, 2018. View at: Publisher Site | Google Scholar
  9. N. J. Smischney, M. O. Seisa, J. Cambest et al., “The incidence of and risk factors for postintubation hypotension in the immunocompromised critically ill adult,” Journal of Intensive Care Medicine, vol. 34, no. 7, pp. 578–586, 2019. View at: Publisher Site | Google Scholar
  10. R. D. Miller, Miller’s Anesthesia, Elsevier, Philadelphia, PA, USA, 8th edition, 2014.
  11. N. J. Smischney, M. L. Beach, R. W. Loftus, T. M. Dodds, and M. D. Koff, “Ketamine/propofol admixture (ketofol) is associated with improved hemodynamics as an induction agent,” Journal of Trauma and Acute Care Surgery, vol. 73, no. 1, pp. 94–101, 2012. View at: Publisher Site | Google Scholar
  12. G. Yousef and K. Elsayed, “A clinical comparison of ketofol (ketamine and propofol admixture) versus propofol as an induction agent on quality of laryngeal mask airway insertion and hemodynamic stability in children,” Anesthesia: Essays and Researches, vol. 7, no. 2, pp. 194–199, 2013. View at: Publisher Site | Google Scholar
  13. A. Gallo de Moraes, C. J. Racedo Africano, S. S. Hoskote et al., “Ketamine and propofol combination (“ketofol”) for endotracheal intubations in critically ill patients: a case series,” American Journal of Case Reports, vol. 16, pp. 81–86, 2015. View at: Publisher Site | Google Scholar
  14. E. V. Willman and G. Andolfatto, “A prospective evaluation of “ketofol” (Ketamine/Propofol combination) for procedural sedation and analgesia in the emergency department,” Annals of Emergency Medicine, vol. 49, no. 1, pp. 23–30, 2007. View at: Publisher Site | Google Scholar
  15. A. Nejati, R. S. Moharari, H. Ashraf, A. Labaf, and K. Golshani, “Ketamine/propofol versus midazolam/fentanyl for procedural sedation and analgesia in the emergency department: a randomized, prospective, double-blind trial,” Academic Emergency Medicine, vol. 18, no. 8, pp. 800–806, 2011. View at: Publisher Site | Google Scholar
  16. G. Andolfatto and E. Willman, “A prospective case series of single-syringe ketamine-propofol (ketofol) for emergency department procedural sedation and analgesia in adults,” Academic Emergency Medicine, vol. 18, no. 3, pp. 237–245, 2011. View at: Publisher Site | Google Scholar
  17. S. Arora, “Combining ketamine and propofol (“ketofol”) for emergency department procedural sedation and analgesia: a review,” The Western Journal of Emergency Medicine, vol. 9, no. 1, pp. 20–23, 2008. View at: Google Scholar
  18. M. Jalili, M. Bahreini, A. Doosti-Irani, R. Masoomi, M. Arbab, and H. Mirfazaelian, “Ketamine-propofol combination (ketofol) vs propofol for procedural sedation and analgesia: systematic review and meta-analysis,” The American Journal of Emergency Medicine, vol. 34, no. 3, pp. 558–569, 2016. View at: Publisher Site | Google Scholar
  19. D. Moher, L. Shamseer, M. Clarke et al., “Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement,” Systematic Reviews, vol. 4, no. 1, p. 1, 2015. View at: Publisher Site | Google Scholar
  20. L. Shamseer, D. Moher, M. Clarke et al., “Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation,” BMJ, vol. 349, no. jan02 1, p. g7647, 2015. View at: Publisher Site | Google Scholar
  21. J. Eden, L. Levit, A. Berg, and S. Morton, Finding what Works in Health Care: Standards for Systematic Reviews, The National Academies Press, Washington, DC, USA, 2011.
  22. S. S.-L. Wong, N. L. Wilczynski, and R. B. Haynes, “Developing optimal search strategies for detecting clinically sound treatment studies in EMBASE,” The Journal of the Medical Library Association, vol. 94, no. 1, pp. 41–47, 2006. View at: Google Scholar
  23. M. H. Murad, “Clinical Practice guidelines,” Mayo Clinic Proceedings, vol. 92, no. 3, pp. 423–433, 2017. View at: Publisher Site | Google Scholar
  24. M. Woodward, Epidemiology: Study Design and Data Analysis, Chapman & Hall/CRC, New York, NY, USA, 2nd edition, 2004.
  25. J. P. T. Higgins and S. G. Thompson, “Quantifying heterogeneity in a meta-analysis,” Statistics in Medicine, vol. 21, no. 11, pp. 1539–1558, 2002. View at: Publisher Site | Google Scholar
  26. J. P. T. Higgins, S. G. Thompson, J. J. Deeks, and D. G. Altman, “Measuring inconsistency in meta-analyses,” BMJ, vol. 327, no. 7414, pp. 557–560, 2003. View at: Publisher Site | Google Scholar
  27. M. W. Abdalla, S. M. El Shal, A. I. El Sombaty, N. M. Abdalla, and R. B. Zeedan, “Propofol dexmedetomidine versus propofol ketamine for anesthesia of endoscopic retrograde cholangiopancreatography (ERCP) (A randomized comparative study),” Egyptian Journal of Anaesthesia, vol. 31, no. 2, pp. 97–105, 2015. View at: Publisher Site | Google Scholar
  28. N. Aghdaii, M. Ziyaeifard, S. Z. Faritus, and R. Azarfarin, “Hemodynamic responses to two different anesthesia regimens in compromised left ventricular function patients undergoing coronary artery bypass graft surgery: etomidate-midazolam versus propofol-ketamine,” Anesthesiology and Pain Medicine, vol. 5, no. 3, Article ID e27966, 2015. View at: Publisher Site | Google Scholar
  29. M. S. Aydogan, S. Demirel, M. A. Erdogan, P. Firat, C. Colak, and M. Durmus, “Effects of ketamine-propofol mixture on intraocular pressure and hemodynamic in elderly patients: a randomized double-blind trial,” Turkish Journal of Anesthesia and Reanimation, vol. 42, no. 1, pp. 12–18, 2014. View at: Publisher Site | Google Scholar
  30. A. G. Baradari, A. Alipour, M. R. Habibi, S. Rashidaei, and A. E. Zeydi, “A randomized clinical trial comparing hemodynamic responses to ketamine-propofol combination (ketofol) versus etomidate during anesthesia induction in patients with left ventricular dysfunction undergoing coronary artery bypass graft surgery,” Archives of Medical Science, vol. 5, no. 5, pp. 1102–1110, 2017. View at: Publisher Site | Google Scholar
  31. M. A. Erdogan, Z. Begec, M. S. Aydogan et al., “Comparison of effects of propofol and ketamine-propofol mixture (ketofol) on laryngeal mask airway insertion conditions and hemodynamics in elderly patients: a randomized, prospective, double-blind trial,” Journal of Anesthesia, vol. 27, no. 1, pp. 12–17, 2013. View at: Publisher Site | Google Scholar
  32. H. Hosseinzadeh, M. Eidy, S. E. Golzari, and M. Vasebi, “Hemodynamic stability during induction of anesthesia in elderly patients: propofol + ketamine versus propofol + etomidate,” Journal of Cardiovascular and Thoracic Research, vol. 5, no. 2, pp. 51–54, 2013. View at: Publisher Site | Google Scholar
  33. M. Iwata, S. Inoue, M. Kawaguchi et al., “Ketamine eliminates propofol pain but does not affect hemodynamics during induction with double-lumen tubes,” Journal of Anesthesia, vol. 24, no. 1, pp. 31–37, 2010. View at: Publisher Site | Google Scholar
  34. U. Ozgul, Z. Begec, K. Karahan et al., “Comparison of propofol and ketamine-propofol mixture (ketofol) on laryngeal tube-suction II conditions and hemodynamics: a randomized, prospective, double-blind trial,” Current Therapeutic Research, vol. 75, pp. 39–43, 2013. View at: Publisher Site | Google Scholar
  35. K. S. Vora, M. S. Prabodhachandran, G. P. Bhosale, N. Singhal, G. P. Parikh, and V. R. Shah, “Comparison of admixtures of propofol-thiopentone, propofol-ketamine and propofol in ambulatory surgery,” Journal of Anaesthesiology Clinical Pharmacology, vol. 21, no. 4, pp. 413–418, 2005. View at: Google Scholar
  36. A. Heffner, D. Swords, J. Kline, and A. Jones, “Frequency and significance of post-intubation hypotension during emergency airway management,” Critical Care, vol. 15, no. Suppl 1, p. P154, 2011. View at: Publisher Site | Google Scholar
  37. K. Maheshwari, A. Turan, G. Mao et al., “The association of hypotension during non‐cardiac surgery, before and after skin incision, with postoperative acute kidney injury: a retrospective cohort analysis,” Anaesthesia, vol. 73, no. 10, pp. 1223–1228, 2018. View at: Publisher Site | Google Scholar
  38. V. Salmasi, K. Maheshwari, D. Yang et al., “Relationship between intraoperative hypotension, defined by either reduction from baseline or absolute thresholds, and acute kidney and myocardial injury after noncardiac surgery,” Anesthesiology, vol. 126, no. 1, pp. 47–65, 2017. View at: Publisher Site | Google Scholar
  39. J. B. Bijker, S. Persoon, L. M. Peelen et al., “Intraoperative hypotension and perioperative ischemic stroke after general surgery,” Anesthesiology, vol. 116, no. 3, pp. 658–664, 2012. View at: Publisher Site | Google Scholar
  40. E. M. Wesselink, T. H. Kappen, H. M. Torn, A. J. C. Slooter, and W. A. van Klei, “Intraoperative hypotension and the risk of postoperative adverse outcomes: a systematic review,” British Journal of Anaesthesia, vol. 121, no. 4, pp. 706–721, 2018. View at: Publisher Site | Google Scholar
  41. J.-Y. Xu, S.-Q. Ma, C. Pan et al., “A high mean arterial pressure target is associated with improved microcirculation in septic shock patients with previous hypertension: a prospective open label study,” Critical Care, vol. 19, no. 1, p. 130, 2015. View at: Publisher Site | Google Scholar
  42. K. Maheshwari, B. H. Nathanson, S. H. Munson et al., “The relationship between ICU hypotension and in-hospital mortality and morbidity in septic patients,” Intensive Care Medicine, vol. 44, no. 6, pp. 857–867, 2018. View at: Publisher Site | Google Scholar
  43. P. Asfar, P. Radermacher, and M. Ostermann, “MAP of 65: target of the past?” Intensive Care Medicine, vol. 44, no. 9, pp. 1551-1552, 2018. View at: Publisher Site | Google Scholar
  44. J. W. Yan, S. L. McLeod, and A. Iansavitchene, “Ketamine-propofol versus propofol alone for procedural sedation in the emergency department: a systematic review and meta-analysis,” Academic Emergency Medicine, vol. 22, no. 9, pp. 1003–1013, 2015. View at: Publisher Site | Google Scholar

Copyright © 2020 Nathan J. Smischney et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


More related articles

 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder
Views306
Downloads275
Citations

Related articles

We are committed to sharing findings related to COVID-19 as quickly as possible. We will be providing unlimited waivers of publication charges for accepted research articles as well as case reports and case series related to COVID-19. Review articles are excluded from this waiver policy. Sign up here as a reviewer to help fast-track new submissions.