Research Article ISSN 2639-846X

Anesthesia & Pain Research

Benefit-Risk Balance of Ketamine versus Midazolam + Fentanyl for

Sedation-Analgesia in Mechanically Ventilated Patients: Randomised
Controlled Trial
Raphaël Mubunda1,2,3, Joseph Nsiala1, Médard Bula-Bula1, Berthe Barhayiga1, Wilfrid Mbombo1,4,
Patrick Mukuna1,2,3, Eric Amisi1, Eric Kam Kampay5, Hugues Kwama1,2, Patrick Makambo1, Adolphe
Mutombo1, Marcel Kamwanga1, Richard Mvwala2,3, Michel Way2, Danny Lokanga2,
Jean-Claude Mwepu3, Jamel Kimbeni3 and Degaule Ndjapanda3
Department of Anesthesia and Intensive Care, University Clinics of
1

Kinshasa (UCK), University of Kinshasa, DR Congo.

*
Correspondence:
Anesthesia-resuscitation department, Ngaliema Clinic, DR Congo.
2
Wilfrid Mbombo, Department of Anesthesia and Intensive Care,
Anesthesia-resuscitation department, Clinique CHIP, DR Congo.
3 University Clinics of Kinshasa (UCK), University of Kinshasa,
DR Congo, Tel:+243810054829.
Monkole hospital centre, DR Congo.
4

Received: 29 Nov 2023; Accepted: 27 Dec 2023; Published: 04 Jan 2024

5
Department of Physical Medicine and Rehabilitation, University Clinics
of Kinshasa (UCK), University of Kinshasa, DR Congo.

Citation: Mubunda R, Nsiala J, Bula-Bula M, et al. Benefit-Risk Balance of Ketamine versus Midazolam + Fentanyl for Sedation-
Analgesia in Mechanically Ventilated Patients: Randomised Controlled Trial. Anesth Pain Res. 2024; 8(1): 1-8.

ABSTRACT
Objective: Ketamine has interesting pharmacological properties for sedation-analgesia in intensive care. However,
there are few studies on its benefit-risk balance. The aim of this study was to evaluate the efficacy and safety of
ketamine compared with midazolam + fentanyl in mechanically ventilated patients.

Methods: Randomised, non-inferiority, open-label, multicentre controlled trial. Patients aged 18 years or older
requiring invasive mechanical ventilation for at least 24 hours were randomised to receive, after rapid sequence
intubation, ketamine at a starting dose of 0.5 mg/kg/h (n = 191) or midazolam 0.2mg/kg/h + fentanyl 1µg/kg/h (n =
191). Infusion rates were subsequently adjusted to achieve a RASS score between -2 and +1. The primary endpoint
was the percentage of time spent in the RASS range -2 to +1 without the use of an alternative sedative; secondary
endpoints included level of analgesia, adverse events (AEs), length of stay and mechanical ventilation, and cost of
sedation.

Results: In total, 73.5% of patients in the ketamine group vs. 71.3% in the midazolam group were within the target
RASS range, a difference of 2.2% [95% CI: -3.2% to 7.5%]; p = 0.18. The most frequently observed AEs in the
ketamine group were hypersalivation (21.2% vs. 2.3%; p<0.001), psychodysleptic phenomena (19.8% vs. 2.6%;
p<0.001) and hallucinations (9.42% vs. 1.04%; p<0.001). Delirium was the only AE more frequent in the Midazolam
group than in the Ketamine group (23.5% vs 43.4%; p < 0.0001). However, the risk of arterial hypertension (7.3%
vs 4.2%; p = 0.188), diarrhoea (0% vs 5%; p = 0.05) and self-extubation (3.1% vs 4.2%; p = 0.452) did not differ
between the 2 groups. The length of stay in intensive care between the 2 groups was 6.3 ± 1.6 days vs 7.3 ± 1.7 days (p
< 0.001) and that of mechanical ventilation 4.1 ± 0.94 days vs 4.84 ± 0.85 days (p < 0.001). The daily cost of sedative
treatment was lower with ketamine than with midazolam ($32.4 ± 0.8 vs $43 ± 6.3; p<0.001).

Conclusion: In this study, the efficacy of ketamine was not inferior to that of the midazolam + fentanyl combination,
but its safety was poorer. Its low cost is a real advantage in our context.

Anesth Pain Res, 2024 Volume 8 | Issue 1 | 1 of 8

Keywords NMDA channels involved in brain damage caused by excitatory
Ketamine, Sedation-analgesia, Mechanical ventilation. amino acids [14]. Provided that capnia is controlled by artificial
ventilation and a GABAergic agent (propofol, benzodiazepine or
Introduction halogen) is co-administered, ketamine reduces oxygen consumption
During a critical care unit (CCU) stay, most intubated and (CMRO2), cerebral blood flow (CBF) and intracranial pressure
ventilated patients receive sedation analgesia (SA) to reduce (ICP), including in cases of intracranial hypertension [15].
discomfort and anxiety, relieve pain and aid ventilator adaptation
[1]. Midazolam, propofol, volatile halogenated anaesthetics and, A recent systematic review and meta-analysis of 15 studies,
more recently, dexmedetomidine in combination with an opioid including 3 randomised studies and 12 observational studies,
are commonly used for this purpose [2]. Despite their proven concluded that it is useful for sedating mechanically ventilated
efficacy, however, these sedation and analgesia agents are not patients [16]. No difference in efficacy was observed between
without adverse effects [3]. Midazolam, for example, because of the groups treated with or without ketamine in terms of the
its long elimination half-life, is responsible for delays in waking proportion of time spent with the required level of sedation [OR
up, which are associated with longer periods of mechanical 0.51 IC95% (0.14 - 1.88)]. However, the results on adverse effects
ventilation, longer stays in critical care units and increased were contradictory and did not allow us to establish its safety or
morbidity and mortality, particularly through the acquisition of benefit-risk balance in this indication. Hence the need for further
nosocomial pneumonia [4,5]. Its use is far from ideal in modern studies to confirm or refute its safety. The aim of this study was to
intensive care, where sedation times are becoming shorter and assess the efficacy and safety of ketamine alone compared with the
shorter, with attempts to wake patients up and wean them off the combination of midazolam + fentanyl.
air every day [6]. Midazolam is also particularly prone to delirium
and acute withdrawal when sedation is stopped [7]. Methods
Study design and setting
An interesting alternative to the drugs mentioned above appears to We conducted a randomised, controlled, non-inferiority, open-
be the use of ketamine. This compound, well known to anaesthetists label study in 2 parallel groups in the intensive care and/or
since the 1960s, produces a dissociative type of anaesthesia resuscitation units of hospitals in the city of Kinshasa. It ran from
characterised at EEG level by dissociation between the limbic March 2020 to March 2022. Our study was approved by the Ethics
and thalamo-cortical systems [8]. The patient appears awake with Committee of the School of Public Health of the University of
eyes open in slow nystagmus, but does not communicate. They Kinshasa under No. ESP/CE/011/2022. Informed consent was
are no longer connected to reality. This characteristic and its systematically signed by patients or their families before inclusion
adverse neuropsychological effects (hallucination, delirium, and in the study. The authors have no conflicts of interest to declare.
agitation) have limited its use in general anaesthesia in favour The study received no external funding.
of other anaesthetic agents. Its use in sedation-analgesia is now
increasingly common in critical care [9,10]. Unlike other agents, Patients selection and randomisation
it produces sedation, amnesia and analgesia while preserving All consecutive patients requiring sedation-analgesia for
respiratory effort, haemodynamic stability and airway reflexes invasive mechanical ventilation were included in this study. To
[8,11]. It is the only sedative agent to provide analgesia. It also be included, patients should be at least 18 years old and require
has a bronchodilator effect comparable to that of halogen, making invasive mechanical ventilation for at least 24 hours. Exclusion
it the agent of choice for patients with COPD or asthma [8,11]. criteria were: psychiatric history, active drug addiction, severe
It also has a powerful antidepressant effect, which could be of liver failure, need for curarisation, tetanus, severe coronary artery
interest to critical care patients, in particular to reduce the possible disease, poorly controlled arterial hypertension. Randomisation
psychological consequences of hospitalisation in intensive care in a 1:1 ratio was centralised in blocks of four. Randomisation
[12]. was carried out by tossing a coin. If the coin came up heads, the
next 4 patients were sedated with Ketamine and the next 4 with
Once contraindicated in cases of head trauma, ketamine is no Midazolam + Fentanyl. If not, the order was reversed. Figure 1
longer contraindicated [13]. More recent studies show that it may summarises the sequence of our study.
exert a neuroprotective and anticonvulsant effect by blocking the

Figure 1: Schematic representation of the study.

Legend: OTI: oro-tracheal intubation; MV: mechanical ventilation; Sch: succinylcholine; R: randomisation.
Anesth Pain Res, 2024 Volume 8 | Issue 1 | 2 of 8
Interventions following formula:
After rapid sequence intubation, patients were randomised to The non-inferiority limit (ΔL) was set at a relative difference
receive either ketamine at a starting dose of 0.5 mg/kg/h (n = 191)
or midazolam 0.2mg/kg/h + fentanyl 1 μg/kg/h (n = 191). Infusion
rates were adjusted (increased or decreased by half) every 30 minutes
thereafter to achieve a RASS score between -2 and +1. Patients
could receive an alternative sedative agent if the desired degree of 10% between the 2 study arms. The sample size calculation
of sedation was not achieved with upward adjustment of the study assumes that the true difference in efficacy (δ) between the 2 arms
agent infusion. Bolus atropine 0.5 mg IVD was authorised to control is equal to zero. The expected efficacy rate in this study was 90%.
hypersalivation at the discretion of the care teams. Intravenous For a power of 80% (β = 20%, U2β = 0.842) and a one-sided α risk of
haloperidol was authorised for the treatment of agitation or delirium 2.5% (uα =1.96), at least 191 patients per arm had to be included. It
in boluses of 1 to 5 mg, repeated every 10 to 20 minutes as required. was decided to include 200 patients to account for study dropouts.
Sedation could be stopped daily every morning at the discretion of The percentage of time spent at the required sedation level was
the care teams to assess the possibility of permanent discontinuation calculated as follows: (time spent at the required sedation level /
of sedation. At any time during the study, the patient could withdraw infusion time) multiplied by 100.
from the protocol if the doctor or his or her family deemed it
necessary. In both groups, the criteria for exiting the protocol were Definition of time spent at required level of sedation: this is
the occurrence of a side effect requiring discontinuation of the the sum of time intervals (in hours) when the patient was at the
treatment, the need to use a curare, the decision of the nursing team required level of sedation (RASS score of -2 to +1) without the
or the decision of the patient or his family. need for rescue medication. Periods when the patient was not at the
required level of sedation were subtracted from this sum. Periods
Data collection when the patient received rescue medication were also subtracted
Data were collected by the members of the team in charge of the from this sum.
patient. A research associate was responsible for checking the
content and completion of the data as each patient was included. Definition of infusion duration: this is the sum of the time intervals
Detailed medical history, basic demographics and reason for (in hours) during which the patient received a continuous infusion
admission to the ICU were collected at the time of study inclusion. of the study drug. Periods of sedation cessation were not counted
Vital signs were recorded at least every 4 hours. Adverse events in the calculation of infusion time.
(AEs) were monitored daily until 48 hours after sedation was
discontinued. These AEs were quantified using the following All statistical analyses were performed using SPSS version 22.0
score: 0 = absent, 1 = minor, treatment not necessary, 2 = moderate, for Windows. Results are expressed as mean ± SD or percentage ±
treatment necessary, 3 = severe, life-threatening or fatal. 95% CI and compared using a Mann-Whitney U test for quantitative
variables or a Fisher exact test for qualitative variables. Kaplan-
Endpoints Meier survival curves were compared using the Log rank test. All
The primary endpoint was the percentage of time spent in the analyses were performed on an intention-to-treat basis. No interim
target RASS range (between -2 and +1) without the use of an analysis was planned. A difference was considered statistically
alternative sedative. The secondary endpoints were frequency of significant when p < 0.05.
adverse events, total duration of mechanical ventilation and ICU
stay, mortality, and average daily cost of drugs used for sedation- Results
analgesia. Patients flow diagram
Figure 2 show patients flow diagram of the 430 patients recruited
In this study, the occurrence of any noxious and unintended during the study period, 30 did not meet the inclusion criteria
response inherent in the 2 study treatments was considered an (Figure 2). After randomisation, the 400 participants were
adverse event. Blood pressure and heart rate were considered divided into 2 groups of 200 patients each to receive either
adverse events if systolic blood pressure was less than 90 or greater ketamine alone (group A) or the combination of midazolam +
than 180 mmHg and heart rate was less than 50 bpm or greater fentanyl (group B). During follow-up, 9 patients in group A
than 120 bpm. Agitation was defined by a RASS score ≥ +2, were excluded (1 patient for ventilation of less than 48 hours, 4
delirium by an ICU, CAM score ≥ 3/4 during daily interruption of for premature discontinuation of treatment, 3 for withdrawal of
sedative infusion or within 48 hours of extubation and withdrawal consent and 1 for need for curarization) and 9 also in group B
syndrome by the presence of at least 5 of the following criteria: (5 patients for premature discontinuation on the decision of the
fever (>38°C), tachycardia (>100 bpm), hypertension (SBP > 180 nursing team, 2 for withdrawal of consent and 2 for mechanical
mmHg), sweating, mydriasis, diarrhoea, vomiting and agitation. ventilation of less than 48 hours). In all, 191 patients were
analysed in each group.
Statistics
The number of subjects to be included (n) was calculated using the

Anesth Pain Res, 2024 Volume 8 | Issue 1 | 3 of 8

 OTI = oro-tracheal intubation; MV = mechanical ventilation; RR =
respiratory failure.

Comparison of the efficacy of sedation-analgesia

There was no difference in efficacy between the 2 treatments (figure
3). The percentage of time in the RASS target range without the
use of another sedative agent was 73.5% for patients treated with
ketamine versus 71.3% for patients treated with midazolam; a
difference of -2.2%; 95% CI [-3.2 - 7.5%] (p = 0.18). The non-
inferiority limit corresponding to a value not to be exceeded
between the 2 groups was set at 10%. The null hypothesis was
therefore rejected in favour of the hypothesis that ketamine was
not inferior to the combination of midazolam + fentanyl in terms
of efficacy. Nor was there any difference in the mean BPS scores
from D1 to D5 (table 2). In addition, the use of an alternative
sedative agent to maintain the depth of sedation within the target
range was similar in the 2 groups (44% vs 54.9%; p = 0.56).

Figure 2: Patient flow diagram. Legend: MV= mechanical ventilation.

Basic characteristics of the population
The 2 groups were broadly comparable (Table 1). The mean age
was 44.3 ± 10.7 years for patients in the ketamine group and 43.3
± 14.1 years for those in the midazolam group, but weight was
slightly higher in the control group. The 2 groups were fairly
homogeneous in terms of co-morbidities, except for asthma. The
reasons for admission to intensive care were similar, with the
majority being medical conditions. The reasons for intubation
were also identical. In both groups, coma was the main reason for
intubation, followed by respiratory failure and cardiac failure.
Figure 3: Comparison of the efficacy of ketamine vs MDZ + Fentanyl.

Table 1: Socio-demographic characteristics and co-morbidities. Table 2: Average BPS score from day 1 to day 5 of mechanical ventilation.
Intervention Midazolam +
Parameters Midazolam + P Ketamine
Ketamine Score BPS Fentanyl p
Fentanyl X ± SD X ± SD
Age (years), X ± SD 43.3 ± 14.1 44.3 ± 10.7 0.44 1 hour after 3 ± 1.3 4.6 ± 1 < 0.001
Sexe, H/F 113/78 121/70 0.401 8th hour 3.8 ± 1.2 4.4 ± 0,9 0.053
Weigth (Kg), X ± SD 69.8 ± 13.2 74.9 ± 9.8 0.001 16th hour 3 ± 1.1 3.2 ± 1.4 0.067
Co-morbidities, n (%) 24th hour 3.2 ± 1 3.4 ± 0.8 0.462
chronic alcoholism 102 (53.4) 90 (47.1) 0.21 1st day 3.2 ± 0.9 3.2 ± 1.4 0.745
Diabete mellitus 65 (17.01) 54 (14.1) 0.224 2nd day 3.1 ± 1.2 3 ± 1.4 0.861
Heart failure 10 (2.6) 27 (7.1) 0.05 3rd day 2.5 ± 1.4 2.7 ± 1.2 0.073
Acute kidney failure 25 (6.5) 24 (6.3) 0.878 4th day 2.4 ± 1.2 2.5 ± 0.8 0.563
COPD 20 (5.2) 12 (3.1) 0.14 5th day 2.1 ± 1.3 2.3 ± 1 0.456
Asthma 22 (5.8) 7 (1.8) 0.004
Legend: X= mean; SD= standard deviation; BPS =behavioral pain score.
HTA 25 (6.5) 14 (3.7) 0.063
Admission reason, n (%)
Medical 100 (52.4) 93 (48.6) 0.5
Comparison of tolerability and daily cost of sedative treatment
Surgical 60 (31.4) 72 (37.6) 0.34 Haemodynamic tolerance during the first 48 hours
Traumatic 31 (8.1) 26 (6.8) 0.473 The tolerance of ketamine was not identical to that of midazolam.
Reason for OTI + MV, n (%) Figure 4 shows that the systolic blood pressure of patients in the
Respiratory failure 62 (16.2) 74 (19.4) 0.2 ketamine group during the first 48 hours was always higher than
Shock 104 (27.2) 81 (21.2) 0.019 that of the midazolam + fentanyl group (p≤0.05), until the second
Coma 95 (24.9) 115 (30.1) 0.040 day. Diastolic blood pressure, on the other hand, showed no
Legend: X = mean; SD = standard deviation; M = male, F = female; COPD significant difference between the two groups (p>0.05). Similarly,
= chronic obstructive pulmonary disease; HTA = arterial hypertension; the heart rate of patients in the ketamine group (figure 5) tended to
Anesth Pain Res, 2024 Volume 8 | Issue 1 | 4 of 8
be higher than that of patients in the midazolam group (p= 0.0001). Comparison of length of stay, duration of mechanical
ventilation and survival curve
Frequency of adverse events Figure 5 show the comparison of heart rate during the first 24
Table 3 compares the frequency of adverse events (AEs) in the hours.
2 groups. The majority of these AEs were of minor to moderate The mean duration of mechanical ventilation was 4.1 ± 0.94 days
intensity and the severity was identical in both arms. No deaths in the ketamine group versus 4.8 ± 0.85 days in the midazolam
were attributed to the study treatments. The most frequently group (p < 0.001). The mean length of stay in the ICU between the
observed AEs in the ketamine group were hypersalivation (21.2% start of sedation with one of the study treatments and the end of
vs. 2.3%; p<0.001), psychodysleptic phenomena (19.8% vs. 2.6%; the first ICU stay was 6.3 ± 1.6 days for patients in the ketamine
p<0.001) and hallucinations (9.42% vs. 1.04%; p<0.001). Delirium group and 7.3 ± 1.7 days in the midazolam group (p < 0.001).
was the only AE more frequent in the Midazolam group than in the Figure 6 shows no significant difference between the 2 survival
Ketamine group (23.5% vs 43.4%; p < 0.001). In contrast, the risk curves. The daily cost of sedative treatment was $32.4 ± 0.8 for
of arterial hypertension (7.3% vs 4.2%; p = 0.188), diarrhoea (0% ketamine compared with $43 ± 6.3 for the midazolam + fentanyl
vs 5%; p = 0.05) and self-extubation (3.1% vs 4.2%; p = 0.452) did combination (p = 0.001).
not differ between the 2 groups.

Figure 5: Comparison of heart rate during the first 24 hours.

p= 0.0001

Figure 4: Comparison of blood pressure during the first 48 hours.

Legend: SBP = systolic blood pressure; DBP = diastolic blood pressure.

Table 3: Frequency of adverse events, duration of mechanical ventilation

and length of stay.
Ketamine MDZ + Fentanyl
Parameters P
n (%) n (%)
Bradycardia 0 (0%) 27 (14.1) < 0.001
Tachycardia 88 (44) 3 (1.6) < 0.001
Hypertension 14 (7.3) 8 (4.2) 0.188
Hypotension 0 (0%) 0 (0%) 1.00
Hypersudation 85 (44.5) 12 (6.3 < 0.001
Hypersalivation 81 (21,2) 9 (2.3) < 0.001
Diarrhoea 0 (0%) 5 (2.61) < 0.001
Vomiting 17 (8.9) 0 (0%) < 0.001
Mydriasis 22 (11.5) 1 (0.52) < 0.001
Agitation 52 (27.2) 9 (4.7) < 0.001
Hallucination 18 (9.42) 2 (1.04) < 0.001 Figure 6: Survival curves for patients in the 2 groups.
psychodysleptic phenomena 38 (19.8) 0 (0%) < 0.001
Delirium 45 (23.5) 83 (43.4) < 0.001 Discussion
Withdrawal syndrome 98 (51.3) 44 (23) < 0.001
The results of this study demonstrated the non-inferiority of
Self-extubation 12 (3.1) 16 (4.2) 0.452
ketamine compared with the combination of midazolam and
Death linked to AE 0 (0%) 0 (0%) 1.00
Total length of stay of MV (day) 4.1 ± 0.94 4.84 ± 0.85 < 0.001
fentanyl on the primary endpoint, i.e. the percentage of time spent
Total length of stay (day) 4.84 ± 0.85 7.3 ± 1.7 < 0.001 in the required RASS interval (between -2 and +1) without the need
for rescue medication. Over and above the sedation objectives, the
Legend: AE = adverse events; MV = mechanical ventilation.
Anesth Pain Res, 2024 Volume 8 | Issue 1 | 5 of 8
study provided us with additional data on the level of analgesia, reuptake of noradrenaline in sympathetic nerve endings [8]. It is
adverse effects, patient outcome and the cost of sedation treatment. not known whether these haemodynamic changes are detrimental
The level of analgesia was comparable between the two treatment or beneficial in critically ill patients. However, this meta-analysis
arms. did not demonstrate whether the use of ketamine has an effect on
reducing the need for exogenous catecholamines.
Systolic blood pressure and heart rate tended to be higher in
the ketamine group. Adverse events were more frequent in the Our study showed a reduction of almost 20% in delirium episodes in
ketamine group than in the midazolam group. A reduction of one the ketamine group compared with the midazolam group. Although
day in the length of stay in intensive care and of 0.74 days in the some studies suggest that benzodiazepines are particularly
duration of mechanical ventilation was observed in the ketamine vulnerable to delirium [7], the literature is controversial on this
group, with no effect on patient survival. Finally, the daily cost of subject. In the meta-analysis by Manasco AT et al. [16], 4 studies
sedative treatment was $10.4 lower in favour of ketamine. evaluated the central nervous system complications of continuous
infusion ketamine for sedation analgesia during mechanical
Our efficacy results are in line with the literature. Indeed, several ventilation in intensive care. The incidence of ketamine-associated
systematic reviews and meta-analyses have confirmed the efficacy delirium was 38.7% compared with 52.5% without ketamine in
of ketamine used alone or in combination with other hypnotics 2 studies [22,23]. The other two studies presented the results as
for the sedation of intubated-ventilated patients [16-18]. The odds ratios. Ketamine was associated with no difference in one
mechanism of action is complex. It is mainly linked to a powerful study [24] and an increased incidence of delirium in the other [25].
non-competitive antagonism of the glutamate N-methyl-D- Thus, although the data currently available in the literature are
aspartate (NMDA) receptor. Blocking NMDA receptors interferes heterogeneous, the trend tends to be in favour of a lower risk of
with the transmission of information from peripheral areas to the delirium with ketamine.
brain. Ketamine also acts as an opioid receptor agonist [8,9,14].
Very recently, in an observational study, Groth et al. [19] assessed Finally, one of the very frequent adverse effects observed in our
sedation-analgesia before and after the addition of ketamine by study was hypersalivation. This result is in line with other studies.
continuous infusion in 25 intensive care units in the USA between In the Pendleton et al. study cited above, sialorrhoea occurred in
2014 and 2017. 6% of patients treated with ketamine, compared with no patients
in the non-ketamine group. In contrast, Umunna et al. [20] showed
A statistically significant increase in the proportion of time spent that there was no increased hypersalivation when ketamine
within the required sedation score range was observed 24 hours was infused at 2.0 mg/kg/h for analgesia and sedation. Thus,
before (57.1%) compared with 24 hours after (64.1%) and 48 hours Casamento A et al. [18], in their meta-analysis of the efficacy
after (68.9%) (p < 0.001) suggesting a positive effect of ketamine. and tolerability of ketamine during mechanical ventilation, were
The same was true for the pain score 24 hours before (68.9%) unable to conclude whether this potential side effect is clinically
versus 24 hours after (78.6%) and 48 hours after (80.3) (p < 0.001). relevant when low-dose ketamine is used for sedation-analgesia
In addition, the addition of ketamine reduced the doses of opioids, in mechanically ventilated intubated adult patients. However, in
midazolam, propofol and dexmedetomidine. However, contrary our opinion, caution must be exercised. A mucus aspirator should
to our hypothesis, a higher proportion of patients in our study not be far away. If necessary, it has been shown that ketamine-
experienced AEs in the ketamine group than in the midazolam group. induced bronchial and salivary hypersecretion can be prevented by
Although minor, these events have in the past been responsible for administering Atropine [26].
a certain reluctance to use this drug in anaesthesia. In intensive care,
several descriptive studies have reported side effects associated With regard to the impact of sedation analgesia in the ICU, the three
with its use. For example, in a retrospective study by Umunna et criteria most frequently measured in the literature are duration of
al. [20] of ventilated intubated patients who received ketamine by mechanical ventilation, length of stay in the ICU and mortality.
continuous infusion for sedation, the incidence of adverse events Our study shows that ketamine reduces the mean duration of
was 13% (CI: 5%-30%). This study included only a small sample of mechanical ventilation by 0.7 days and the mean length of stay
patients. More recently, Pendleton et al. [21] evaluated the incidence in intensive care by 1 day. By way of comparison, in the meta-
of adverse events associated with ketamine used as an intensive care analysis cited above [16], three studies (n = 287) presented data
sedative in adult patients mechanically ventilated for more than 24 on the duration of mechanical ventilation, showing no difference
hours. At least one unintended effect attributed to ketamine was between the groups (mean difference 0.4 days [CI95%: 0.6 - 1.4],
documented in 24% of cases. p= 0.47) [22,23,27]. For ICU length of stay, analysable data
were reported in four studies (n=312). In contrast to our study,
In our study, we observed a benign increase in blood pressure and sedation with ketamine was associated with a longer ICU stay
heart rate with no consequence on the need for catecholamines. (mean difference 2.4 days [95% CI: 1.3 - 3.5], p<0.001) but the
This result is in agreement with the meta-analysis by Manasco AT studies were very heterogeneous. Conversely, Robinette et al. [25]
et al. [16]. According to several authors, ketamine produces these found no difference in ICU length of stay. Furthermore, the lack of
cardiovascular effects by stimulating the central nervous system difference in mortality observed in our study has been reported by
and the sympathetic system and, to a lesser extent, by inhibiting the several authors [22,24,27-30].
Anesth Pain Res, 2024 Volume 8 | Issue 1 | 6 of 8
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Midazolam was chosen as the reference treatment because it is of sedative infusions in critically ill patients undergoing
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ventilation in the literature [2]. However, our study has limitations 7. Ng KT, Shubash CJ, Chong JS. The effect of dexmedetomidine
that are important to note. Firstly, the 2 groups were not completely on delirium and agitation in patients in intensive care:
homogeneous despite randomisation. Some patient characteristics systematic review and meta-analysis with trial sequential
differed between the 2 groups. Secondly, the study was conducted analysis. Anaesthesia. 2019; 74: 380-392.
in a single-blind fashion. The investigator assessed the patient while
8. Peltoniemi MA, Hagelberg NM, Olkkola KT, et al. Ketamine:
being aware of the treatment received by the patient. Measurement
a review of clinical pharmacokinetics and pharmacodynamics
bias cannot therefore be ruled out. However, conducting a double-
in anesthesia and pain therapy. Clin Pharmacokinet. 2016; 55:
blind study requires considerable logistical resources, which we
1059-1077.
did not have for this study.
9. Hurth KP, Jaworski A, Thomas KB, et al. The reemergence of
Conclusion ketamine for treatment in critically ill adults. Crit Care Med.
In this study, the efficacy of ketamine in terms of maintaining 2020; 48: 899-911.
depth of sedation and level of analgesia was not inferior to that 10. Gershengorn HB, Wunsch H. Temporal trends and variability
of the combination of midazolam and fentanyl. In addition, the in ketamine use for mechanically ventilated adults in the
use of ketamine was associated with a reduction in the duration United States. Ann Am Thorac Soc. 2022; 19: 1534-1542.
of mechanical ventilation and the length of stay in intensive care. 11. Nowacka A, Borczyk M. Ketamine applications beyond
On the other hand, the overall rate of adverse events was higher anesthesia - A literature review. Eur J Pharmacol. 2019; 860:
in the group of patients who received ketamine compared with 172547.
those who received midazolam. Nevertheless, these adverse events
12. Duman RS, Li N, Liu RJ, et al. Signaling pathways
were generally not severe and had no impact on mortality. Finally,
underlying the rapid antidepressant actions of ketamine.
the daily cost was significantly lower in favour of ketamine. It is
Neuropharmacology. 2012; 62: 35-41.
therefore highly probable that ketamine has a similar efficacy to the
combination of midazolam + fentanyl, and it is therefore tolerance 13. Mads Christian Tofte Gregers, Søren Mikkelsen, Katrine Prier
and cost that should be discriminating factors when choosing Lindvig, et al. Ketamine as an Anesthetic for Patients with
a hypnotic agent for the sedation-analgesia of mechanically Acute Brain Injury: A Systematic Review. Neurocrit Care.
ventilated patients in intensive care. The results of our study 2020; 33: 273- 282.
further encourage its wider use in a context of limited resources 14. Sleigh J, Harvey M, Voss L, et al. Ketamine — more
and/or control of healthcare expenditure. mechanisms of action than just NMDA blockade. Trends
Anaesth Crit Care. 2014; 4: 76-81.
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