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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_1450_Библиотеки_им_академика_М_И_Перельмана
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Perioperative Considerations in Patients Who Use Cannabis 431
recreational use. CBD is a weakly psychoactive cannabinoid that is considered safer
than THC and is associated with few adverse effects [18].
Pharmacodynamics
Endocannabinoid receptors are found throughout the body including within the
nervous system, connective tissue, immune cells, as well as other locations [18,
19]. The predominant receptor types for cannabis are G protein-coupled receptors
identified as CB1 and CB2 receptors, with CB1 being the principal receptor type
in the central nervous system [19]. CB1 receptors are located in the basal ganglia,
hippocampus, cerebellum, association cortices, spinal cord, and peripheral nerves.
These receptors are located in the presynaptic membrane and when stimulated, lead to
a decrease in the release of acetylcholine and glutamate, thus inducing their inhibitory
effects. This leads to a disruption of an individual’s psychomotor function, time
perception, mood, memory, and learning, all contributing to impaired judgment [18].
Pharmacokinetics
The most common routes of cannabis use are inhalation, either via smoking or vapor-
ization, and ingestion [18]. The mode of use determines the bioavailability, onset,
and duration of effects as shown in Table 1.
Cannabis is highly lipophilic which results in its absorption by the liver, kidneys,
muscles, and adipose tissue. The result of multi-organ and tissue absorption is a
prolonged and unpredictable effect. The half-life of THC in infrequent users ranges
from 1.3 days to 5–13 days in frequent users [18]. This lengthy half-life can increase
the likelihood of toxicity and other adverse effects. In the perioperative setting, these
potential adverse events are dependent to a large extent on the temporal contiguity
of the patient’s most recent use prior to surgery.
THC is metabolized by the liver, with phase 1 oxidation and phase 2 hydroxylation
reactions via the cytochrome p450 system. A small amount undergoes extrahepatic
metabolism in the lungs. The inactive metabolites are excreted primarily in the feces
Table 1 Mode of cannabis
use, onset time, and time to
peak concentration effect [18]
Mode of cannabis use Onset time Peak concentration
Inhalation Fast 22 minutes
Oral Slow 1–2 hours
Sublingual Fast 30 minutes
Rectal Fast 15 minutes
Transcutaneous Slow 2 hours
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(65%) and in the urine (20%), with the majority of the compound excreted within 5
days of consumption [20].
Drug Interactions
THC and CBD inhibit CYP 3A4 and CYP 2C9 and induce CYP 1A2. These resulting
processes can lead to altered metabolism of drugs metabolized by the CYP450
system, resulting in prolonged or decreased effect of medications. For example,
warfarin is metabolized by the CYP450 system and concomitant cannabis use can
lead to bleeding secondary to reduced warfarin metabolism. The durations of action
of lithium and tricyclic antidepressants are also prolonged with cannabis use [21].
Furthermore, in patients taking medications that inhibit or induce the CYP450
system, there is an increased risk of experiencing a cannabis overdose versus inad-
equate effect, respectively. Thus, it is imperative to know all medications that a
patient is taking to evaluate potential drug interactions, mitigate deleterious effects,
and adjust dosages as necessary.
3 Physiological Impacts and Complications of Cannabis
Use
Cannabis is known to adversely affect multiple organ systems in the acute and chronic
settings. A summary of potential complications related to prolonged cannabis use is
presented in Fig. 1.
Effects on the Autonomic Nervous System
At lower doses, cannabis stimulates the sympathetic nervous system and inhibits
the parasympathetic nervous system [20]. This may result in tachycardia and hyper-
tension. The systemic vasodilation associated with cannabis use may also result in
reflex tachycardia [20, 21]. The use of propranolol prior to cannabis use is asso-
ciated with decreased tachycardia, further supporting sympathetic nervous system
activation’s role in tachycardia [20]. Decreased vagal slowing can occur, as would
be expected with Valsalva maneuvers, indicating inhibition of the parasympathetic
nervous system [20]. However, with higher doses, cannabis use may result in
parasympathetic stimulation, leading to bradycardia and hypotension [20].
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Perioperative Considerations in Patients Who Use Cannabis 433
Complications
of cannabis use
Myocardial
infarction
Prothrombotic
state
Cannabinoid
hyperemesis
syndrome
Chronic
bronchitis
Infections
Autonomic
dysregulation
Psychiatric
disturbances
Nephrotoxicity
Fig. 1 Complications related to prolonged cannabis use [20, 37, 38, 40, 41]
Psychiatric Effects
Cannabis use has also been associated with either new onset psychiatric disturbances
or a worsening of preexisting conditions such as psychosis, anxiety, or depres-
sion [21], and may compound elevated anxiety during the perioperative period.
Kuepper et al. examined the incidence of psychotic symptoms in individuals with
ongoing marijuana use in a 10-year follow-up cohort study. They found a statisti-
cally significant increase in the incidence of psychotic symptoms, despite adjusting
for confounding variables such as age, other drug use, and environmental stressors
[22].
Hines et al. performed a cohort study to assess the r elationship between high-
potency cannabis use and mental health illnesses. Patients with high-potency
cannabis use were four times more likely to use cannabis at least weekly and had
a four times higher chance of having generalized anxiety disorder. However, other
factors such as environmental stressors may play a role in this, as they can increase
the likelihood of substance use disorders or mental health illnesses independently
[23].
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Effects on the Cardiovascular System
From a cardiovascular standpoint, acute cannabis use leads to a dose-related increase
in heart rate and cardiac index lasting up to 72 hours and studies have linked these find-
ings to increased perioperative cardiovascular complications [24, 25]. The increased
cardiac risk is highest within an hour following cannabis use, leading to a 4.8-fold
higher risk of suffering a MI when compared to periods of non-use, and the risk
rapidly decreases after that time [26]. Tachycardia associated with cannabis use can
result in increased myocardial oxygen demand which can lead to decreased myocar-
dial oxygen supply and myocardial ischemia in these patients [20]. Tachycardia
also predisposes patients who use cannabis to an increased risk of arrhythmias, most
commonly atrial fibrillation, but also premature contractions, ventricular tachycardia,
and ventricular fibrillation [20].
For patients with CUD who are not actively intoxicated at the time of surgery, there
remains an elevated risk of cardiovascular complications. Specifically, a retrospective
study identified statistically significant increases in MI and stroke risk among patients
undergoing vascular surgery [8] and a 1.88 adjusted odds ratio of perioperative MI
in patients with cannabis use disorder undergoing elective surgery [7].
Effects on the Respiratory System
In addition to these cardiovascular risks, cannabis products may contribute to peri-
operative pulmonary concerns, as these products are most frequently consumed by
way of inhalation, notably smoking rolled, unfiltered cigarettes, and vaping either
flower or oil concentrates. Use of smoked and vaped products results in the inhalation
of several carcinogenic chemicals and irritants such as formaldehyde, tar, benzopy-
rene, and benzanthracene at much greater levels than during tobacco inhalation [27].
Regular use of smoked cannabis products has not been clearly linked to long-term
significant lung dysfunction [28]. While it may provide some bronchodilation in
the short-term [27, 29] via interaction with the CB1 receptor [30], there are also
negative respiratory effects. Cannabis use is associated with hypersecretion [31],
large airway inflammation, increased airway resistance, hyperinflation [32], uvulitis
and airway obstruction [33, 34], all of which can impact patients in the perioper-
ative period. Moreover, like with tobacco, cannabis smoking has been associated
with lung parenchymal diseases such as chronic bronchitis and emphysema [21].
Cannabis use can also adversely affect the immune system, increasing susceptibility
to infections such as pneumonia [35]. There may also exist an association with lung
adenocarcinoma with concomitant tobacco smoking [36]. However, the risk of lung
cancer from cannabis use alone in not well defined [21], with the high incidence of
tobacco use among cannabis users making investigation of t he relationship between
cannabis use and lung cancer challenging.
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Perioperative Considerations in Patients Who Use Cannabis 435
Effects on the Renal System
Studies indicate that cannabis, especially synthetic cannabinoids, may cause renal
injury and adversely affect renal function, especially in patients who have impaired
renal function at baseline. In the multicenter Assessment, Serial Evaluation, and
Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) study, patients with
an estimated glomerular filtration rate (eGFR) of less t han 60 ml/min/1.73 m
2
had a
more rapid decline in renal function compared to individuals with an eGFR greater
than 60 at baseline [37]. One postulated mechanism is that cannabis adversely affects
the mitochondrial function of the proximal tubule [37]. These patients are more likely
to be diagnosed with acute tubular necrosis through kidney biopsies [37]. Thus, it
is important to have a high index of suspicion of cannabis use in individuals with
unexplained kidney dysfunction [37]. Cannabis can cause both intrarenal and prerenal
injuries, with the latter being due to hypovolemia related to cannabinoid hyperemesis
syndrome.
Effects on the Gastrointestinal System
Parikh and colleagues performed a retrospective study comparing gastrointestinal
symptomatology in cannabis vs non-cannabis users. This study determined that
abdominal pain was the most common presenting symptom among cannabis users,
with heartburn being the second most common. They also compared endoscopy
findings in cannabis vs non-cannabis users and identified significant inflammatory
changes such as gastritis and esophagitis in the cannabis group. With manometry,
they found significantly impaired esophageal bolus clearance and greater lower
esophageal sphincter pressures in the cannabis group [38].
Cannabinoid hyperemesis syndrome (CHS) is another phenomenon seen in
cannabis users. CHS is associated with cyclic nausea, vomiting, and abdominal pain
[39]. The syndrome presents in 3 phases: the prodromal phase, hyper-emetic phase,
and recovery phase. Patients in the prodromal phase typically present with nausea,
anxiety, and autonomic symptoms that can last several months before progressing
to the hyper-emetic phase [40]. During the hyper-emetic phase, individuals typically
have paroxysms of severe and persistent nausea, vomiting, and abdominal pain, and
compulsively begin taking hot showers and baths to alleviate the symptoms [39,
40]. Typical antiemetics are not useful for management of these patients. Rather,
they appear to respond better to anxiolytics, sedatives, and antipsychotics. The only
definitive treatment is abstinence from cannabis. There is no clear mechanism for this
disorder, although one postulated mechanism is prolonged stimulation of the CB1
receptor due to sustained cannabis use leads to dysregulation of the endocannabinoid
system, which leads to emesis [40].
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Effects on the Hematologic System
Cannabis use is associated with an increased risk of thrombosis due to several
different mechanisms. This may be caused by the presence of CB1 and CB2 recep-
tors on the platelet surface leading to enhanced platelet activation. It may also be
due to endothelial dysfunction or increased expression of the GP IIb IIIa receptor
on the platelet surface [20]. A prothrombotic state coupled with cannabis-induced
tachycardia causing increased myocardial demand may further increase the risk of
myocardial ischemia. Finally, a prothrombotic state may also increase the risk of
peripheral vascular disease and systemic thrombotic events such as stroke [21].
4 Medical Benefits of Cannabinoids
Up to this point, we have focused on several complications or adverse effects of
cannabis use. However, there may also be benefits. The most commonly reported
indication for medical cannabis is chronic pain [42]. Several studies evaluating the
efficacy of cannabis on pain alleviation have been published. In a systematic review,
Whiting and colleagues examined 28 trials, with 22 assessing the efficacy of plant-
based cannabinoids and 5 examining the effect of synthetic cannabinoids. All of these
trials compared cannabis to a control group such as amitriptyline, with the exception
of a single trial which compared cannabis to a placebo group. The majority of the
trials assessed efficacy for neuropathic pain, while the remaining considered muscu-
loskeletal, rheumatologic, cancer-induced, chemotherapy-induced, or pain due to
multiple sclerosis. The results of this review suggested that patients experienced
significant improvement in their chronic pain symptoms with the use of cannabis [43].
However, Schatman points out several methodological limitations of this systematic
reviewand meta-analysis of medical cannabinoids. It incorporated studies of a variety
of cannabis preparations with differing consumption methods, along with including
studies of several pain conditions with varying responses to cannabinoids. Further-
more, the article did not address the wide range of adverse events, dosing issues, and
THC/CBD content variance [44], leaving it difficult to make reliable conclusions
about the role of cannabinoids in the broad management of chronic pain condi-
tions, without accounting for these limitations. More specifically, cannabis has been
shown to be effective in treatment of neuropathic pain [45]. However, it is important
to note that these effects are dose-dependent [46] on THC content, and while helpful
for neuropathic pain, patients may have significant side effects [45] and impaired
neurocognition [46], limiting its use in more functional patients.
Cannabis may also offer benefits as a treatment for nausea and vomiting caused
by chemotherapy. While cannabis has been shown to be superior in comparison to
a placebo, several studies have failed to demonstrate superiority in comparison to
standard antiemetics such as ondansetron or prochlorperazine [43].
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Perioperative Considerations in Patients Who Use Cannabis 437
Other potential benefits of cannabis use include reduced spasticity associated with
multiple sclerosis and reduced insomnia [43] but further evidence may be required
before cannabis can be definitively recommended for these indications.
5 Preoperative Considerations
Because of its ubiquity and broad-spanning physiologic impact, recently published
guidelines by the Perioperative Pain and Addiction Interdisciplinary Network (PAIN)
and the American Society of Regional Anesthesia and Pain Medicine (ASRA Pain
Medicine) suggest patients should be screened preoperatively for cannabis use [16,
17]. It has been documented that the potency and dosage of cannabis products have
increased over the years [47–49]. In addition, labeled doses may significantly over or
underestimate actual cannabinoid content [50, 51], and as a result, accurate quantifi-
cation of usage amounts may be difficult or impossible. Further, given the likelihood
of concomitant use of other substances [42, 52, 53], providers should be aware of
the physiologic impacts that these other substances may have and how they present.
Current guidelines recommend that, in order to better understand the effects
of cannabis use on our patients, we should ask about the method of consumption
(smoking, vaping, ingesting, etc.), how often it is used, the individual’s response
to cannabis, any withdrawal symptoms experienced, and when the patient last used
cannabis or any other substances [16, 17, 54]. This information can help healthcare
professionals gain insight into the acute and chronic effects of cannabis or other
substances on their patients. The PAIN guidelines recommend quantifying the total
dose of cannabis in milligrams or grams per day, given that most products are sold
accounting for either percentage of mass in THC or CBD, milligrams of THC/CBD
per gram of product, or simply milligrams of cannabis. In terms of defining signifi-
cant use, the PAIN group defined it as 1.5 g/day of inhaled cannabis, 300 mg/day of
CBD oil, and 20 mg/day of THC oil, or by frequency of two to three times of usage/
day [16]. A validated screening tool [55, 56] can help determine whether a patient
has a Cannabis Use Disorder (CUD) and might benefit from a preoperative referral
to an addiction medicine specialist. Assays for cannabis and its metabolites exist for
determining serum levels of THC [57, 58], though no standardized nomogram or tool
exists to correlate use with physiologic impact. Accordingly, toxicology screening
is not routinely recommended unless testing for acute intoxication.
Determining whether a patient is experiencing signs and symptoms of acute
cannabis use may be challenging, as patients present variably depending on chronicity
of use, individual physiologic response and type of cannabis product used. Symp-
toms of cannabis intoxication can include conjunctivitis, paranoia, anxiety, delirium,
hyperkinesis, and hypotension [59, 60]. Both acute and chronic users of cannabis,
due to hippocampal effects, are also susceptible to dose-dependent impairment of
cognitive function, memory, and ability to process information [35, 61]. An aspect
of patient assessment also includes determining whether a patient meets the criteria
for consenting to non-emergency surgery. There is evidence that cannabis users may
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demonstrate susceptibility to false memories [62], so any informed consent process
should include thorough documentation of what was discussed and consideration
of postponing elective surgery in patients who may not be considered capable of
providing consent.
Cannabis use has been associated with tachycardia, arrhythmias [63–65], coronary
spasm [66], sudden death [67], and stroke [68]. In discussing anesthetic risk as an
element of informed consent, cannabis-using patients should be made aware of their
elevated perioperative risk and screened for angina-free functional capacity. Patients
with CUDs also are at greater risk of postoperative MI when presenting for elective
surgery (adjusted OR 1.88) [7] and greater risk of perioperative MI and stroke when
undergoing vascular surgery [8]. In addition to counseling patients that may be at
risk for or have coronary artery disease on the potential increase of perioperative MI,
the ASRA Pain Medicine guidelines recommend postponing elective surgery for at
least 2 hours subsequent to cannabis use due to this elevated risk [17].
As mentioned previously, smoked and vaped cannabis products may be associ-
ated with an increased risk of respiratory morbidity. According to one retrospective
cohort analysis of over 400,000 patients undergoing elective spine surgery, cannabis
users had a twofold increase in the odds of respiratory complications (OR 2.0,
95% CI 1.4–2.9) [9]. Discussing the potential for airway compromise and increased
pulmonary complications is recommended by recent guidelines [17]. In addition,
providers should consider administration of steroids for treatment of airway edema
noted perioperatively [34]. As part of preoperative evaluation and determination of
whether to proceed with a given procedure, surgeons and anesthesiologists should
weigh the risks and benefits of postponing elective surgery in patients who have
recently used cannabis, based on patient comorbidities, surgery-specific pulmonary
risk, method and dose of cannabis consumption, and recency of use.
There is conflicting information r egarding the relationship between cannabis use
before surgery and a higher use of opioids during the perioperative period, as well
as how this affects acute pain. However, for patients with chronic pain and opioid
use, cannabis use may alleviate pain and reduce chronic opioid consumption [69–72].
Despite the potential benefits of cannabinoids in chronic pain patients perioperatively,
these patients demonstrate elevated pain scores postoperatively, lower quality of life,
and greater likelihood of using benzodiazepines and opioids for up to 6 months
postoperatively [13]. As a result of these potential negative effects, whether patients
should taper or discontinue use of cannabis products perioperatively, remains a major
concern. The ASRA Pain Medicine guidelines do not recommend for or against a
tapering strategy [17]. Further, the Perioperative Pain and Addiction Interdisciplinary
Network guideline recommends considering a dose reduction to less than 1.5 g/day
of smoked cannabis, 300 mg/day of CBD oil, or 20 mg/day of THC oil within 7 days
of surgery, but makes no consensus recommendations regarding tapering between 1
and 6 days preoperatively, and recommends against tapering within 1 day prior to
surgery [16]. A U-shaped response to cannabis, with low and elevated THC levels
being associated with no reduction in pain [73] suggests a narrow therapeutic window.
The narrowness of this window may influence future tapering recommendations,
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Perioperative Considerations in Patients Who Use Cannabis 439
although further research would be necessary to identify the specific duration of this
window.
When tapering or discontinuing cannabis preoperatively, one should also consider
the risk of cannabis withdrawal syndrome (CWS), discussed in further detail later,
among those patients who consume a significant amount of cannabis [16], and
determine if this warrants treatment preoperatively.
6 Intraoperative Considerations
Given the broad physiologic and pharmacologic effects of cannabis, one should
be diligent when caring for a cannabis user undergoing anesthesia. Unfortunately,
there is a paucity of robust clinical research to guide the intraoperative manage-
ment of these patients. Once a patient’s cannabis use has been identified, including
the amount, frequency, route, and time of most recent use, the anesthesiologist can
better determine how a patient’s cannabis history might affect his/her potential intra-
operative anesthetic risks. As with other substances, chronic cannabis use and acute
intoxication may exert opposing effects and may need to be addressed differently in
the perioperative period.
Several clinical studies suggest that chronic cannabis users require higher induc-
tion and maintenance doses of anesthesia. A prospective study [69] compared the
dose of propofol required to induce general anesthesia and successfully place a
laryngeal mask airway in 60 patients, 30 of whom used cannabis more than once a
week versus non-using controls and concluded that chronic cannabis use increases the
propofol dose required. Similarly, a retrospective study of patients undergoing gastric
endoscopies demonstrated that daily or weekly users of cannabis required signifi-
cantly increased doses of fentanyl, midazolam and propofol, i.e., 14, 19.6 and 220.5%
more medication, respectively, when compared to non-users of cannabis.[74] In addi-
tion, a retrospective study of patients undergoing open reduction internal fixation of
tibial fractures demonstrated a statistically significant increase in sevoflurane dosage
for maintenance of anesthesia. However, no significant difference in total dosages
of propofol, dexmedetomidine, etomidate, ketamine, desflurane, midazolam, and
fentanyl were identified. The definition of cannabis users in this study was broader
when compared to the aforementioned studies, with cannabis users defined as any
cannabis use within the past month, which may explain why significant differences
were not identified with propofol and fentanyl, as had been evidenced in other studies
[75].
In contrast to chronic use, acute cannabis intoxication appears to have the oppo-
site effect on tolerance to anesthesia, as evidenced by several animal studies. A
reduction in the minimal alveolar concentration (MAC) of sevoflurane in rats [76]
and halothane in dogs [77] was identified when the test subjects were treated with
THC prior to exposure to inhaled anesthetics. Although animal studies are consid-
ered imperfect predictors of human responses, it is logical to conclude that cannabis
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follows a similar trend with substances such as alcohol, in which it is well docu-
mented that acute intoxication leads to decreased MAC anesthesia [78]. In their
2021 consensus recommendations for perioperative management of cannabis users,
the PAIN guidelines concluded that acutely intoxicated cannabis users might have
lower anesthetic requirements, whereas chronic cannabis users may require higher
medication dosages to achieve an adequate depth of anesthesia. In both scenarios,
the authors advise considering use of intraoperative EEG monitoring to assist with
monitoring [16]. However, recently published consensus guidelines from ASRA Pain
Medicine regarding cannabis users concluded that there is still insufficient evidence
to support the routine use of intraoperative EEG for depth of anesthesia monitoring
in cannabis using patients [17]. The guidelines cite a study comparing bispectral
index ( BIS) values under general anesthesia between control patients and those
who received premedication with cannabis extract Nabiximols. Cannabis premedi-
cation was found to increase the BIS value in anesthetized patients, and the authors
suggested it was due to a cannabinoid-induced alteration in EEG activity rather than
a shallower anesthetic state [79].
7 Postoperative Considerations
The complexity of caring for cannabis users does not end when the patient leaves the
operating room. Rather, some of the greatest challenges may lie in the postoperative
phase of care. One area of considerable interest is the effect that cannabis use has
on achieving effective postoperative analgesia. Studies repeatedly demonstrate that
cannabis users experience worse postoperative pain and often require higher doses
of opioids as compared to non-users. A study of 3973 patients undergoing major
orthopedic surgeries determined that those using recreational or medicinal cannabis
had higher pain scores at rest and with movement in the early postoperative period, as
well as increased sleep disturbances [14]. Analysis of motor vehicle accident patients
across 4 trauma centers determined that habitual cannabis users reported higher pain
scores and had increased opioid requirements when compared to non-users and infre-
quent cannabis users [80]. McAfee and colleagues [13] conducted a prospective study
of 1335 patients in which they evaluatedclinical characteristics and surgical outcomes
of elective surgery patients. The authors determined that not only did cannabis users
report higher pain scores both prior to and following surgery, but they also had greater
functional impairment, more fatigue, greater sleep disturbances and more symp-
toms of anxiety and depression versus non-cannabis users. A complicating factor
to managing pain in cannabis users is the interaction between cannabinoids and the
cytochrome P450 enzymes. Cannabinoids have the potential to increase the effects of
medications like warfarin [81], acetaminophen, and benzodiazepines and opioids by
inhibition of cytochrome P450 enzymes [82], leading to prolonged half-lives [83].
In vitro and animal studies suggest that cannabinoids can also inhibit cyclooxy-
genase and may cause a reduced response to non-steroidal anti-inflammatory drugs
(NSAIDs) [84]. Despite these interactions, there are no contraindications to common
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