Propofol is believed to have an inter-action with GABA receptors resulting in effects as a sedative hypnotic with no analgesic effect.. Owing to its cerebroprotective effects, propofol
Trang 1central venous return, and decreases in both
intra-cerebral blood flow and intraintra-cerebral pressure These
systemic effects are exacerbated in hypovolemic,
dis-tributive shock patients.
Benzodiazepines bind to benzodiazepine receptors,
enhancing GABA effects Similar to barbiturates,
ben-zodiazepines are negative inotropes with sedative
hyp-notic properties and no analgesic effect They are useful
adjuvants for induction of intubation and are often
combined with opioids during RSI.
Benzodiazepines are lipophilic This is particularly
true of midazolam, which has become the most
com-monly used benzodiazepine for induction Midazolam is
not a tissue irritant and can be given via intramuscular
administration.
Benzodiazepines potentiate respiratory depression
and hypotension effects when used in combination with
opioids Benzodiazepines produce amnesia, are
anxio-lytic, and are potent muscle relaxants They have the
unique advantage, compared to other induction agents,
of being reversible with flunazemil.
Opioids, specifically Fentanyl, may also be useful for
anesthesia induction, in addition to premedication A
large dose of fentanyl is used for induction, ranging
from 3 to 25 mcg/kg, depending on the adjuvant
med-ications used and the rate of infusion Hypotension and
respiratory depression are associated with fentanyl use in
this setting Chest wall rigidity has been associated with
rapidly infused fentanyl at high doses Opioids also have
the advantage of being reversible with naloxone.
Propofol is an alkylphenol with an unknown
mecha-nism of action Propofol is believed to have an
inter-action with GABA receptors resulting in effects as a
sedative hypnotic with no analgesic effect Propofol
produces amnesia similar to benzodiazepines Similar to
barbiturates, propofol is a myocardial and respiratory
depressant that causes hypotension by a reduction in
systemic vascular resistance and negative inotropy Fluid
boluses have been shown to mediate this drop in blood
pressure.
Propofol causes decreases in ICP, intraocular pressure
(IOP), and cerebral perfusion pressure (CPP) It also
acts as an anticonvulsant and antiemetic Owing to its
cerebroprotective effects, propofol has been touted as
the induction agent of choice in isolated head trauma
or status epilepticus The hypotension and negative
ionotropic effects limit its use in multitrauma patients and other clinical scenarios commonly associated with hemodynamic instability.
Ketamine is a phenylcycline derivative It is a ciative agent that selectively inhibits the cortex and thalamus while stimulating the limbic system These effects produce a catecholamine release, specifically endogenous norepinephrine The resultant cumulative outcome is an anesthetic dissociative state accompanied
disso-by bronchodilation, tachycardia, laryngospasm, tension, and bronchorrhea Ketamine has been found to increase ICP and IOP, and is therefore contraindicated
hyper-in patients hyper-in whom elevations hyper-in ICP or IOP would be deleterious.
There is clinical evidence to suggest that ketamine increases cardiac output and blood pressure, thereby increasing myocardial oxygen consumption and poten- tiating cardiac ischemia These effect may, however, be advantageous in the hemorrhagic or septic shock patient Ketamine is noted for its lack of inhibition of sponta- neous ventilation or laryngeal/pharyngeal reflexes These properties, along with its bronchodilation and bronchor- rhea, have prompted suggestions that ketamine is a useful induction agent in asthma and chronic obstructive pulmonary disease No patient outcome studies have been performed to substantiate these applications.
Etomidate is an imidazole derivative, sedative notic The mechanism of action for etomidate as an induction agent is unclear Etomidate is believed to have GABA-like effects and is known to activate alpha 2b adrenoreceptors Etomidate has no analgesic effects The use of etomidate is associated with no increase in ICP or cerebral oxygen consumption, making it an ideal agent for head injured patients and others where cere- broprotective properties are valued Etomidate has minimal effects on the cardiovascular system making it
hyp-an excellent choice for patients with suspected or known hemodynamic instability.
Adrenal suppression is a known effect of etomidate administration This effect has been associated with increased mortality in the setting of continuous infusion for prolonged sedation As a consequence, etomidate is primarily restricted to its use as a single dose induction agent as well as, more recently, procedural sedation Adrenal axis suppression has been reported in etomidate studies considering a single induction dose.
Trang 2This effect is dose dependent and appears to last less
than 12 hr Given this brief period, as well as the
heightened cortisol levels routinely present in critically
ill patients, there does not appear to be an adverse
clinical effect associated with this adrenal suppression.
However, recent studies demonstrating adrenal
sup-pression in many septic patients have caused many
clinicians to question the potential for harm with
eto-midate induction in this population No controlled or
definitive studies have been performed to date to
address this question Given the current evidence,
eto-midate use should likely be removed from practice in
those patients with a high clinical likelihood of sepsis.
Alternatively, adjunctive treatment with a steroid, such
as dexamethasone, at the time of etomidate induction
can also serve to offset this concern in septic patients.
Scopolamine is an anticholinergic muscarinic agent
that acts by blocking acetylcholine (ACh) at muscarinic
receptors Scopolamine has both a sedative and amnesic
effect, but no analgesia Scopolamine use may cause
tachycardia and resultant increased myocardial oxygen
consumption, but is otherwise unremarkable for
signifi-cant hemodynamic effects For this reason, scopolamine
has been used as an induction agent in uncompensated
shock A significant side effect to scopolamine use is the
development of acute psychotic reactions These events
appear to be dose related and have limited its routine use
for induction.
Neuromuscular Blocking Agents/Paralytics
Neuromuscular blocking agents, when added to
induc-tion agents, have been found to greatly increase the ease
and success of tracheal intubation by optimizing alization and patient muscle relaxation Paralytics have a site of action at the motor endplate of the ACh receptor There are two classes of paralytics: depolarizing agents and nondepolarizing agents (Table 38-3 ).
visu-Depolarizing neuromuscular blocking agents bind ACh receptors noncompetitively, leading to prolonged de- polarization and muscle paralysis Succinylcholine is a dimer of acetylcholine molecules First, it causes sodium channels to open leading to cell membrane depolariza- tion, which manifests as muscle fasciculation Succinyl- choline then blocks synaptic transmission by blocking the ACh receptor with the resultant effect of muscular paralysis Succinylcholine degradation occurs in plasma and the liver by pseudocholinesterases.
Succinylcholine is the time-honored and most monly used short-acting paralytic agent for RSI The main complicating factors associated with the use of succinylcholine as a neuromuscular blocking agent are hyperkalemia, cardiac dysrhythmias, and malignant hyperthermia.
com-The change in potassium levels induced by choline appears to range from –0.04 to 0.6 mmol/l Elevations in potassium associated with succinylcholine appear to peak at 5 min postinjection and resolve within 15 min The hyperkalemia response appears to be the most significant in patients with large total body surface area burns greater than 24 hr old, patients with crush injuries (typically greater than 7 days old), paralysis, tetanus, myopathies, acute rhabdomyolysis, and sepsis There have been reported deaths secondary
succinyl-to succinylcholine-induced hyperkalemia, though most
Table 38-3 Neuromuscular blocking agents for consideration during RSI
Adults Pediatrics
Succinylcholine 1.5–2.0
mg/kg IV
0.1–0.15mg/kg IV
1–2 min 8–11 min Any emergent
RSI where notcontraindicated
Hyperkalemia,cardiacdysarrhythmias,malignanthyperthermia,prolonged paralysisRocuronium 1.0 mg/kg IV 0.6 mg/kg IV 2–3 min 60 min When succinylcholine
is contraindicated
Apnea,bronchospasm
Trang 3of these cases have been children with undiagnosed
myopathies.
It has been suggested that caution be exercised with
the use of succinylcholine in renal patients A recent
literature review has revealed that succinylcholine
appears to be safe if there are no other risk factors for
hyperkalemia present at the time of induction
Succi-nylcholine-associated dysrhythmias are typically
char-acterized as bradyarrhythmias with rare reports of
asystole and ventricular tachyarrhythmias These
arrhythmias typically occur in the pediatric population
or in adults who receive more than a single dose of
succinylcholine For this reason, a dose of atropine is
routinely administered in children as pretreatment and
prior to repeat dosing of succinylcholine in adults.
A history of malignant hyperthermia existing in the
patient or the patient’s family is a contraindication to
the use of succinylcholine Studies have found that
patients who have a masseter spasm with induction
using thiopental or fentanyl are also at increased risk of a
succinylcholine-induced hyperthermic event.
Prolonged apnea can occur whenever succinylcholine
is administered, and preparations for this event should
be made before the use of the drug Succinylcholine
breakdown occurs in the liver by pseudocholinesterases.
This metabolism can be decreased by a variety of
con-ditions including hepatic disease, anemia, renal disease,
pregnancy, extremes of age, cancer, cocaine intoxication,
or a genetic pseudocholinesterase deficiency.
Nondepolarizing neuromuscular blocking agents
com-petitively block ACh receptors without stimulating the
receptor These agents are typically used in the emergent
RSI setting when succinylcholine is contraindicated.
Nondepolarizing agents have fewer side effects and
may also be reversed with cholinesterase inhibitors
such as neostigmine and edrophonium Nondepolarizing
neuromuscular blocking agents may be divided into
long-acting and intermediate-acting agents with a
varying time of onset.
Pancuronium has the longest onset time and longest
duration of action among nondepolarizing agents,
specifically with cumulative dosing Pancuronium has
complications of vagolytic effects (tachycardia,
hyper-tension, and increased cardiac output), prolonged
paralysis, and histamine release that can lead to
bron-chospasm or even anaphylaxis Pancuronium has for the
most part been abandoned as an RSI medication owing
to these adverse effects and its long onset time and duration It has been replaced by the intermediate-acting depolarizing agents.
The intermediate-acting, nondepolarizing muscular blocking agents include Atracurium, Miva- curium, Vercuronium, and Rocuronium Rocuronium has the shortest onset time and has shown the most promise
neuro-as an emergent RSI selection agent in clinical scenarios where the use of succinylcholine is contraindicated or considered inappropriate These agents all have longer durations of action than succinylcholine The ability to successfully bag-valve mask ventilate a patient should be assured prior to their administration.
SUMMARY
Rapid sequence induction has become a necessary and frequent procedure for the emergency physician A working knowledge of RSI medications and techniques
is essential to the provision of emergent airway skills.
3 Thompson JD, Fish S, Ruiz E Succinylcholine for endotracheal intubation Ann Emerg Med 1982;11:526–528.
4 Dufour DG, Larose DL, Clement SC Rapid-sequence intubation in the emergency department J Emerg Med 1995;12:705–710.
5 Sivilotti MLA, Filbin MR, Murray HE, Slasor P, Walls RM Does the sedative agent facilitate emergency rapid sequence intubation Acad Emerg Med 2003;10:612–620.
6 Miller RD, Anesthesia, 5th edn New York: Churchill Livingstone, 2000.
7 Robinson N, Clancy M In patients with head injury undergoing rapid sequence intubation, does pretreatment with intravenous lignocaine/lidocaine lead to an improved neurological outcome? A review of the literature Emerg Med J 2001;18:453–457.
8 Levitt MA, Dresden GM The efficacy of esmolol versus lidocaine to attenuate the hemodynamic response to intubation in isolated head trauma patients Acad Emerg Med 2001;8:19–24.
9 Clancy M, Halford S, Walls R, Murphy M In patients with head injuries who undergo rapid sequence intuba- tion using succinylcholine, does pretreatment with a
Trang 4competitive neuromuscular blocking agent improve
out-come? A literature review Emerg Med J 2001;18:373–375.
10 Brucia JJ, Owen DC, Rudy EB The effects of lidocaine
on intracranial hypertension J Neurosci Nurs 1992;24:
205–214.
11 Koenig KL Rapid–sequence intubation of head trauma
patients: Prevention of fasciculations with pancuronium
versus minidose succinylcholine Ann Emerg Med
1992;21:929–932.
12 Bergen JM, Smith DC A review of etomidate for rapid sequence intubation in the emergency department J Emerg Med 1997;15:221–230.
13 Perry J, Lee J, Wells G Are intubations conditions using rocuronium equivalent to those using succinylcholine? Acad Emerg Med 2002;9:813–823.
14 Perry J, Lee J, Wells G Rocuronium versus succinylcholine for rapid sequence induction intubation Cochrane Data- base Syst Rev 2003;1:CD002788.
Trang 5Richard Riker and Gilles Fraser
SCOPE OF THE PROBLEM
CLINICAL ASSESSMENT
PAIN AND SEDATION CONSIDERATIONS
PAIN AND SEDATION MANAGEMENT
Opiates Opiate choices Controversial issues Opiate-based ‘‘sedation.’’
Benzodiazepines Controversial issues Propylene glycol toxicity.
Benzodiazepine-induced delirium Propofol
Controversial issues Bradycardia, acidosis, propofol infusion syndrome (pris) Propofol as a preferred long-term sedative option?
Haloperidol Controversial issues Haloperidol improves outcomes?
Atypical Antipsychotic Agents Dexmedetomidine
Controversial issues Long-term dexmedetomidine useSUMMARY
BIBLIOGRAPHY
SCOPE OF THE PROBLEM
Despite our best efforts to provide a humane
environ-ment for critically ill patients, up to 74% become
agi-tated during their intensive care unit (ICU) stay, and
as many recall unpleasant memories of their ICU stay
including unrelieved pain, sleep deprivation, anxiety,
nightmares, and hallucinations All of these experiences
may be associated with development of adverse
out-comes, including posttraumatic stress disorder In
addi-tion, agitation is commonly associated with unplanned
patient removal of endotracheal tubes or other devices
such as vascular catheters and enteral feeding tubes These
events may contribute to increased patient morbidity and additional hospital expense.
Clearly inadequate sedation and analgesia are cally detrimental, but excessive sedation is also unde- sirable because it may lead to prolonged mechanical ventilatory support, ICU length of stay, and increased neurodiagnostic testing These factors extend the eco- nomic burden of sedating medications beyond the estimated $1 billion spent yearly for the purchase of this group of drugs.
clini-Finding a balance between the provision of patient comfort and oversedation has been difficult Agitated ICU patients offer many unique challenges to clinicians.
268
Trang 6They often suffer from multiple organ dysfunction,
require prolonged periods of therapy, and may not be
able to communicate their needs.
Recently published ICU sedation and analgesia
guidelines provide a framework for choosing
appropri-ate therapeutic strappropri-ategies designed to maximize the
provision of patient comfort The foundation for these
recommendations is based on three issues: (a) the
iden-tification of the cause of agitation whenever possible,
(b) specific patient comorbidities, and (c) drug
phar-macokinetics, pharmacodynamics, and side-effect profile
(Table 39 -1 ).
It should be emphasized that although appropriate
drug selection is important, accurate dose titration of
sedatives and analgesics may be a more vexing and
clin-ically relevant concern for physicians caring for a critical
care patient The use of validated scoring tools embedded
in protocols has been recommended by the Society of
Critical Care Medicine along with a daily evaluation of
underlying mental status and depth of sedation These
strategies have been shown to markedly improve clinical
outcomes (Table 39-2 ).
CLINICAL ASSESSMENT
Critical care practitioners easily recognize pain resulting
from trauma, chest tube placement, pancreatitis, or
from surgical incisions Despite this, as many as 30% of
patients report that their analgesic needs were not met
during their ICU stay When surveyed about the causes
of discomfort, patients suggest that the more mundane
aspects of critical care are very troubling and are neither
acknowledged nor treated by their caregivers The mere
presence of an endotracheal tube or various vascular or
drainage catheters, and even repositioning are significant
stressors for the critically ill patient Adding to the
dilemma is the fact that these patients are often unable
to communicate their needs to clinicians As a result, clinicians must rely on physiologic and behavioral clues such as moaning, grimacing, splinting, and the presence
of elevated blood pressure and heart rates for evaluation
of pain.
PAIN AND SEDATION CONSIDERATIONS Owing to the difficulties in identifying pain or dis- comfort in many patients and because oligoanalgesia is the most prominent cause of ICU agitation, analgesic medications are often thought to be an appropriate initial therapeutic option when the etiology of agitation
is uncertain Caregivers can evaluate the contribution
of pain to these patient behaviors by intravenously administering a bolus dose of a rapid-acting opiate such
as fentanyl and assessing patient response As this strategy has evolved, many now consider that the initial provision of opiates, with supplemental sedation as needed, represents the most humane strategy to alleviate agita tion in many IC U patients (Figur e 39-1 ) This approach is effective for initial patient management and may result in reduced mechanical ventilatory require- ments and ICU length of stay.
PAIN AND SEDATION MANAGEMENT Opiates
Sir William Osler once referred to morphine as ‘‘God’s own medicine.’’ Indeed it is difficult to overstate the impact of this medication and the other opiates for relief
of pain and suffering All opiates share similar macology by interacting with various opiate receptors in the body Although relief of pain is generally the most desired pharmacologic effect of the opiates, other aspects
phar-of opiate treatment are just as prominent (albeit in a less positive way) in the critically ill patient, including respi- ratory depression, gastrointestinal dysmotility, tolerance, and drug withdrawal.
Opiate choices Distinctions among the opiates can help guide the choice
of medications in a particular patient (Table 39-3 ) The liver metabolizes all opiates except remifentanil, and some have active metabolites that can accumulate in the setting
Table 39-1 Essential factors for choosing
appropriate ICU therapeutic strategies designed to
maximize the provision of patient comfort
Define the cause of agitation whenever possible
Consider specific patient comorbidities
Consider analgesic and sedative drug pharmacokinetics,
pharmacodynamics, and side-effect profiles
Trang 7of renal disease For instance, accumulation of the
glu-curonide salts of morphine may lead to excessive narcosis
whereas normeperidine, the metabolite of meperidine,
may cause neurotoxicity As a result, the opiates of choice
in patients with a reduced glomerular function include
fentanyl and hydromorphone Selecting between these
two agents is determined by the need for a more rapid
onset (fentanyl) or prolonged duration
(hydromor-phone).
Another pharmacologic distinction between the
opi-ates is the tendency of morphine to cause histamine
release The resultant vasodilatation may represent a
therapeutic advantage when preload reduction is
desir-able On the other hand, hypotension and
broncho-spasm associated with histamine release may represent a risk to the patient with unstable hemodynamics and reactive airways disease Fentanyl may be a better option for these patients.
Methadone is a unique opiate because it acts as a mu receptor agonist and an N-methyl-D-aspartate (NMDA) antagonist This agent can often restore analgesic activity
to patients tolerant to standard opiates and at doses that are only 10–15% of expected ‘‘equivalent’’ doses The long half-life of this agent, good bioavailability, and low cost make methadone a reasonable analgesic espe- cially for patients who require high doses of standard opiates or who are transitioning from an intravenous opiate infusion to an enteral formulation Methadone
Table 39-2 Studies that have evaluated the impact of analgesia and sedation assessment on ICU
patient outcomes
patients
Patienttype
Benefits
Kress Ramsay with protocol
target¼ wakefulnessand daily sedationinterruption
by 33%, ICU stay by35%, neurodiagnostictesting by 67%
Schweickert Ramsay with protocol
target¼ wakefulnessand daily sedationinterruption
Blinded, retrospectivereview of RCT
complications (VAP,bacteremia, barotrau-mas, VTE, cholestasis,sinusitis) by 50%
De Jonghe ATICE with algorithm
target¼ wakefulness
Prospective controlledstudy
102 MICU Reduced ventilator time by
57%, ICU stay by 47%,pressure sores by 50%Kress Ramsay with protocol
target¼ wakefulnessand daily sedationinterruption
RCT with follow-uppsychologic evaluation
32 MICU Reduced incidence of
PTSD (31% vs 0%,
p¼ 0.06)Brook Ramsay with protocol
target¼ wakefulness
28%, ICU stay by 30%,tracheostomies by 53%Brattebo MAAS with protocol to
‘‘avoid excessivesedation’’
Before-after 285 SICU Reduced ventilatory time
by 28%
Chanques Systematic BPS, NRS,
RASS evaluations
Two-phase prospectivecontrolled
230 Mixed Reduced incidence of pain
by 33% and agitation by59%
Notes: For all results except where noted, p< 05
RCT, randomized controlled trial; MICU, medical ICU; SICU, surgical ICU; VAP, ventilator-associated pneumonia; VTE, venous thromboembolicdisorder; ATICE, adaptation to the intensive care environment; MAAS, motor activity assessment scale; PTSD, posttraumatic stress disorder; BPS,behavioral pain scale; NRS, numerical rating scale; RASS, Richmond agitation sedation scale
Trang 8is also unique in that it can prolong the QTc on the
electrocardiogram The current literature strongly
sug-gests that methadone-associated QTc interval
prolonga-tion may heighten the risk of torsades des pointes In
addition to QT prolongation, bradycardia has also been
linked to high-dose methadone use in ICU patients.
Meperidine remains a less desirable medication to
treat pain in the ICU patient because of its neurotoxic
potential and its association with delirium Meperidine
may stimulate central serotonin release and, in
con-junction with other serotonin active agents
(mono-amine oxidase inhibitors, selegiline, and possibly the
selective serotonin reuptake inhibitors), may be
asso-ciated with the potentially lethal serotonin syndrome –
confusion, restlessness, tremor, myoclonus, hyperreflexia,
ataxia, tachycardia, hypertension, fever, and
rhabdo-myolysis.
Remifentanil is a recently approved ultra acting parenteral opiate with a half-life of 3–10 min It is metabolized by blood and tissue esterases Use of remi- fentanil in the critical care setting is supported by a number of studies It may offer an advantage over stan- dard opiates because it is easily titratable as a continuous infusion and may not adversely affect intracranial pres- sures A potential disadvantage of remifentanil is the rapid development of tolerance with a relative loss of analgesic activity.
short-Controversial issues
sup-ports the contention that ICU agitation may be tively treated with opiates alone or in combination with traditiona l sedativ es (Ta ble 39-4 ) This therap eutic strategy acknowledges that the source of agitation is
effec-Yes
Reassess goal daily,Titrate and taper therapy to maintain goal,Consider daily wake-up,
Taper if > 1 week high-dose therapy & monitorfor withdrawal
No
Set GoalforAnalgesia
Hemodynamically Unstable
Fentanyl 25 - 100 mcg IVP Q 5-15 min, or Hydromorphone 0.25 - 0.75 mg IVP Q 5 - 15 min
Hemodynamically stable
Morphine 2 - 5 mg IVP Q 5 - 15 min
Repeat until pain controlled, then scheduled doses
+ prn
Set GoalforSedation
Acute Agitation #
Midazolam 2 - 5 mg IVP Q 5 - 15 min until
acute event controlled
Ongoing Sedation #
Lorazepam 1 - 4 mg IVP Q 10-20 min until
at goal then Q 2 - 6 hr scheduled + prn, or
Propofol start 5 mcg/kg/min, titrate Q 5 min
until at goal
Set Goalfor Control
of Delirium
Haloperidol 2 - 10 mg IVP Q 20 - 30 min,
then 25% of loading dose Q 6hr
IVP Dosesmore often than Q2hr?
Consider continuousinfusion opiate orsedative
> 3 Days Propofol?
(except neuro pt.)
Convert toLorazepam
Yes
Benzodiazepine or Opioid:Taper Infusion Rate by10-25% Per Day
Yes
Doses approximate for 70kg adult
Rule out and Correct Reversible Causes
Use Non-pharmacologic Treament,
Optimize the Environment
ALGORITHM FOR SEDATION AND ANALGESIA OF MECHANICALLY VENTILATED PATIENTS
Use Pain Scale * to
Assess for Pain
Use Sedation Scale **
to Assess for
Agitation/Anxiety
Use Delirium Scale ***
to Assess for Delirium
Is the Patient Comfortable & at Goal?
Use a low rate and IVP loading doses
Figure 39-1 Algorithm for sedation and analgesia of mechanically ventilated patients
Trang 9often unrecognized patient discomfort and focuses on
analgesia therapy while reserving sedatives for refractory
cases This strategy also recognizes that traditional modes
of sedation carry avoidable risks – benzodiazepines and
delirium, propofol and cardiovascular impairment.
Comparative studies have demonstrated a reduction in
the need for mechanical ventilation as well as ICU stay
with opiate-based ‘‘sedation.’’ It should be noted that a
range of patients, 30–74%, will require benzodiazepine or
propofol sedative rescue with this strategy.
Benzodiazepines
Benzodiazepines are gamma-aminobutyric acid (GABA)
agonists that offer anxiolysis and amnestic effects that
may be useful for ICU patients The benzodiazepine agents most commonly used are midazolam and lorazepam Pharmacokinetic and pharmacodynamic distinctions will direct the choice of one benzodiazepine agent over another In the physiologic milieu of blood pH, mid- azolam becomes a highly lipid soluble moiety resulting
in a more rapid onset of action than lorazepam azolam is metabolized in the liver by cytochrome P450 3A4 with a half-life of approximately 3 hr The uncon- jugated alpha-hydroxy metabolite of midazolam has nearly two-thirds the activity of the parent drug and accumulates in renal failure Formation and accumula- tion of the active metabolite, accumulation of the parent drug in adipose tissue, and altered midazolam clearance resulting from a number of CYP 3A4 mediated drug interactions help to explain the consistent finding
Mid-of prolonged sedation with long-term midazolam use ( >3 days).
Controversial issues
insoluble in aqueous media requiring the inclusion of the diluent propylene glycol (PG) to permit parenteral administration Although the Food and Drug Admin- istration (FDA) regards PG as ‘‘generally recognized as
Table 39-3 Opiate considerations for analgesia and sedation in the critically ill patient – agents listed by descending duration of clinical activity (for dosing refer to Figure 39-1 ).
Associated with deliriumMorphine Liver Histamine release
Longer acting than short-acting agentsHydromorphone Liver Longer acting than short-acting agents
Good selection with impaired renal function
Short half-lifeGood selection with impaired renal functionRemifentanil Esterases in
blood andbody tissues
Rapid onsetUltra short half-lifeRelatively rapid development of toleranceNote: GFR, glomerular filtration rate; QTc, corrected Q-T interval
Table 39-4 Commonly utilized agents for sedation
in the critically ill patient (for dosing refer to
Trang 10safe,’’ many accounts describing PG toxicity have been
published in the medical literature Acute tubular
necrosis was noted in 15%, metabolic acidosis in 70%,
and hyperosmolality in 50% of these patients Risk
factors for developing PG toxicity from parenteral
lor-azepam therapy include long-term use, high doses, renal
and hepatic derangement, pregnancy, age less than 4
years, and treatment with metronidazole.
The osmol gap correlates with PG concentrations and
represents a widely available, inexpensive surrogate
marker to identify possible PG toxicity Monitoring the
osmol gap 2–3 times weekly when daily lorazepam doses
exceed 50 mg or approach 1 mg/kg/day is suggested An
osmol gap greater than 10–15 may be associated with
toxic PG levels, and this threshold may help clinicians
avoid the adverse events associated with PG toxicity.
that the use of lorazepam (and probably midazolam) is an
independent risk factor for the development of delirium in
ICU patients One study found that 20 mg lorazepam
resulted in the transition to delirium in the following 24 hr
in 100% of patients The most concerning aspect of these
data is that the medications that are often administered to
patients for anxiety may result in the development of
an-other psychological issue – delirium.
Propofol
Propofol is popular for short-term sedation in critical
patients because it is eminently titratable with a unique
consistency in onset and offset The pharmacology of
this agent has not been well described, but it is thought
to affect GABA receptors at a site distinct from the
benzodiazepines It has no analgesic activity and its
amnestic effects may be less pronounced than that of the
benzodiazepines (although this finding is contentious).
Propofol is administered as an emulsion in a
phospho-lipid vehicle, which contributes 1.1 kcal/ml to the patient’s
total caloric intake Propofol has been associated with a
variety of adverse events including (in the order of strength
of association) decreases in vascular tone, respiratory
depression, hypertriglyceridemia, pancreatitis, interference
with myocardial contractility, and neuroexcitatory
symp-toms It has only recently been discovered that propofol
may inhibit CYP 3A4 function, leaving open the potential
for a myriad of drug interactions.
Controversial issues
B R A D Y C A R D I A , A C I D O S I S , P R O P O F O L I N F U S I O NSYNDROME (PRIS)First described in association with the deaths of five children in 1992, PRIS has now been reported in adults as well The common aspects in children and adults include sustained (usually longer than 48 hr) high-dose propofol (>75 mcg/kg/min or 4.5 mg/kg/h) with elevated triglycerides, metabolic acidosis, rhabdomyolysis (myoglobinuria and/or elevated serum creatine kinase), hypotension, and bradycardia leading to asystole and death Variants of these criteria (i.e., isolated metabolic acidosis or bradycardia) have also been reported with prolonged ICU use and more recently during short-term, high-dose, intraoperative propofol use.
In the largest adult PRIS case series, Cremer identified PRIS in 7 (10%) of 67 brain-injured patients, 5 occur- ring after changing to 2% propofol As with other reports, those with PRIS received higher doses of pro- pofol (108 mcg/kg/min) compared to the 60 patients that did not develop PRIS Recent reviews identify other potential factors in the development of this often-lethal syndrome, including corticosteroid therapy, sepsis, and systemic inflammatory response syndrome, catechol- amine use, and brain injury.
Several potential mechanisms have emerged porting the biologic plausibility of this syndrome Mitochondrial cytochrome oxidase enzyme deficiencies were identified on muscle biopsy from two children with PRIS, and abnormal fatty acid metabolism was associ- ated with PRIS in several pediatric cases, suggesting acquired metabolic disorders result in mitochondrial skeletal and myocardial myopathy Additional cell cul- ture work has identified a potential connection between propofol and nitric oxide metabolism via the interme- diary nitrosopropofol that interferes with mitochondrial energy metabolism in a concentration-dependent man- ner; this may explain the association with sepsis or systemic inflammatory response in some cases.
sup-Although a causal relationship between propofol and this syndrome is not proven, extreme caution and a heightened sensitivity should be applied when admin- istering doses of propofol greater than 75–80 mcg/kg/ min (4.5 mg/kg/hr), monitoring closely for components
of the syndrome (creatine kinase, liver function tests, triglyceride concentrations, evolving metabolic acidosis,
Trang 11and bradycardia or hypotension) The pediatric and
adult patient deaths associated with PRIS have often
occurred with little warning, and waiting for signs of
cardiac impairment prior to decreasing or stopping
propofol infusions may not be prudent As propofol
doses approach the threshold for risk, preemptive
strategies may include the addition or substitution of
alternate sedating agents Survival after the development
of PRIS has now been reported in several pediatric cases,
suggesting that in addition to discontinuing propofol,
potential treatments such as continuous hemofiltration
or hemodialysis, possibly in concert with mechanical
circulatory support (i.e., ECMO) may avert the high
fatality rates reported previously.
P R O P O F O L A S A P R E F E R R E D L O N G - T E R M S E D A T I V E
OPTION?Although the Society for Critical Care Medicine
currently recommends only short-term use of propofol,
except for neurologic patients, recent data suggest that its
use may result in shorter ventilator times than patients
treated with intermittent lorazepam to a similar level of
consciousness Anecdotal experience suggests that nursing
compliance with daily sedation evaluations – also known as
‘‘sedation vacations’’ – is more common with
propofol-treated patients because nurse observation time is generally
shorter than when the benzodiazepines are used.
Haloperidol
Haloperidol is a dopamine antagonist that is often used
for the treatment of ICU delirium Although not FDA
approved for IV use, haloperidol is often administered
as an IV bolus or as an infusion Its onset of activity is
delayed up to 20–30 min, and dose titration is complex.
Other features that limit the usefulness of haloperidol
include an association with prolongation of the
cor-rected QT interval on the ECG, uncommonly leading to
the development of ventricular arrhythmias such as
Torsades de pointes Evidence suggests that this effect
may be dose related with administration of more than
35 mg identified as a safety threshold The presence of
underlying cardiac disease may represent another risk
factor for haloperidol-induced Torsades.
Controversial issues
analysis of ICU patients suggested a higher survival rate
in mechanically ventilated ICU patients treated with haloperidol even when data were adjusted for age, comorbidities, severity of illness, organ dysfunction, and other confounders Three mechanisms were proposed to explain the possible protective effects of this drug: (a) the use of haloperidol might avoid the excessive use of other agents which commonly lead to prolonged ICU ventilation requirements and lengths of stay; (b) halo- peridol may stabilize cognitive function thus interrupt- ing the negative effects of neuroimmunomodulation associated with delirium; and (c) this agent may have clinically important anti-inflammatory activity Or, as Schweickert and Hall suggest, the agitated patient may
be in the recovery phase of their illness and haloperidol use may be a surrogate marker of clinical improvement.
Atypical Antipsychotic Agents
As alternatives to haloperidol, many of the newer
‘‘atypical’’ antipsychotic agents (such as olanzapine, quetiapine, ziprasidone, and risperidone) have been used in small numbers of patients with delirium Cur- rently, it is impossible to assess the risk-to-benefit ratio
of the atypical antipsychotics for the critical care patient The side-effect profile of each agent is somewhat unique The gain in lowered frequency of movement disorders associated with these agents may be countered by life- threatening hyperglycemia, neuroleptic malignant syn- drome (NMS), hypotension, and QTc prolongation.
Dexmedetomidine Dexmedetomidine is a novel agent because it offers anxiolysis, analgesia, sedation, and sympatholysis, all the while retaining the patient’s ability to be aroused Additionally, dexmedetomidine does not interfere with respiratory drive The value of this medication is in the quality of sedation offered Patients treated with dex- medetomidine are able to cooperate with therapeutic interventions (such as deep breathing and coughing) and are often able to interact with caregivers and family.
The unique attributes of dexmedetomidine bility and lack of respiratory depression) hold great promise to optimize ICU resource consumption by avoiding both prolonged mechanical ventilation and diagnostic evaluations for unexpected mental status changes that may be iatrogenic in origin Unfortunately,
Trang 12(arousa-rigorous data to define the role of dexmedetomidine in
the ICU are currently sparse.
Dexmedetomidine is a highly selective alpha
2-adre-noceptor agonist with both sedative and analgesic
properties Dexmedetomidine sedation occurs via a
mechanism that is unknown but presumably involves
attenuation of increases in central sympathetic nervous
system activity particularly in the locus coeruleus The
analgesic effects of dexmedetomidine are not blocked
by naloxone, suggesting a mechanism of action that is
independent of the opioid mu receptor
Dexmedeto-midine also provides sympatholysis and may blunt
hyperdynamic cardiovascular responses to noxious or
other stimuli.
Dexmedetomidine is metabolized by the liver via
glucuronidation, methylation, and oxidation via CYP
2A6 to a variety of metabolites; none is thought to exert
important pharmacologic activity The elimination
half-life of dexmedetomidine is 2 hr with an approximately 5
min onset of activity; offset is measured in minutes as
well, with a complete return to baseline mental status
within 4 hr.
Although there are no formal FDA criteria for
con-traindications, dexmedetomidine should used with
extreme caution in patients reliant on sympathetic tone
and endogenous circulating catecholamines to
main-tain hemodynamic stability (i.e., shock or vasopressor
use, sepsis, hypovolemia, active myocardial dysfunction,
etc.), and also in those with significant hepatic
derange-ment or cardiac conduction disorders Hypertension can
occur with rapid administration of a dexmedetomidine
loading dose (<20 min) Hypotension and bradycardia
are commonly encountered adverse effects of this
sym-patholytic medication These events generally respond
well to volume infusion though clinicians must be
prepared to use pressors or chronotropic-supporting
interventions.
Controversial issues
dexmedetomidine use approved by the FDA was limited
to 24 hr, reflecting the duration of treatment in phase III
studies Several recent studies report use of
tomidine for up to 7 days In these reports,
dexmede-tomidine use longer than 24 hr has been well tolerated
when compared with other agents, including midazolam,
with a similar incidence of hypotension and bradycardia Additional case reports have noted safe clinical use beyond 24 hr to treat sedative-hypnotic withdrawal and facilitate ventilator weaning for up to 7 days.
Ongoing long-term use studies will address important issues such as the effect of this medication on adrenal function, the importance of metabolite accumulation, the potential for withdrawal tachycardia and hyperten- sion, and the behavior of the drug in renal dysfunction.
SUMMARY Data strongly suggest that appropriate choice and ti- tration of sedative medications has a major influence on
a variety of critical care patient outcome measures It is also important that the risk-to-benefit ratio for each therapeutic option be carefully evaluated Although re- cent advances in the development of sedatives has been rather limited, a fuller understanding of their adverse event profiles has evolved and should be considered when therapeutic decisions are made.
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