V. CONVENIO NUMERO 122 DE LA OIT RELATIVO A LA POLÍTICA DE EMPLEO DE 9 DE
3.4. Legislación Antidiscriminatoria En Derecho Comparado
Wendy C. Ziai, MD, MPH and Rehan Sajjad, MD
for agitation, confusion, or sympathetic hyper-activity.
Hypoxemia or hypercarbia related to decreased
◾
respiratory drive or poor airway protection must be detected and treated appropriately.
Metabolic disturbances, including acidosis,
hypo-◾
natremia, hypoglycemia, hypercalcemia, hyper-amylasemia, hyperammonemia, or hepatic or renal insufficiency may contribute to behavioral changes in critically ill patients.
Infection is also a frequent trigger of delirium in
◾
hospitalized and critically ill patients.
Cardiac ischemia, hypotension, and associated
◾
cerebral hypoperfusion may also contribute to mental status changes, and must be ruled out as a cause of delirium in critically ill neurologic patients.
Concomitant administration of other
psycho-◾
active medications such as antidepressants, anticonvulsants, peptic ulcer prophylactics and interactions with promotility agents, corticoster-oids, or even antibiotics and antiretroviral, may adversely affect cognition and behavior.
Goals of sedation in the neurocritical care patient:
Treat anxiety and pain.
◾
Facilitate mechanical ventilation.
◾
Facilitate neurologic exams.
◾
Avoid deleterious change in intracranial pressure
◾
and cerebral perfusion pressure.
Sedation consists of anxiolysis, hypnosis, and amnesia. In neurologically ill patients, an ideal sedation regimen will either preserve the neuro-logic examination as required for constant clinical
W.c. Ziai and r. Sajjad 50
monitoring or has the potential to be discontinued with rapid return of an uncompromised examina-tion. Preferred agents therefore should have rapid onset, short duration of action, and a large thera-peutic window without significant hemodynamic effects. Periodic interruption of sedative infusions and titration to the lowest effective dose are associ-ated with shorter duration on mechanical ventila-tion, fewer tracheostomies, and shortened ICU stay.
Sedation assessment
subjeCtive assessmeNt of sedatioN aNd agitatioN
Frequent assessment of the degree of sedation or agitation may facilitate the titration of sedatives to predetermined endpoints. An ideal sedation scale should provide data that are simple to compute and record, accurately describe the degree of sedation or agitation within well defined categories, guide the titration of therapy, and have validity and reliability in ICU patients (see Fig. 5.1).
A sedation goal or endpoint should be established and regularly redefined for each patient. Regular assessment and response to therapy should be systematically documented. The use of a validated sedation assessment scale (SAS, MAAS, or VICS) is recommended (Table 5.1). Objective measures of sedation using, for example, a Bispectral Index (BIS) monitor have not been completely evaluated and are not yet proven useful in the ICU.
PatieNt ClassifiCatioN sedatioN goal Acutely ill (weaning not a goal): 5–9
Ventilated patient being weaned: 7–10
Chronic ventilated patient: 6–9 (weaning not a goal) Nonventilated patient: 7–9
PharmaCology of seleCted sedatives Benzodiazepines and propofol are currently the sedative agents most commonly administered in the Neuro ICU.
Benzodiazepines
Mechanism of action: Interacts at specific binding
◾
sites on neuronal γ-aminobutyric acid (GABA) receptors.
Sedative, hypnotic, but lacks intrinsic analgesic
◾
benefits.
Potentiates effects of narcotics.
◾
Induces anterograde amnesia, not retrograde.
◾
CNS advantages: Anticonvulsant, decreases
cere-◾
bral blood flow (CBF), decreases cerebral meta-bolic rate of oxygen demand (CMRo2), no change in intracranial pressure (ICP), central muscle relaxation.
Reversible with flumazenil (0.2–1.0 mg;
maxi-◾
mum dose 3 mg), a benzodiazepine (BZ) antago-nist which acts at the BZ binding site on the GABA receptor with
Onset of action: 5 minutes
▸
Elimination half-life: 60 minutes
▸
Duration of action: 0.5–3.5 hours
▸
May require continuous infusion or alternative
▸
airway support
Precipitates withdrawal in
benzodiazepine-▸
dependent patients
May precipitate seizures or status epilepticus
▸
With prolonged use: Tachyphylaxis, reversible
▸
encephalopathy
Withdrawal syndrome, possible seizures on
▸
acute cessation
Paradoxical reactions causing increased
agita-▸
tion and delirium in patients with preexisting CNS pathology can occur due to altered sen-sory perception
Decrease tidal volume, compensated by
▸
increase in respiratory rate
Blunts response to hypoxia and hypercarbia
▸
midazolam (versed)
Drug of choice for acute and short-term sedation;
◾
3–4 times more potent than diazepam, shortest half life of all BZs, no significant active metabo-lites, water soluble.
Highly lipophilic; therefore, crosses the blood–
◾
brain barrier quickly, resulting in a rapid onset of action, 2–5 minutes
Prescribed dose for maintenance of sedation in
◾
critically ill adult patients: 2–5 mg/h (0.02–0.1 mg/kg per hour)
Short duration of action (2–6 hours) due to rapid
◾
metabolism by the liver to an inactive metabolite Distribution half-life: 7–10 minutes infusion) depends on infusion duration.
51
Is the patient comfortable and at goal? Rule out and correct reversible causes Use nonpharmacologic treatment, optimize the environment Use pain scale to assess for paina Use sedation scale to assess for agitation/anxietyb Use delirium scale to assess for deliriumc
Set goal for sedation Convert to lorazepam
Set goal for analgesia yes
NoYes Reassess goal daily; Titrate and taper therapy to maintain goal; Consider daily wake-up; Taper if >1 wk high-dose therapy and monitor for withdrawal yes
Hemodynamically unstable Fentanyl: 25–100 g IVP q 5–15 min or Hydromorphone: 025–075 mg IVP q 5–15 min Hemodynamically stable Morphine: 2–5 mg IVP q 5–15 min Set goal for control of delirium
Repeat until pain controlled, then scheduled doses + prn 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, them q 2–6 hr scheduled + prn or Propofol: start 5 g/kg/min, titrate q 5 min until at goal Haloperidol: 2–10 mg IVP q 20–30 min, then 25% of loading dose q 6 hr
≥3 days propofol? (except neurosurgery pts)
IVP doses more often than every 2 hr? Consider continuous infusion opioid or sedative Lorazepam via infusion? Use a low rate and IVP loading doses Benzodiazepine or opiod taper infusion rate by 10–25% per day
1 2 3 4 aNumeric rating scale or other pain scale bRiker Sedation-Agitation Scale or other sedation scale cConfusion Assessment Methord for the ICU figure 5.1. Algorithm for the sedation and analgesia of mechanically ventilated patients. This algorithm is a general guideline for the use of analgesics and seda- tives. Refer to the text for clinical and pharmacologic issues that dictate optimal drug selection, recommended assessment scales, and precautions for patient monitoring. Doses are approximate for a 70-kg adult. IVP = intravenous push.
W.c. Ziai and r. Sajjad 52
table 5.1. Sedation assessment scales
Score Description Definition
riker Sedation–agitation Scale (SaS)
7 Dangerous agitation Pulling at endotracheal tube (ETT); trying to remove catheters; climbing over bed rail; striking at staff; thrashing side-to-side.
6 Very agitated Does not calm despite frequent verbal reminding of limits; requires physical restraints, biting ETT.
5 Agitated Anxious or mildly agitated; attempts to sit up; calms down to verbal instructions.
4 Calm and cooperative Calm, awakens easily; follows commands.
3 Sedated Difficult to arouse; awakens to verbal stimuli or gentle shaking but drifts off again; follows simple commands 2 Very sedated Arouses to physical stimuli but does not communicate
or follow commands; may move spontaneously.
1 Unarousable Minimal or no response to noxious stimuli; does not communicate or follow commands.
motor activity assessment Scale (maaS)
6 Dangerously agitated No external stimulus is required to elicit movement and patient is uncooperative, pulling at tubes or catheters or thrashing side to side or striking at staff or trying to climb out of bed and does not calm down when asked.
5 Agitated No external stimulus is required to elicit movement
and attempting to sit up or moves limbs out of bed and does not consistently follow commands (e.g., will lie down when asked but soon reverts back to attempts to sit up or move limbs out of bed).
4 Restless and cooperative No external stimulus is required to elicit movement and patient is picking at sheets or tubes or uncovering self and follows commands.
3 Calm and cooperative No external stimulus is required to elicit movement and patient is adjusting sheets or clothes purposefully and follows commands.
2 Responsive to touch or name Opens eyes or raises eyebrows or turns head toward stimulus or moves limbs when touched or name is loudly spoken.
1 Responsive only to noxious stimulus Opens eyes or raises eyebrows or turns head toward stimulus or moves limbs with noxious stimulus.
0 Unresponsive Does not move with noxious stimulus.
ramsay Scale
1 Awake patient anxious and agitated or restless or both.
2 Patient cooperative, oriented and tranquil.
3 Patient responds to commands only.
analgesia, Sedation, and Paralysis 53
Score Description Definition
4 Asleep; a brisk response to a light glabellar tap or loud auditory stimulus.
5 A sluggish response to a light glabellar tap or loud auditory stimulus.
6 No response to a light glabellar tap or loud auditory stimulus.
aVriPaS – revised Sedation Scale agitation alertness
1 Unresponsive to command/1 difficult to arouse, eyes remain closed physical stimulation.
2 Appropriate response to physical 2 mostly sleeping, eyes closed stimuli/calm.
3 Mild anxiety/delirium/agitation 3 dozing intermittently, arouses easily (calms easily).
4 Moderate anxiety/delirium/agitation 4 awake, calm.
5 Severe anxiety/delirium/agitation 5 wide awake, hyperalert.
respiration
1 Intubated, no spontaneous effort.
2 Respirations even, synchronized with ventilator.
3 Mild dyspnea/tachypnea; occasional asynchrony.
4 Frequent dyspnea/tachypnea; ventilator asynchrony.
5 Sustained, severe dyspnea/tachypnea.
Special precautions:
◾
Elderly and patients with liver disease:
▸
Increased volume of distribution and dec-reased elimination
Increased effect in patients with renal failure
▸
due to increase in active unbound portion Repeated doses or continuous IV can lead to
pro-◾
longed sedation because of sequestration in fat stores although respiratory and cardiovascular depression are minimal with continuous infusion due to lower peak plasma concentration than with bolus dosing .
lorazePam (ativaN)
Five to six times more potent than Diazepam;
◾
most potent BZ in ICU
Slower onset of action, 5–10 minutes due to lower
◾
lipid solubility; therefore, less appealing for acute agitation
Prescribed dose: 0.044 mg/kg every 2–4 hours;
◾
infusion rates up to 10 mg/h safe and effective in ICU patients
Greater water solubility which prolongs its serum
◾ half-life
Distribution half-life: 3–10 minutes
▸
Context sensitive half-life: 12–14 hours
▸
Elimination half-life: 10–20 hours
▸
No active metabolite; therefore resistant to drug
◾
interactions except valproic acid, which inhibits lorazepam metabolism
Solvent used (propylene glycol) may cause acute
◾
but reversible renal tubular necrosis .
W.c. Ziai and r. Sajjad
Prescribed dose: 0.1–0.2 mg/kg every 2–4 hours
◾
Distribution half life: 50–120 minutes
◾
Elimination half-life: 20–40 hours. Active
metab-◾
olite, desmethyl-diazepam, with elimination half-life of 96 hours, results in accumulation of both the parent diazepam and metabolite with repeated doses; further converted to oxazepam (t1/2 10 hours).
Limited use in ICU due to potent active
metabo-◾
lites that depend on renal excretion
Resedation occurs after reversal with flumazenil
◾
because of its long duration of action.
Formulated in sterile fat emulsion (previously in
◾
propylene glycol) which has reduced complica-tions (thrombophlebitis, thrombosis, metabolic acidosis)
Minimal cardiovascular depressant effects on
◾
blood pressure and respiratory drive
Synergistic Sedation regimens with Benzodiazepines
Haloperidol + BZ
◾
Decreases dose of BZ required to produce
▸
sedation; therefore less potential for impaired respiratory drive.
Decreased risk of extrapyramidal symptoms
▸
caused by haloperidol Propofol + BZ
◾
Better homodynamic stability and faster
wean-▸
ing from ventilator with lower total doses of both drugs
ProPofol (2,6-diisoProPyl PheNol) Mechanism of action: Enhances
◾ γ-aminobutyric
acid transmission; antagonist at N-methyl-d-aspartate receptors.
Pure sedative–hypnotic, little analgesic action,
◾
some antegrade amnesia.
Useful for sedation in neuro-intensive care due to
◾
titratability facilitating serial neurologic exams.
Also used to treat status epilepticus and raised
and seizure like events: Nonictal myoclonus,
pseudoseizures; potential for proconvulsant activity at low doses although not common.
Usual dosage in ICU: 1–3 mg/kg per hour.
◾
CNS: Decreases CBF, CMR
◾ o2, ICP, and
poten-tially cerebral perfusion pressure (CPP); may impair autoregulation in traumatic brain injured patients; pressors often required to maintain mean arterial pressure (MAP) and CPP.
Laboratory evidence of neuroprotection has not
◾
been substantiated in human studies
CVS: Decreases MAP, systemic vascular
resis-◾
tance (SVR), central venous pressure (CVP), car-diac output (CO), and heart rate (HR).
In general sedative infusion doses of propofol
◾
cause minimal hemodynamic alteration without compromising CPP.
Produces general anesthesia at induction dose of
◾
2 mg/kg.
Onset of action: 1–2 minutes.
◾
Ultra-short-acting due to:
◾
Highly lipophilic structure and extensive tissue
▸
redistribution
Extrahepatic metabolism
▸
After cessation of continuous infusion,
recov-◾
ery from unconsciousness to awake, respon-sive state occurs within 10–15 minutes without withdrawal or tolerance; more reliable weaning from mechanical ventilation than midazolam infusion.
Predictable kinetics even in presence of hepatic
◾
Terminal half-life, during which propofol is
▸
eliminated from tissue fat, 300–700 minutes Unfavorable characteristics:
◾
▸ Hypotension, especially in hypovolemic patients; however, better cardiovascular stabil-ity compared with barbiturate therapy
▸ Respiratory depressant; infusions increase respiratory rate and reduce ventilation res-ponse to hypercarbia; impair upper airway reflexes; bronchodilator effects in patients with reactive airways disease; increases CO2 produc-tion – requires increased minute ventilaproduc-tion to maintain normal acid–base status
▸ Hypertriglyceridemia and pancreatitis because it is mixed as an emulsion in a phospholipid vehicle
analgesia, Sedation, and Paralysis 55
Potential for
▸ infection and drug incompatibility requiring a dedicated IV catheter
▸ Pain with peripheral injection necessitating central access; consider lidocaine before adm-inistration
Tonic–clonic
▸ seizures when abruptly stopped after days of infusion
Rarely, urine, hair, and nail beds turn green
▸
ProPofol iNfusioN syNdrome (Pris) Syndrome of metabolic acidosis, rhabdomyolysis,
◾
elevated creatine kinase, renal failure, myocardial failure, cardiac arrhythmias, and hyperlipidemia Pathogenesis related to propofol-induced
block-◾
ade of mitochondrial fatty oxidation and accumu-lation of free fatty acids with proarrhythmic effects Most cases reported in children, resulting in part
◾
from reduced energy stores and higher sympa-thetic tone
Approximately 20 adult cases reported, usually in
◾
setting of head injury or other brain injury includ-ing status epilepticus
Recommended to avoid prolonged propofol
infu-◾
sion (>18 hours) at rates >5 mg/kg per hour in adults
Patients on long-term propofol infusions (>72
◾
hours) should be monitored for hypertrigly-ceridemia .
α2-agonists
dexmedetomidiNe (PreCedex)
Mechanism of action: Highly selective
◾ α2
-adrenergic agonist, decreases sympathetic activity Unique properties: Sedative, analgesic, not a
◾
respiratory depressant or amnestic agent, easy arousability
Recommended for short term sedation <24 hours
◾
Shown to provide adequate sedation without
◾
affecting respiratory drive and facilitates neuro-logic exams in patients with neurosurgical condi-tions without clinically significant changes in ICP or CPP
Decrease in ICP reported in experimental studies
◾
and may be due to α2-receptor-induced arteriolar vasoconstriction causing decreased CBV
Usual dosage: Load at 0.1 μg/kg IV for 10 minutes,
◾
then 0.2–0.7 μg/kg per hour; avoid bolus dose to minimize hypotension
Elimination half-life: 2 hours; duration of action:
◾
2–6 hours
Route of elimination: 95% renal
◾
Side effects: Hypotension and bradycardia,
◾
agitation
Multicenter studies revealed that
dexmedeto-◾
midine recipients required no additional sup-plements for sedation; however, due to lack of amnestic properties, benzodiazepines and nar-cotics may be required to improve amnesia and analgesia .
CloNidiNe (CataPres) Mechanism of action: Central
◾ α2-agonist
Uses: Sedative, analgesic, hypertension, blunt
◾
manifestations of substance abuse withdrawal, postoperative shivering
CNS: Decrease CBF; decrease CPP, no clear effect
◾
Side effects: Sedation, dry mouth, rebound HTN
◾
approximately 18 hours after clonidine is discon-tinued, decrease MAP
Usual dose: 0.1 mg q8–24h; up to 0.6 mg/day;
◾
duration of action: 12–48 hours
Studied as adjuvant to morphine PCA: bolus of
◾
clonidine at end of operation improved analge-sia for first 12 hours postoperatively and addition of clonidine to PCA (20 µg; 5 minutes LI) signifi-cantly reduced nausea and vomiting in females undergoing lower abdominal surgery
Neuroleptics
haloPeridol (butyroPheNoNe)
Mechanism of action: Central postsynaptic
dopa-◾
mine antagonist
Not recommended as first-line drug for sedation
◾
Sedative and antipsychotic; no analgesic or
◾
amnestic properties
Usual dose (for delirium): 1–5 mg increments IV,
◾
q hourly; infusions of approximately 300 mg/24 h shown to provide sedation without respiratory depression
Distribution half-life: 5–17 minutes
◾
Elimination half-life: 10–19 hours
◾
Metabolized by liver and excreted by kidneys
◾
Contraindication: Allergy to droperidol, Parkinson’s
◾
disease, pregnancy, seizure (decreases seizure threshold)
W.c. Ziai and r. Sajjad 56
Complications:
◾
Extrapyramidal symptoms (acute dystonic
▸
Symptoms and signs: Hyperthermia, muscle
▹
rigidity, autonomic instability, increased CPK, granulocytosis, hyperglycemia Pathophysiology: Dysautonomia due to
dop-▹
Mechanism of action: Central postsynaptic
dop-◾
amine antagonist
Like haloperidol, useful for decreasing anxiety
◾
associated with psychosis, but less effective for situational anxiety; antiemetic effect
Usual sedative dose: 0.625–2.5 mg IV q4–24 h; up
◾
to 5 mg in 24 hours
Duration of action: 2–12 hours
◾
Side effects: Extrapyramidal reactions,
hypo-◾
tension, dysphoria, akathisia, depressed carotid body drive to ventilate
other Sedatives
etomidate
Mechanism of action: Pharmacologically active
◾
component is dextroisomer, which produces sedation through stimulation of GABA receptor Nonanalgesic sedative and drug of choice for
◾
emergent intubation
Usual dose for induction of anesthesia: 0.3 mg/kg
◾
Elimination half-life: Approximately 30 minutes
◾
Metabolized by liver to inactive carboxylic acid
◾ ester
CNS: Decreases CBF, decreases CMR
◾ o2, decreases
ICP, increases CPP
CVS: No hypotension, unchanged CO and HR;
◾
therefore useful in patients with limited cardio-vascular reserve
Side effects: Nausea, vomiting, thrombophlebitis
◾
(due to propylene glycol formulation), general-ized seizures, myoclonus, adrenal suppression in repeated doses, increase IOP
Contraindications: Acute intermittent porphyria,
◾
seizures
Prolonged infusions for sedation in critically ill
◾
patients associated with increased mortality,
likely resulting from suppression of adrenal ste-roid synthesis
ketamiNe
Mechanism of action: Phencyclidine (angel dust)
◾
derivative; interacts with the following receptors:
N-methyl-d-aspartate (NMDA), opioid, mono-aminergic, and muscarinic and voltage-sensitive calcium channels and sodium channels
Short-acting IV anesthetic, hypnotic, profound
◾
amnestic, excellent analgesic
Stimulates the limbic system, such as the
hippo-◾
campus and suppresses thalamocortical region, leading to a dissociative state.
Most useful in ICU to facilitate brief, but painful
◾
Metabolized by hepatic microsomal enzymes to
◾
active metabolite norketamine, then hydrolyzed to inactive glucuronide metabolite
Beneficial effects of ketamine include patients
◾
ability to maintain spontaneous ventilation, bronchodilation and cardiovascular stimulation by activation of the sympathetic nervous system;
potentially useful for induction of anesthesia in patients with acute hypovolemia and asthma CNS: Increase CBF, increase CMRO2, increase
Contraindication: Increase ICP, seizure disorder,
◾
ischemic heart disease
Side effects: Epileptogenic, nightmares and
hal-◾
lucination (attenuated by cotreatment with ben-zodiazepines), delirium, excessive salivation and lacrimation (limited by use of anticholinergic – glycopyrrolate), increased ICP; rapid tolerance barbiturates
Mechanism of action: Interacts at specific
bar-◾
biturate receptor on neuronal GABA receptor complex; also acts on chloride channels at high concentrations
Generally not used for sedation in ICU patients
◾
Primary uses in the ICU: treatment of seizures
◾
and intractable intracranial hypertension Progressive increase in dose results in sedation,
◾
hypnosis, and then anesthesia
analgesia, Sedation, and Paralysis 57
◾ Thiopental (Pentothal):
Usual dose: Induction of anesthesia –
thiopen-▸
tal: 5 mg/kg IV; rapid short-term treatment for increased ICP: 25–50 mg IV, while awaiting effect of longer acting agents; significant hypotension may occur
Elimination half-life: 5–12 hours, but duration
▸
of action short (after single bolus injection) due to rapid diffusion from brain back to inactive peripheral sites
◾ Phenobarbitol (Luminal):
Usual dose (sedation): Phenobarbital: 1–3 mg/
▸
kg IV or IM; up to 200 mg in 24 hours
Duration of action: 10–24 hours (elimination
▸
may take up to 120 hours)
◾ Pentobarbital (Nembutal):
Usual dose (drug-induced coma):
Pentobar-▸
bital: 10 mg/kg IV loading dose, followed by infusion of 1–2 mg/kg per hour; thiopental (less often used for this indication): 5–11 mg/kg loading dose, followed by infusion of 4–6 mg/
kg per hour
Metabolism: Hepatic; enzyme inducer; affects
▸
metabolism of other drugs
CNS: Decreases CBF, decreases CMR
▸ o2,
dec-reases ICP, decdec-reases CPP
CVS: Decreases MAP, decreases SVR,
tachycar-▸
dia in hypovolemic patients with hypotension Side effects: Central respiratory depression,
▸
apnea, hyper salivation, bronchospasm, laryn-geal spasm, renal artery constriction and dec-reased urine output; potential lethal withdrawal syndrome; allergic reaction in 2%; depression of gastrointestinal motility; cardiac contractility and white blood cell function
Patients in barbiturate coma require
mechani-▸
cal ventilation, vasoactive agents, nasogastric decompression often with parenteral nutrition, and surveillance cultures due to high risk of
cal ventilation, vasoactive agents, nasogastric decompression often with parenteral nutrition, and surveillance cultures due to high risk of