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- 1. SEDO-ANALGESIA in ICU Prof. Dr. Sait Karakurt Marmara University Medical School Pulmonary and Critical Care Medicine
- 3. ANALGESIA • The primary goal of analgesia is optimizing patient comfort • The secondary goals are attenuation of the negative physiologic responses to pain including – hypermetabolism – increased oxygen consumption – hypercoagulability – alterations in immune function
- 4. TO ASSESS PAIN • Assessment of pain in conscious and interactive patients – VRS (Verbal Rating Scale) – VAS (Visual Analogue Scale) – NRS (Numeric Rating Scale) – Behavioral-Physiological Scale • Assessment of pain is more complicated in semiconscious or noncommunicative patients. Pain should be suspected in the presence of signs of discomfort (eg, grimacing, writhing) or sympathetic activation (eg, tachycardia, hypertension). The critically ill patient may not be able to adequately communicate their level of pain and, as such, pain control in the critical care setting is often inadequate. The degree of pain often is underestimated and the clinician should err on the side of assuming the patient is in pain.
- 5. Visual analog pain scale For conscious patients, a pain rating of 3 or less out of 10, or 2 or less out of 5, has been suggested as a desirable goal of analgesia. However, analgesic goals are patient-specific and depend upon the clinical situation, and patient tolerance of pain and side effects. Some patients may prefer to tolerate some pain to maintain a degree of alertness whereas others will not.
- 6. NONPHARMACOLOGIC THERAPY •To prevent sleep deprivation •To treat anxiety and delirium •Nonpharmacologic interventions include minimizing irritating stimuli (eg, traction on the endotracheal tube) and uncomfortable positioning. •Complementary therapies – relaxation techniques – music therapy (based upon the gate control theory of pain)
- 7. ANALGESIA • Analgesics reduce the sensation of pain by – altering perception of pain in the central nervous system (eg, opiate analgesics, acetaminophen) – inhibiting local pain mediator production (eg, blockade of prostaglandin synthesis by nonsteroidal antiinflammatory drugs) – interrupting neural impulse in the spinal cord (eg, neuraxial block) • In critically ill patients, alleviation of pain is predominantly accomplished via central mechanisms
- 8. Opioid analgesics Loading dose Maintenance dose Onset (min) Duration of intermittent dose (min) Morphine sulfate 2-10 mg 2 to 4 mg every 1 to 2 hours intermittent AND/OR 2 to 30 mg/hour infusion 5-10 240-300 Hydromorphone 0.5-2 mg 0.2 to 0.6 mg every 1 to 2 hours intermittent AND/OR 0.5 to 3 mg/hour infusion 5-10 240-300 Fentanyl 1 to 2 mcg/kg 0.35 to 0.5 mcg/kg every 0.5 to 1 hour intermittent AND/OR 0.7 to 10 mcg/kg/hour infusion <1-2 30-60 Remifentanil 1.5 mcg/kg 0.5 to 15 mcg/kg/hour infusion 1-3 5-10 Nonopioid analgesics (adjunctive or opiate sparing) Paracetamol none 325 to 1000 mg every 4 to 6 hours (oral, rectal) 650 mg IV every 4 hours to 1000 mg IV, every 6 hours (IV), or 15 mg/kg every 6 hours for patients weighing <50 kg, Maximum ≤4 g/day 30-60 (oral) Variable (rectal) 5-10 (IV) 240-360 Ibuprofen none 400 mg orally every 4 hours (maximum 2.4 g/day chronic) 400 to 800 mg IV every 6 hours (maximum 3.2 g/day acute) 25 (oral) 240-360 Ketorolac Optional: 30mg IV once Age <65 years and weight ≥50 kg: 15 to 30 mg IV every 6 hours; maximum 120 mg/day for up to 5 days Age ≥65 years or weight <50 kg: 15 mg IV every 6 hours; maximum 60 mg/day for up to 5 days 10 360-480 Gabapentin none Initially 100 mg orally three times per day Maintenance dose 900 to 3600 mg orally per day in 3doses variable -
- 9. ANALGESIA For parenteral analgesia, fentanyl, morphine, or hydromorphone are most commonly used. ●Fentanyl or hydromorphone are recommended instead of morphine for patients with renal insufficiency or hemodynamic instability (IIB). ●Fentanyl may be preferred to morphine in patients with acute bronchospasm. ●Morphine or hydromorphone are preferred to fentanyl for intermittent bolus therapy due to their longer duration of action. ●Remifentanil may be selected for patients with multiple organ dysfunction due to metabolism that is not dependent upon hepatic or renal function. It is generally used in mechanically-ventilated patients due to the high incidence of respiratory depression Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit, CCM 2013
- 10. Intravenous opiates ●Bolus intravenous injections -moderate pain, with doses titrated to analgesic requirements and avoidance of respiratory depression and hemodynamic instability. -bedside procedures that may cause pain with additional dosing given during the procedure, as needed. ●Continuous intravenous infusions -moderate-to-severe pain that is poorly controlled with repeated bolus injections ●Patient-controlled analgesia (PCA) may be preferable in conscious patients, particularly in the postoperative setting. This technique allows self-dosing with opiates up to a predetermined limit set by the clinician.
- 11. Fentanyl • A synthetic derivative of morphine and approximately 100 times more potent • More lipid-soluble than morphine improved penetration of the blood-brain barrier a more rapid onset of action and a shorter half-life (two to three hours) than morphine • Clinically significant histamine release rarely occurs with fentanyl dosages up to 50 mcg/kg and, thus, fentanyl may be preferred in the presence of hemodynamic instability or bronchospasm
- 12. Remifentanil • Analgesic potency approximately equal to fentanyl • An ultra-short acting opioid metabolized by nonspecific plasma esterases to inactive metabolites • The rapid onset and offset and lack of accumulation with renal and hepatic dysfunction are potential advantages • Despite the unique pharmacokinetic properties, in a meta-analysis of eleven trials, remifentanil was not associated with reduced mortality, duration of mechanical ventilation, length of intensive care unit stay, or agitation
- 13. ANALGESIA • Other parenteral agents that may become useful for controlling pain in intensive care unit patients include ketamine and paracetamol. • Intravenous NSAIDs can be used in some patients as a short-term adjunct to other analgesic agents. • However, NSAIDs are associated with an increased risk of cardiovascular thrombotic events and gastrointestinal complications including gastritis, bleeding, ulcers and perforation.
- 14. Indications of Sedation • Mechanical ventilation • Invasive procedures • Acute interventions • Decrease O2 requirement • Prevent self damage • Paralysis • Adjunction of analgesia • End of life period • Control and measure physiological parameters
- 15. Causes of anxiety/agitation • Cardiovascular (angina pectoris, myocardial infarction, hypertension…) • Pulmonary(asthma, COPD, respiratory failure…) • Endocrine/metabolic(adrenal insufficiency, hypocalcemia, hypercalcemia, hyperkalemia, hypoglysemia….) • Neurologic(serebral tumor/trauma, convulsion…) • Some organic diseases(anemia, carcinoid syndrome…) • Drugs(ACEI, analgesics, fluoroquinolone….)
- 16. Selection of an agent • No sedative-analgesic agent is sufficiently superior to other agents to warrant its use in all clinical situations. Selection of an agent must be individualized according to patient characteristics and the clinical situation. • The Society of Critical Care Medicine guidelines favor nonbenzodiazepine agents (propofol or dexmedetomidine) due to evidence of shorter duration of mechanical ventilation (+2B). • Important considerations when selecting a sedative-analgesic agent include – the etiology of the distress – expected duration of therapy – clinical status of the patient – potential interactions with other drugs
- 17. Selection of an agent- Etiology of the distress – Dyspnea or pain opioids – Delirium antipsychotics (haloperidol) – Anxiety benzodiazepines – More than one cause combination therapy As an example, a benzodiazepine plus an opioid is appropriate for a patient whose agitation is due to anxiety and pain. – For patients who are intubated and mechanically ventilated and not able to clearly communicate the source of agitation, analgesia should always be provided first
- 18. Benzodiazepins Loading dose Maintenance dose Onset (min) Duration of intermittent dose(min) Midazolam 0.01 to 0.05mg/kg (0.5-4 mg) 0.02-0.1mg/kg/hour 2 to 8mg/hour 2-5 30 Lorazepam 0.02 to 0.04mg/kg 1-2 mg 0.02 to 0.06 mg/kg every 2 to 6 hours intermittent AND/OR 0.01 to 0.1 mg/kg/hour infusion (0.5 to 10 mg/h) 15-20 360-480 Diazepam 0.05 to 0.2 mg/kg (5 to 10 mg) 0.03 to 0.1 mg/kg every 0.5 to 6 hours intermittent Continuous infusion is not recommended 2-5 20-60 Anesthetic-sedative Propofol 5 micrograms/kg/minute 5 to 50 micrograms/kg/minute Titrate every 5 to 10 minutes in increments of 5 to 10 micrograms/kg/minute <1-2 3-10 Ketamin 0.1 to 0.5 mg/kg 0.05 to 0.4 mg/kg/hour 0.5 10 Central alpha-2 agonist Dexmedetomidine Optional 1 microgram/kg over 10 minutes if hemodynamically stable Usually not give 0.2 to 0.7 micrograms/kg/hour Initiate at 0.2 micrograms/kg/hour and titrate every 30 minutes 5-10 15 (without loading d) 60-120 Antipsychotics Haloperidol 0.03 to 0.15 mg/kg 0.03 to 0.15 mg/kg every 30 minutes to 6 hours 30-60 30-360 Olanzapine 5 to 10 mg IM,may repeat every 2 to 4 hours if needed (maximum total 30 mg) Initially 5 to 10 mg orally once daily; increase every 24 hours as needed by 5 mg increments up to 20 mg per day 15-45 >120 Quetiapine None Initially 50 mg orally every 12 hours; increase every 24 hours as needed up to 400 mg per day 60 (initial) ≥24 hours (full effect) 6-12 Ziprasidone 10 mg IM may repeat every 2 hours if 10 to 40 mg orally every 12 hours 30 >90
- 19. DEXMEDETOMIDINE ADVANTAGES • Central alpha-2 agonist • Moderate anxiolytic and analgesic • A good choice for short and long-term sedation in critically ill patient without relevant cardiac condition • No significant effect on respiratory drive • Easily awakened patient DISADVANTAGES • Potentially significant hypotension and bradycardia that do not resolve quickly upon abrupt discontinuation • Dose reduction recommended with renal/hepatic insufficiency • Rapid administration of loading dose may be associated with cardiovascular instability, tachycardia, bradycardia, heart block
- 20. RAMSEY SEDATION SCALE Level/score Clinical description 1 Anxious, agitated, restless 2 Cooperative, oriented, tranquil 3 Responds only to verbal commands 4 Asleep, brisk response to light stimulation 5 Asleep, sluggish response to stimulation 6 Unarousable
- 21. Avoid excess sedation • Intermittent infusions • Daily interruption
- 22. Daily interruption p=0.02 p<0.001 John P. Kress et al.Daıly ınterruptıon of sedatıve ınfusıons ın crıtıcally ıll patıents undergoıng mechanıcal ventılatıon, N Engl J Med 2000;342:1471-7.
- 23. Daily sedative interruption vs standart sedation • A meta-analysis of nine trials – Reductions in the duration of mechanical ventilation (13 percent), – Reductions in ICU and hospital length of stay (10 and 6 percent, respectively) – No difference • in risk of death • Rate of accidental endotracheal tube removing • New onset delirium • Doses of sedative Burry L, Rose L, McCullagh IJ, et al. Daily sedation interruption versus no daily sedation İnterruption for critically ill adult patients requiring invasive mechanical ventilation. Cochrane Database Syst Rev 2014; 7:CD009176.
- 24. Early Intensive Care Sedation Predicts Long-Term Mortality in Ventilated Critically Ill Patients Time to extubation Survival Deep sedation within 4 hours of commencing ventilation as an independent negative predictor of the time to extubation, hospital death, and 180-day mortality. The early phase of ICU sedation is usually unaccounted for in randomized controlled trials due to late randomization. Yahya Shehab et al. Am J Respir Crit Care Med Vol, 2012, 186, Iss. 8, pp 724–731
- 25. WITHDRAWAL • The analgesics should be tapered last • Abrupt discontinuation is acceptable – a short duration (≤7 days). – greater than 7 days who are deeply sedated from prolonged accumulation of medication. • However, a gradual reduction (~10 to 25 percent per day) is necessary – if the sedative-analgesic agent has been administered for >7 days – the patient exhibits evidence of tachyphylaxis,
- 26. WITHDRAWAL Benzodiazepine withdrawal symptoms include – agitation, confusion, anxiety, tremors, tachycardia, hypertension, and fever. – Seizures may also occur. – The administration of intermittent IV or oral lorazepam (0.5-1 mg, every 6 to 12 hours) Opiate withdrawal symptoms include – agitation, anxiety, confusion, rhinorrhea, lacrimation, diaphoresis, mydriasis, piloerection, stomach cramps, diarrhea, tremor, nausea, vomiting, chills, tachycardia, hypertension, and fever. – To preventing opioid withdrawal, including • de-escalating the dose • converting to a longer acting oral equivalent • converting to a long-acting barbiturate (eg, phenobarbital), and adding an alpha-2-agonist (clonidin, dexmedetomidine, 0.7 mcg/kg/hr (with or without a loading dose)
- 27. Conclusions 1-Nonpharmacologic therapy should be firstly used 2-Scales should be used for objective assessment 3-For parenteral analgesia, fentanyl, morphine, or hydromorphone are most commonly used 4-Intravenous NSAIDs can be used in some patients as a short-term adjunct to other analgesic agents 5-The Society of Critical Care Medicine guidelines favor nonbenzodiazepine agents (propofol or dexmedetomidine) due to evidence of shorter duration of mechanical ventilation (+2B) 6-No sedative-analgesic agent is sufficiently superior to other agents 7-The analgesics should be tapered last
Editor's Notes
- The primary goal of analgesia is optimizing patient comfort; however, attenuation of the negative physiologic responses to pain including hypermetabolism, increased oxygen consumption, hypercoagulability, and alterations in immune function are secondary goals that may be particularly important in severely ill patients
- NONPHARMACOLOGIC THERAPY — Sleep deprivation and anxiety decrease pain threshold and increase patient stress. Lack of sleep may also alter tissue repair and impair cellular immunity [56]. Thus, it is essential to minimize stimuli which can disturb normal diurnal sleep patterns, such as noise, artificial lighting, unpleasant ambient temperature, frequent vital signs or invasive procedures. Other nonpharmacologic interventions include minimizing irritating stimuli (eg, traction on the endotracheal tube) and uncomfortable positioning [57]. Prompt treatment of anxiety and delirium is also important [6,58]. (See "Delirium and acute confusional states: Prevention, treatment, and prognosis".) Sedative-hypnotics should not be used routinely to manage pain in critically ill patients because of a lack of non-oral dosage forms, unpredictable oral absorption, potential drug accumulation and alteration of mental status. (See "Sedative-analgesic medications in critically ill adults: Selection, initiation, maintenance, and withdrawal".) Complementary therapies — Complementary interventions, such as relaxation techniques and music therapy are low cost, safe, and easy to provide, though data regarding efficacy in critically ill patients are limited [22]. These therapies are based upon the gate control theory of pain in which these interventions are believed to inhibit ascending transmission of noxious stimuli from the periphery or stimulate descending inhibitory control from the brain. Although theoretically desirable, therapies that involve physical manipulation are not appropriate for critically ill patients due to hemodynamic instability that could be brought on by the physical manipulation or potential negative impact on mechanical ventilation or other equipment. For less critically ill patients, relaxation therapy may improve sleep [59,60]. Music decreases analgesic requirements in some operative settings, and may also be a useful adjunct in critically ill patients [61,62]. A systematic review identified 51 randomized trials evaluating music intervention but few studies included critically ill patients [62]. The authors concluded that listening to music reduces pain intensity levels and opioid requirements but the overall magnitude of the difference in pain with and without music is small. Another trial evaluating the effect of music during routine turning of intensive care unit patients did not find a significant benefit
- Intravenous opiates can be delivered in three different ways: ●Bolus intravenous injections are often used for moderate pain, with doses titrated to analgesic requirements and avoidance of respiratory depression and hemodynamic instability. Bolus doses of opioids should always be given prior to bedside procedures that may cause pain with additional dosing given during the procedure, as needed. ●Continuous intravenous infusions of opiates are used for moderate-to-severe pain that is poorly controlled with repeated bolus injections. After an initial bolus dose, a low continuous infusion rate is set with subsequent adjustment for adequate analgesia. ●Patient-controlled analgesia (PCA) may be preferable in conscious patients, particularly in the postoperative setting [21]. This technique allows self-dosing with opiates up to a predetermined limit set by the clinician. An underlying basal rate can be initiated at the same time or added later using the patient-selected dosing to determine the need for and dose of basal infusion
- Fentanyl — Fentanyl is a synthetic derivative of morphine and is approximately 100 times more potent. It is also more lipid-soluble than morphine, and therefore has improved penetration of the blood-brain barrier which leads to a more rapid onset of action and a shorter half-life (two to three hours) than morphine. Compared with other opioids, fentanyl is virtually devoid of histamine-releasing properties. Clinically significant histamine release rarely occurs with fentanyl dosages up to 50 mcg/kg and, thus, fentanyl may be preferred in the presence of hemodynamic instability or bronchospasm.
- analgesic potency approximately equal to fentanyl. an ultra-short acting opioid metabolized by nonspecific plasma esterases to inactive metabolites. The rapid onset and offset and lack of accumulation with renal and hepatic dysfunction are potential advantages. Despite the unique pharmacokinetic properties, in a meta-analysis of eleven trials, remifentanil was not associated with reduced mortality, duration of mechanical ventilation, length of intensive care unit stay, or agitation [26]. Recommended doses are presented in the table
- ●Pain is an unpleasant sensation due to a variety of causes. The critically ill patient may not be able to adequately communicate their level of pain and, as such, pain control in the critical care setting is often inadequate. (See 'Introduction' above.) ●Assessment of pain in conscious and interactive patients is commonly accomplished with patient questionnaires, visual analog and numeric rating scales. Assessment of pain is more complicated in semiconscious or noncommunicative patients. Pain should be suspected in the presence of signs of discomfort (eg, grimacing, writhing) or sympathetic activation (eg, tachycardia, hypertension). The degree of pain often is underestimated and the clinician should err on the side of assuming the patient is in pain. (See 'Assessment and monitoring' above.) ●The mainstay of pain control in critically ill patients is the administration of intravenous opioids including morphine, hydromorphone and fentanyl. Fentanyl provides the most rapid onset of analgesia. For critically ill patients with renal insufficiency or hemodynamic instability, we suggest fentanyl or hydromorphone over morphine (Grade 2B). Fentanyl may also be preferred in the presence of bronchospasm. (See 'Opioids' above.) ●We prefer to use intravenous administration of analgesics over intramuscular or subcutaneous administration in critically ill patients because of unpredictable absorption due to variability in regional muscle or skin perfusion. For patients with ongoing pain, analgesia is more consistent if medications are administered continuously or scheduled as intermittent boluses compared with “on demand” dosing. (See 'Analgesic drugs' above.) ●Other parenteral agents that may become useful for controlling pain in intensive care unit patients include ketamine and paracetamol; however, additional studies are needed to determine their effectiveness and safety in this subset of patients. Intravenous NSAIDs can be used in some patients as a short-term adjunct to other analgesic agents; however, NSAIDs are associated with an increased risk of cardiovascular thrombotic events and gastrointestinal complications including gastritis, bleeding, ulcers and perforation. (See 'Non-opioid analgesics' above.) ●Although medication is central to pain management, environmental factors in the intensive care unit contribute to a lowered pain threshold by causing anxiety, sleep deprivation and stress. Control of these factors may lessen pain perception and lower pain medication requirements.
- We suggest that sedation strategies using nonbenzodiazepine sedatives (either propofol or dexmedetomidine) may be preferred over sedation with benzodiazepines (either midazolam or lorazepam) to improve clinical outcomes in mechanically ventilated adult ICU patients (+2B). Selection of an agent — No sedative-analgesic agent is sufficiently superior to other agents to warrant its use in all clinical situations. The Society of Critical Care Medicine guidelines favor nonbenzodiazepine agents due to evidence of shorter duration of mechanical ventilation, but the optimal agent for short-term or long-term therapy is not known [3]. Selection of an agent must be individualized according to patient characteristics and the clinical situation [15]. Important considerations when selecting a sedative-analgesic agent include the etiology of the distress, expected duration of therapy, clinical status of the patient, and potential interactions with other drugs: ● Etiology of the distress – The appropriate initial pharmacological agent for managing agitation due to distress depends upon the cause of the distress. For distress due to dyspnea or pain, opioids are the agents of choice. For distress due to delirium, antipsychotics (eg, haloperidol, quetiapine) are preferred. For distress due to anxiety, benzodiazepines should be considered. Combination therapy is appropriate for patients with more than one cause of distress. As an example, a benzodiazepine plus an opioid is appropriate for a patient whose agitation is due to anxiety and pain. For patients who are intubated and mechanically ventilated and not able to clearly communicate the source of agitation, analgesia should always be provided first
- For distress due to dyspnea or pain, opioids are the agents of choice. For distress due to delirium, antipsychotics (eg, haloperidol, quetiapine) are preferred. For distress due to anxiety, benzodiazepines should be considered. Combination therapy is appropriate for patients with more than one cause of distress. As an example, a benzodiazepine plus an opioid is appropriate for a patient whose agitation is due to anxiety and pain. For patients who are intubated and mechanically ventilated and not able to clearly communicate the source of agitation, analgesia should always be provided first
- Avoid excess sedation — Sedative-analgesic medications should not be overused because excess sedation may unnecessarily prolong the duration of mechanical ventilation [16,36,37]. Two strategies have been shown in randomized trials to reduce duration of mechanical ventilation and complications related to prolonged mechanical ventilation: intermittent infusions [16,38] and the daily interruption of continuous infusions [39-42]. Intermittent infusions — An observational study of 242 patients compared the duration of mechanical ventilation among patients who received a continuous sedative-analgesic infusion to those who received either intermittent sedative-analgesic infusions or no sedative-analgesics based on a nursing protocol [38]. The group that received intermittent infusions or no medication had a shorter duration of mechanical ventilation (median of 56 hours) than the group that received a continuous infusion (median of 185 hours). Daily interruption — Daily interruption of sedation refers to discontinuing the continuous sedative-analgesic infusion until the patient is awake and following instructions, or until the patient is uncomfortable or agitated, and deemed to require the resumption of sedation. The rationale for the daily interruption of continuous sedative-analgesic infusions is that it facilitates assessment of the patient's underlying neurologic status, as well as the patient's need for ongoing sedation. Randomized trials and meta-analyses report possible benefit from daily interruption with regard to reducing duration of mechanical ventilation and length of stay. However, there is considerable heterogeneity among trials which limits interpretation of the analysis. As examples: ● In a trial of 128 patients who were receiving mechanical ventilation and a continuous sedative-analgesic infusion, patients were randomly assigned to continue conventional management or to undergo daily spontaneous awakening trials [39]. The spontaneous awakening trials consisted of interruption of the continuous infusion until the patient was awake. The group whose continuous infusion was interrupted daily had a shorter duration of mechanical ventilation (4.9 versus 7.3 days) and length of ICU stay (6.4 versus 9.9 days), as well as fewer neurodiagnostic tests. Limitations of the trial include that it was performed in a single center, ventilator weaning was not standardized, and the spontaneous awakening trials were monitored closely by study personnel, which is not feasible in most ICUs. ● A similar trial randomly assigned 336 patients to a daily spontaneous breathing trial and either a daily spontaneous awakening trial or conventional sedation management [43]. The daily spontaneous awakening trial group had decreased one-year mortality (but not 28-day mortality), an increased number of ventilator-free days, a decreased length of ICU stay, and a decreased length of hospital stay. The group also had less cognitive impairment at three months (absolute risk reduction of 20 percent), although there was no difference at 12 months [44]. ● A meta-analysis of nine trials demonstrated only marginal reductions in the duration of mechanical ventilation (13 percent), ICU and hospital length of stay (10 and 6 percent, respectively) when compared with strategies that do not utilize daily sedative interruption [45]. There was no difference in risk of death, rate of accidental endotracheal tube removal, incidence of new onset delirium, or in the doses of sedative administered. The confidence intervals were wide which indicates imprecision and limits interpretation of the analysis. While these trials indicate that daily interruption of continuous sedative-analgesic infusions are beneficial, compliance to protocols can be challenging, and the benefit may be less or absent if a sedation protocol is also being concurrently used [46-48]. This was illustrated by a multicenter trial in which 430 mechanically-ventilated patients were randomly assigned to receive protocolized sedation (PS) alone or protocolized sedation plus daily interruption (PS+DI) of their continuous sedative-analgesic infusion [49]. The median time to successful extubation, the primary outcome, was seven days in both groups. The PS+DI group had higher mean doses of infusions of midazolam and fentanyl as well as a greater number of boluses of benzodiazepines and opiates, than the PS group. No differences were noted in the rates of unintentional removal of medical devices, ICU delirium, diagnostic neuroimaging, or tracheostomy. Of note, the average daily dose of midazolam was higher in both groups in this study than in the daily interruption trial described above [39]. The seemingly disparate results from the two clinical trials may be reconciled by the notion that protocolized weaning of sedation by the bedside nurse (as in the control group of the PS versus PS+DI study [49]) can effectively achieve the minimal effective sedative dose requirement for patients. This would explain the lack of any further benefit, when the minimal effective dose is interrupted. Concerns related to patient safety have been a significant obstacle to implementation of daily interruption of continuous sedative-analgesic infusions [50,51]. These concerns include the possibility of long-term psychological sequelae (eg, posttraumatic stress disorder [PTSD]) and myocardial ischemia. There is little evidence to support these concerns, as demonstrated by the following studies: ● An observational study performed using patients from the first randomized trial described above plus contemporaneous patients that were not enrolled in that trial found that patients who received daily interruption of their continuous sedative-analgesic infusion did not experience adverse psychological outcomes and were less likely to have symptoms of PTSD than those who received conventional management [52]. ● In the trial described above that randomly assigned 336 patients to a daily spontaneous breathing trial and either a daily spontaneous awakening trial or conventional sedation management [43], there was no difference in the frequency of PTSD at 3 or 12 months [44]. ● A prospective cohort study evaluated 74 patients with risk factors for coronary artery disease who were receiving mechanical ventilation [53]. Electrocardiographic monitoring was performed during the continuous sedative-analgesic infusion and during interruption of the continuous infusion. Myocardial ischemia (defined as ST segment elevation or depression >0.1 mV from baseline lasting 10 minutes or longer) was identified in 24 percent of the patients at some time during the study. Myocardial ischemia was not more common during interruption of the continuous infusion, although heart rate, blood pressure, respiratory rate, and catecholamines increased significantly. The study did not address the cumulative effects of multiple days of interrupting the continuous infusion. We believe there is sufficient evidence to justify efforts to minimize sedative-analgesic infusions, although the optimal method (eg, protocol-driven intermittent infusions, daily interruption, or a combination) is not known. Additional studies focusing on efficacy, feasibility, and safety are needed to determine the optimal approach.
- We followed patients daily from admission until ICU discharge, death, or 28 days in the ICU, whichever came first. During this time we assessed and recorded sedation level using the RASS scale every 4 hours (4). A RASS of -2to +1 was considered “light sedation” and a RASS of -3to-5 “deep sedation.” A RASS between +2to+4 was considered “agitation.” For the daily RASS assessments over the 28 days, patients may fall into more than one RASS category on the same day; however, no duplicate ranges were counted (i.e., a patient with three RASS assessments in deep sedation range had one RASS in deep sedation only counted for that day). Presence of pain was assessed by the bedside nurses with every RASS assessment. The visual analog scale was used in patients who were able to report pain, whereas in patients unable to report pain, Critical Care Pain Observation (19) descriptors were used to guide nursing assessment for the presence or absence of pain. CAM-ICU was assessed daily and only during light sedation (RASS, -2to+1) to avoid overdiagnosis. Patients were considered delirious if their CAM-ICU (5) assessment was positive (when the RASS was -2to+1).
- WITHDRAWAL — When pharmacological sedation is no longer necessary, the sequence and rate of discontinuing the sedative-analgesic agents must be determined: ● For patients receiving more than one sedative-analgesic medication (eg, a benzodiazepine and an opioid), the opioid should be tapered last so that the patient does not awake in pain. ● The rate of the reduction should be individualized. Generally speaking, abrupt discontinuation is acceptable if the sedative-analgesic agent has been administered for a short duration (≤7 days). In addition, abrupt discontinuation is also appropriate in patients who have received sedation for greater than seven days who are deeply sedated from prolonged accumulation of medication. However, a gradual reduction (~10 to 25 percent per day) is necessary if the sedative-analgesic agent has been administered for >7 days and the patient exhibits evidence of tachyphylaxis, with increasing dosage required over time to achieve the same level of sedation. It is important for clinicians to realize that there may be a delay (ie, days) between the moment that reduction of the sedative-analgesic agent begins and the patient begins to awaken, particularly following long-term therapy. This is because lipophilic drugs accumulate in tissue stores and must be mobilized for elimination. During the reduction of the sedative-analgesic medication, the patient should be closely observed for withdrawal symptoms. Acute withdrawal symptoms in this setting appear to be common. In an observational study of 28 mechanically ventilated patients who had been in the ICU for greater than one week, nine patients (32 percent) developed acute withdrawal symptoms when their sedative-analgesic medication was reduced [54]. Higher doses of benzodiazepines and opiates conferred a higher risk of withdrawal. Benzodiazepine withdrawal symptoms include agitation, confusion, anxiety, tremors, tachycardia, hypertension, and fever. Seizures may also occur. The administration of intermittent intravenous or oral lorazepam (0.5 to 1 mg every 6 to 12 hours) may help protect the patient from developing withdrawal symptoms as the continuous benzodiazepine infusion reduced. Opiate withdrawal symptoms include agitation, anxiety, confusion, rhinorrhea, lacrimation, diaphoresis, mydriasis, piloerection, stomach cramps, diarrhea, tremor, nausea, vomiting, chills, tachycardia, hypertension, and fever. Several strategies have been proposed for preventing opioid withdrawal, including de-escalating the dose, converting to a longer acting oral equivalent, converting to a long-acting barbiturate (eg, phenobarbital), and adding an alpha-2-agonist (clonidine, dexmedetomidine) [55,56]. However, there are no controlled trials of any strategy and there is no consensus as to the best strategy. Data are limited to case reports, including two reports in which dexmedetomidine was initiated at a dose of 0.7 mcg/kg/hr (with or without a loading dose) and successfully facilitated opioid withdrawal [57,58].
- During the reduction of the sedative-analgesic medication, the patient should be closely observed for withdrawal symptoms. Benzodiazepine withdrawal symptoms include agitation, confusion, anxiety, tremors, tachycardia, hypertension, and fever. Seizures may also occur. The administration of intermittent intravenous or oral Lorazepam (0.5 to 1 mg every 6 to 12 hours) may help protect the patient from developing withdrawal symptoms as the continuous benzodiazepine infusion reduced Opiate withdrawal symptoms include agitation, anxiety, confusion, rhinorrhea, lacrimation, diaphoresis, mydriasis, piloerection, stomach cramps, diarrhea, tremor, nausea, vomiting, chills, tachycardia, hypertension, and fever. Several strategies have been proposed for preventing opioid withdrawal, including de-escalating the dose, converting to a longer acting oral equivalent, converting to a long-acting barbiturate (eg, phenobarbital), and adding an alpha-2-agonist (clonidin, dexmedetomidine) Data are limited to case reports, including two reports in which dexmedetomidine was initiated at a dose of 0.7 mcg/kg/hr (with or without a loading dose) and successfully facilitated opioid withdrawal.