CLINICAL OBSTETRICS AND GYNECOLOGY Volume 57, Number 4, 844–850 r 2014, Lippincott Williams & Wilkins
Mechanical Ventilation During Pregnancy: Sedation, Analgesia, and Paralysis LUIS D. PACHECO, MD,* GEORGE R. SAADE, MD,w and GARY D.V. HANKINS, MDw *Departments of Obstetrics, Gynecology, and Anesthesiology, Divisions of Maternal Fetal Medicine and Surgical Critical Care; and w Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of Texas Medical Branch, Galveston, Texas Abstract: Pregnant women occasionally require mechanical ventilation. Ventilated patients commonly need some form of analgesia and/or sedation with or without paralytics. The use of these agents is common in the intensive care unit setting, but most maternal-fetal medicine specialists are unfamiliar with their use. In the vast majority of cases, guidelines and recommendations regarding the use of these agents should be followed as recommended for nonpregnant individuals. This article discusses the most relevant issues of sedatives, analgesics, and neuromuscular blockers used in modern critical care practice. Key words: sedation, analgesia, neuromuscular blockers, mechanical ventilation, pregnancy
Correspondence: Luis D. Pacheco, MD, Departments of Obstetrics, Gynecology, and Anesthesiology, Divisions of Maternal Fetal Medicine and Surgical Critical Care, University of Texas Medical Branch, Galveston, 301 University Blvd., Galveston, TX. E-mail: ldpachec@ utmb.edu The authors declare that they have nothing to disclose. CLINICAL OBSTETRICS AND GYNECOLOGY
844 | www.clinicalobgyn.com
/
Introduction Mechanical ventilation is occasionally required during pregnancy. Many patients will need some form of sedation/analgesia while on the ventilator as patients are exposed to stressful and painful stimuli, such as airway suctioning, central venous catheters placement, chest tubes, urinary catheters, and prolonged bed rest. Even in the absence of a recent surgical procedure, most critically ill patients report pain.1 Providing adequate sedation/analgesia to patients commonly facilitates nursing care, decreases the incidence of patientventilator dyssynchrony, and decreases oxygen consumption in critically ill individuals. Unfortunately, excessive use of such agents has been associated with a number of undesirable outcomes, such as prolonged mechanical ventilation, longer VOLUME 57
/
NUMBER 4
/
DECEMBER 2014
Mechanical Ventilation During Pregnancy intensive care unit (ICU) stays, increased incidence of delirium, increased risk of ventilator-acquired pneumonia, increased risk of thromboembolic complications, and increased mortality.2 Recent guidelines recommend maintaining light levels of sedation in the ICU with the use of established tools, such as the Richmond Agitation and Sedation Scale.3 Ideally, patients should be resting comfortably but should also be easily aroused and able to follow simple commands. Achieving these goals—as opposed to pharmacologically inducing comas— results in fewer days on mechanical ventilation and fewer days in the ICU.4 Daily sedation, pain, and delirium assessments are mandatory while in the ICU, and the presence of pain, delirium, or agitation should be addressed immediately. Another strategy associated with improved outcomes is the practice of daily sedative interruption coupled with a spontaneous breathing trial. This strategy involves interrupting a patient’s sedatives every morning allowing and the patient to wake up. Once the patient is sufficiently awake, a spontaneous breathing trial is performed to evaluate the possibility of extubation. This practice has also been associated with improved outcomes, including fewer days spent on mechanical ventilation, and shorter ICU stays.5 A recent trial evaluated the potential additive benefit of combining a strategy of maintaining light levels of sedation with daily sedative interruption.6 The trial found no benefit from daily sedative interruption when a light sedation goal protocol was already in place. Details about the duration of sedation interruption and patient management in the cited trial are not clear. The issue of prescribing preferred analgesic agents or sedative agents to mechanically ventilated critically ill patients has also been addressed in recent guidelines.3 It is recommended to start with analgesic agents and add sedatives only
845
if required as in many cases the cause of the agitation is poorly managed pain (analgesia-first sedation). The initial use of analgesic agents as opposed to the indiscriminate use of sedatives has resulted in fewer days spent in the ICU and in the ventilator.7 The message from recent literature is clear: less profound sedation results in improved clinical outcomes and should be the current standard of care. There are rare situations in which profound sedation is desirable, such as patients with severely elevated intracranial pressure, patients with severe acute respiratory distress syndrome (ARDS) in whom adequate oxygenation is difficult to achieve, and patients who are receiving paralytics. Patients receiving chemical paralysis for conditions, such as severe ARDS, status asthmaticus, or open abdomens, should receive adequate doses of both sedatives and analgesics to inhibit pain and awareness of being paralyzed.2 There is no reason to believe that these recommendations do not also apply to the critically ill pregnant patient and, as such, should be followed when indicated. A clinical description of the most commonly used sedatives, analgesic agents, and paralytics along with the recommendations for their use follows next.
Analgesic Agents MORPHINE
Narcotics are commonly used to achieve analgesia, sedation, and anxiolysis.8 Morphine sulfate is a m-opiod agonist widely utilized in ICUs worldwide. Side effects include increased histamine release and venodilation with concomitant systemic hypotension. The latter is uncommon among normovolemic individuals but may be important in hemodynamically unstable patients. In an unstable patient, other narcotics such as fentanyl or hydromorphone may be more suitable. Morphine is metabolized in the liver by www.clinicalobgyn.com
846
Pacheco et al
glucuronidation and converted into morphine-6-glucuronide (active metabolite) and morphine-3-glucuronide (inactive metabolite), both of which are cleared renally. Consequently, morphine should be avoided in women with acute kidney injury or chronic kidney disease as the active metabolite morphine-6-glucuronide will accumulate, resulting in prolonged residual sedation.9 Again, agents such as fentanyl and hydromorphone are preferred when morphine is not a good option. Similar to other narcotics, side effects include nausea, vomiting, constipation, urinary retention, ileus, pruritus, and respiratory depression. Intravenous infusions of 1 to 10 mg/h are commonly used in an intubated patient. Morphine is not considered teratogenic and, if necessary, should be used as indicated in the ICU. If used close to the delivery time, neonatology personnel should be alerted as mechanical ventilation may be required transiently and infants may develop withdrawal symptoms.
transiently and infants may develop withdrawal symptoms.
FENTANYL
REMIFENTANIL
Fentanyl is another m-opiod agonist that is 100 times more potent than morphine. Fentanyl is metabolized by hepatic oxidation and has no active metabolites.2 As discussed previously, it is preferred over morphine in cases of renal disease or hypotension as it is not associated with massive histamine release and has no active metabolites that require the kidneys for elimination. The half-life of fentanyl is 3 hours, and it is highly lipid soluble, resulting in rapid onset of action (1 to 2 min compared with 5 to 10 min with morphine). In the ICU setting, infusions between 25 and 100 mg/h are commonly used. The use of high-dose boluses may result in chest rigidity. Fentanyl is not teratogenic and may be used in the critically ill pregnant patient if indicated. If used close to the delivery time, neonatology personnel should be alerted as mechanical ventilation may be required
Remifentanil is a m-opiod agonist with an ultra short half-life of 3 minutes.10 Metabolism occurs through plasma esterases independent of liver or kidney function, which results in lack of accumulation after prolonged infusions. As the half-life of this agent is only 3 minutes, it is usually administered as a bolus of 0.5 mg/kg followed by an infusion at 0.5 to 2 mg/kg/ min.2 There is no evidence that remifentanil is teratogenic.
www.clinicalobgyn.com
HYDROMORPHONE (DILAUDID)
Hydromorphone, a m-opiod agonist, is commonly used in the ICU setting. Its half-life is 3 hours (similar to morphine and fentanyl), and it is metabolized in the liver through glucuronidation and converted into inactive metabolites.2 Hydromorphone is ideal to use on patients with renal disease as it lacks active metabolites that could accumulate in serum. Unlike morphine, hydromorphone induces minimal histamine release. Intravenous infusions of 0.5 to 2 mg/h are commonly used.3 Hydromorphone may be used in patients who develop tachyphylaxis to morphine or fentanyl. Hydromorphone is not teratogenic and may be used during pregnancy if indicated. If used close to the delivery time, neonatology personnel should be alerted as mechanical ventilation may be required transiently and infants may develop withdrawal symptoms.
Sedative Agents Historically, sedation in mechanically ventilated individuals has been accomplished with the use of benzodiazepines, such as diazepam, midazolam, and lorazepam. Recent evidence suggests that the use of nonbenzodiazepine-based regimens (mainly using propofol or dexmedetomidine) is associated with fewer
Mechanical Ventilation During Pregnancy days spent on mechanical ventilation, fewer days in the ICU, and less incidence of delirium.11 Current guidelines recommend the use of propofol or dexmedetomidine as first-line sedatives in the ICU.3 It is important to note that agitation may be a sign of sepsis, hypoxia, hypoglycemia, hypotension, alcohol or drug withdrawal, or pain, and each of these triggers should be addressed and managed accordingly before simply sedating the patient. MIDAZOLAM
Benzodiazepines (all g-aminobutyric acid agonists) are anxiolytics, amnestics, sedatives, and hypnotics. They do not provide analgesia. Similar to opiates, benzodiazepines are associated with minimal hemodynamic consequences in euvolemic patients. Respiratory depression is an important concern and is potentiated with the concomitant use of narcotics. Midazolam is highly lipid soluble and, consequently, has a rapid onset of action (2 to 5 min). The half-life is 3 to 11 hours. Midazolam is metabolized in the liver by oxidation through the cytochrome P450 yielding the active metabolite 1-hydroxymethyl midazolam that is eliminated in the kidneys, which explains why prolonged infusions of midazolam are to be avoided in patients with compromised renal function. Midazolam may be administered as intermittent intravenous boluses of 1 to 5 mg every 1 to 2 hours as needed for agitation or as a continuous infusion at doses of 1 to 10 mg/h. The use of intermittent boluses is preferred to continuous infusions. Prolonged infusions of midazolam (>48 h) should be avoided as they result in more residual sedation than with lorazepam as midazolam will significantly accumulate in adipose tissue secondary to its increased lipid solubility with a resultant increase in the volume of distribution.12 Benzodiazepines have been associated with neonatal respiratory depression and floppy baby
847
syndrome when used close to delivery. Neonatology personnel should be aware of their use before delivery. The association between exposure to benzodiazepines early in pregnancy and congenital anomalies is controversial, and the available literature is contradictory. A recent review suggested a relationship between lorazepam exposure and anal atresia but no association with oral clefting.13 The latter is a preliminary association that requires further data. If a critically ill pregnant patient requires a benzodiazepine infusion for optimal critical care delivery, it should not be withheld. LORAZEPAM
Compared with midazolam, lorazepam has a slower onset of action (5 to 20 min), secondary to decreased lipid solubility.2 The half-life of lorazepam is 8 to 15 hours, and it is metabolized in the liver by glucuronidation, resulting in no active metabolites. For this reason, lorazepam is a better than midazolam in patients with kidney disease. As discussed previously, prolonged infusions of lorazepam are associated with less residual sedation than midazolam as lorazepam has less lipid affinity and, consequently, will not accumulate extensively in extravascular tissues. Lorazepam may be given as intermittent intravenous boluses of 1 to 4 mg or as a continuous infusion of 1 to 10 mg/h. Higher-dose infusions should be avoided because of the possibility of propylene glycol-induced metabolic acidosis. The latter may be diagnosed by documenting a serum osmolar gap >10 to 12 mOsm/L.14 Benzodiazepines have been associated with neonatal respiratory depression and floppy baby syndrome when used close to delivery. Neonatology personnel should be aware of their use before delivery. The association between exposure to benzodiazepines early in pregnancy and congenital anomalies is controversial, and the available literature is contradictory. A recent review www.clinicalobgyn.com
848
Pacheco et al
suggests a relationship between lorazepam exposure and anal atresia but no association with oral clefting.13 The latter is a preliminary association that requires further data. If a critically ill pregnant patient requires a benzodiazepine infusion for optimal critical care delivery, it should not be withheld. PROPOFOL
Propofol is an effective sedative/anxiolytic, amnestic, and anticonvulsant that acts on several binding sites, including the GABA, glycine, muscarinic, and nicotinic receptors. It has no analgesic properties. It is suspended in a 10% lipid emulsion that provides a caloric load of 1 kcal/mL. This agent has high lipid solubility, allowing a rapid onset of action and rapid redistribution from peripheral tissues (within minutes) leading to a short duration of action.15 Propofol has high-hepatic and extrahepatic clearance, and dose adjustments are not required in patients with renal disease or moderate liver failure. Infusions of 5 to 50 mg/kg/min are used in mechanically ventilated patients. During an infusion, the half-life is 30 minutes.2 Propofol should be avoided in patients with hemodynamic instability as it induces peripheral vasodilation and decreases cardiac contractility. High doses of propofol (70 to 80 mg/kg/min) should not be administered for prolonged periods of since it may cause a serious condition known as propofol infusion syndrome, which is associated with mitochondrial dysfunction, bradiarrhythmias, decreased cardiac output, metabolic acidosis, fatty liver, pancreatitis, hyperkalemia, acute kidney injury, and rhabdomyolysis.16,17 The mortality rate of propofol infusion syndrome may be as high as 33%. There is no evidence that propofol causes congenital anomalies.18 DEXMEDETOMIDINE
Dexmedetomidine is a selective a-2 agonist that provides both sedation and www.clinicalobgyn.com
analgesia together with a sympatholytic effect without inducing respiratory depression. The half-life is 2 to 3 hours, and it is metabolized in the liver. Patients sedated with this medication in the ICU setting are commonly easily awakened with minimal stimulation, allowing frequent neurological evaluations if required. As dexmedetomidine decreases central nervous system output of catecholamines, it should not be used in patients with bradycardia or hemodynamic instability. A trial comparing dexmedetomidine and midazolam found the former to be associated with fewer days on the ventilator, less incidence of delirium, and fewer nosocomial infections.19 In the ICU, dexmedetomidine is commonly used as a continuous infusion of 0.2 to 1.5 mg/ kg/h and may be safely administered for a period of 1 week.19 The use of an initial bolus in the ICU may be associated with hemodynamic instability in critically ill patients. As no respiratory depression is associated with the use of this agent, dexmedetomidine is a great option for sedation during the extubation period in extremely agitated and uncooperative patients. There is no evidence that dexmedetomidine is teratogenic despite the fact that placental transfer is likely to occur.
Paralytic Agents The use of pharmacological paralysis is indicated in certain scenarios in the ICU, such as ARDS with a P/F ratio (partial pressure of oxygen/inspired fraction of oxygen)
Mechanical Ventilation During Pregnancy: Sedation, Analgesia, and Paralysis LUIS D. PACHECO, MD,* GEORGE R. SAADE, MD,w and GARY D.V. HANKINS, MDw *Departments of Obstetrics, Gynecology, and Anesthesiology, Divisions of Maternal Fetal Medicine and Surgical Critical Care; and w Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of Texas Medical Branch, Galveston, Texas Abstract: Pregnant women occasionally require mechanical ventilation. Ventilated patients commonly need some form of analgesia and/or sedation with or without paralytics. The use of these agents is common in the intensive care unit setting, but most maternal-fetal medicine specialists are unfamiliar with their use. In the vast majority of cases, guidelines and recommendations regarding the use of these agents should be followed as recommended for nonpregnant individuals. This article discusses the most relevant issues of sedatives, analgesics, and neuromuscular blockers used in modern critical care practice. Key words: sedation, analgesia, neuromuscular blockers, mechanical ventilation, pregnancy
Correspondence: Luis D. Pacheco, MD, Departments of Obstetrics, Gynecology, and Anesthesiology, Divisions of Maternal Fetal Medicine and Surgical Critical Care, University of Texas Medical Branch, Galveston, 301 University Blvd., Galveston, TX. E-mail: ldpachec@ utmb.edu The authors declare that they have nothing to disclose. CLINICAL OBSTETRICS AND GYNECOLOGY
844 | www.clinicalobgyn.com
/
Introduction Mechanical ventilation is occasionally required during pregnancy. Many patients will need some form of sedation/analgesia while on the ventilator as patients are exposed to stressful and painful stimuli, such as airway suctioning, central venous catheters placement, chest tubes, urinary catheters, and prolonged bed rest. Even in the absence of a recent surgical procedure, most critically ill patients report pain.1 Providing adequate sedation/analgesia to patients commonly facilitates nursing care, decreases the incidence of patientventilator dyssynchrony, and decreases oxygen consumption in critically ill individuals. Unfortunately, excessive use of such agents has been associated with a number of undesirable outcomes, such as prolonged mechanical ventilation, longer VOLUME 57
/
NUMBER 4
/
DECEMBER 2014
Mechanical Ventilation During Pregnancy intensive care unit (ICU) stays, increased incidence of delirium, increased risk of ventilator-acquired pneumonia, increased risk of thromboembolic complications, and increased mortality.2 Recent guidelines recommend maintaining light levels of sedation in the ICU with the use of established tools, such as the Richmond Agitation and Sedation Scale.3 Ideally, patients should be resting comfortably but should also be easily aroused and able to follow simple commands. Achieving these goals—as opposed to pharmacologically inducing comas— results in fewer days on mechanical ventilation and fewer days in the ICU.4 Daily sedation, pain, and delirium assessments are mandatory while in the ICU, and the presence of pain, delirium, or agitation should be addressed immediately. Another strategy associated with improved outcomes is the practice of daily sedative interruption coupled with a spontaneous breathing trial. This strategy involves interrupting a patient’s sedatives every morning allowing and the patient to wake up. Once the patient is sufficiently awake, a spontaneous breathing trial is performed to evaluate the possibility of extubation. This practice has also been associated with improved outcomes, including fewer days spent on mechanical ventilation, and shorter ICU stays.5 A recent trial evaluated the potential additive benefit of combining a strategy of maintaining light levels of sedation with daily sedative interruption.6 The trial found no benefit from daily sedative interruption when a light sedation goal protocol was already in place. Details about the duration of sedation interruption and patient management in the cited trial are not clear. The issue of prescribing preferred analgesic agents or sedative agents to mechanically ventilated critically ill patients has also been addressed in recent guidelines.3 It is recommended to start with analgesic agents and add sedatives only
845
if required as in many cases the cause of the agitation is poorly managed pain (analgesia-first sedation). The initial use of analgesic agents as opposed to the indiscriminate use of sedatives has resulted in fewer days spent in the ICU and in the ventilator.7 The message from recent literature is clear: less profound sedation results in improved clinical outcomes and should be the current standard of care. There are rare situations in which profound sedation is desirable, such as patients with severely elevated intracranial pressure, patients with severe acute respiratory distress syndrome (ARDS) in whom adequate oxygenation is difficult to achieve, and patients who are receiving paralytics. Patients receiving chemical paralysis for conditions, such as severe ARDS, status asthmaticus, or open abdomens, should receive adequate doses of both sedatives and analgesics to inhibit pain and awareness of being paralyzed.2 There is no reason to believe that these recommendations do not also apply to the critically ill pregnant patient and, as such, should be followed when indicated. A clinical description of the most commonly used sedatives, analgesic agents, and paralytics along with the recommendations for their use follows next.
Analgesic Agents MORPHINE
Narcotics are commonly used to achieve analgesia, sedation, and anxiolysis.8 Morphine sulfate is a m-opiod agonist widely utilized in ICUs worldwide. Side effects include increased histamine release and venodilation with concomitant systemic hypotension. The latter is uncommon among normovolemic individuals but may be important in hemodynamically unstable patients. In an unstable patient, other narcotics such as fentanyl or hydromorphone may be more suitable. Morphine is metabolized in the liver by www.clinicalobgyn.com
846
Pacheco et al
glucuronidation and converted into morphine-6-glucuronide (active metabolite) and morphine-3-glucuronide (inactive metabolite), both of which are cleared renally. Consequently, morphine should be avoided in women with acute kidney injury or chronic kidney disease as the active metabolite morphine-6-glucuronide will accumulate, resulting in prolonged residual sedation.9 Again, agents such as fentanyl and hydromorphone are preferred when morphine is not a good option. Similar to other narcotics, side effects include nausea, vomiting, constipation, urinary retention, ileus, pruritus, and respiratory depression. Intravenous infusions of 1 to 10 mg/h are commonly used in an intubated patient. Morphine is not considered teratogenic and, if necessary, should be used as indicated in the ICU. If used close to the delivery time, neonatology personnel should be alerted as mechanical ventilation may be required transiently and infants may develop withdrawal symptoms.
transiently and infants may develop withdrawal symptoms.
FENTANYL
REMIFENTANIL
Fentanyl is another m-opiod agonist that is 100 times more potent than morphine. Fentanyl is metabolized by hepatic oxidation and has no active metabolites.2 As discussed previously, it is preferred over morphine in cases of renal disease or hypotension as it is not associated with massive histamine release and has no active metabolites that require the kidneys for elimination. The half-life of fentanyl is 3 hours, and it is highly lipid soluble, resulting in rapid onset of action (1 to 2 min compared with 5 to 10 min with morphine). In the ICU setting, infusions between 25 and 100 mg/h are commonly used. The use of high-dose boluses may result in chest rigidity. Fentanyl is not teratogenic and may be used in the critically ill pregnant patient if indicated. If used close to the delivery time, neonatology personnel should be alerted as mechanical ventilation may be required
Remifentanil is a m-opiod agonist with an ultra short half-life of 3 minutes.10 Metabolism occurs through plasma esterases independent of liver or kidney function, which results in lack of accumulation after prolonged infusions. As the half-life of this agent is only 3 minutes, it is usually administered as a bolus of 0.5 mg/kg followed by an infusion at 0.5 to 2 mg/kg/ min.2 There is no evidence that remifentanil is teratogenic.
www.clinicalobgyn.com
HYDROMORPHONE (DILAUDID)
Hydromorphone, a m-opiod agonist, is commonly used in the ICU setting. Its half-life is 3 hours (similar to morphine and fentanyl), and it is metabolized in the liver through glucuronidation and converted into inactive metabolites.2 Hydromorphone is ideal to use on patients with renal disease as it lacks active metabolites that could accumulate in serum. Unlike morphine, hydromorphone induces minimal histamine release. Intravenous infusions of 0.5 to 2 mg/h are commonly used.3 Hydromorphone may be used in patients who develop tachyphylaxis to morphine or fentanyl. Hydromorphone is not teratogenic and may be used during pregnancy if indicated. If used close to the delivery time, neonatology personnel should be alerted as mechanical ventilation may be required transiently and infants may develop withdrawal symptoms.
Sedative Agents Historically, sedation in mechanically ventilated individuals has been accomplished with the use of benzodiazepines, such as diazepam, midazolam, and lorazepam. Recent evidence suggests that the use of nonbenzodiazepine-based regimens (mainly using propofol or dexmedetomidine) is associated with fewer
Mechanical Ventilation During Pregnancy days spent on mechanical ventilation, fewer days in the ICU, and less incidence of delirium.11 Current guidelines recommend the use of propofol or dexmedetomidine as first-line sedatives in the ICU.3 It is important to note that agitation may be a sign of sepsis, hypoxia, hypoglycemia, hypotension, alcohol or drug withdrawal, or pain, and each of these triggers should be addressed and managed accordingly before simply sedating the patient. MIDAZOLAM
Benzodiazepines (all g-aminobutyric acid agonists) are anxiolytics, amnestics, sedatives, and hypnotics. They do not provide analgesia. Similar to opiates, benzodiazepines are associated with minimal hemodynamic consequences in euvolemic patients. Respiratory depression is an important concern and is potentiated with the concomitant use of narcotics. Midazolam is highly lipid soluble and, consequently, has a rapid onset of action (2 to 5 min). The half-life is 3 to 11 hours. Midazolam is metabolized in the liver by oxidation through the cytochrome P450 yielding the active metabolite 1-hydroxymethyl midazolam that is eliminated in the kidneys, which explains why prolonged infusions of midazolam are to be avoided in patients with compromised renal function. Midazolam may be administered as intermittent intravenous boluses of 1 to 5 mg every 1 to 2 hours as needed for agitation or as a continuous infusion at doses of 1 to 10 mg/h. The use of intermittent boluses is preferred to continuous infusions. Prolonged infusions of midazolam (>48 h) should be avoided as they result in more residual sedation than with lorazepam as midazolam will significantly accumulate in adipose tissue secondary to its increased lipid solubility with a resultant increase in the volume of distribution.12 Benzodiazepines have been associated with neonatal respiratory depression and floppy baby
847
syndrome when used close to delivery. Neonatology personnel should be aware of their use before delivery. The association between exposure to benzodiazepines early in pregnancy and congenital anomalies is controversial, and the available literature is contradictory. A recent review suggested a relationship between lorazepam exposure and anal atresia but no association with oral clefting.13 The latter is a preliminary association that requires further data. If a critically ill pregnant patient requires a benzodiazepine infusion for optimal critical care delivery, it should not be withheld. LORAZEPAM
Compared with midazolam, lorazepam has a slower onset of action (5 to 20 min), secondary to decreased lipid solubility.2 The half-life of lorazepam is 8 to 15 hours, and it is metabolized in the liver by glucuronidation, resulting in no active metabolites. For this reason, lorazepam is a better than midazolam in patients with kidney disease. As discussed previously, prolonged infusions of lorazepam are associated with less residual sedation than midazolam as lorazepam has less lipid affinity and, consequently, will not accumulate extensively in extravascular tissues. Lorazepam may be given as intermittent intravenous boluses of 1 to 4 mg or as a continuous infusion of 1 to 10 mg/h. Higher-dose infusions should be avoided because of the possibility of propylene glycol-induced metabolic acidosis. The latter may be diagnosed by documenting a serum osmolar gap >10 to 12 mOsm/L.14 Benzodiazepines have been associated with neonatal respiratory depression and floppy baby syndrome when used close to delivery. Neonatology personnel should be aware of their use before delivery. The association between exposure to benzodiazepines early in pregnancy and congenital anomalies is controversial, and the available literature is contradictory. A recent review www.clinicalobgyn.com
848
Pacheco et al
suggests a relationship between lorazepam exposure and anal atresia but no association with oral clefting.13 The latter is a preliminary association that requires further data. If a critically ill pregnant patient requires a benzodiazepine infusion for optimal critical care delivery, it should not be withheld. PROPOFOL
Propofol is an effective sedative/anxiolytic, amnestic, and anticonvulsant that acts on several binding sites, including the GABA, glycine, muscarinic, and nicotinic receptors. It has no analgesic properties. It is suspended in a 10% lipid emulsion that provides a caloric load of 1 kcal/mL. This agent has high lipid solubility, allowing a rapid onset of action and rapid redistribution from peripheral tissues (within minutes) leading to a short duration of action.15 Propofol has high-hepatic and extrahepatic clearance, and dose adjustments are not required in patients with renal disease or moderate liver failure. Infusions of 5 to 50 mg/kg/min are used in mechanically ventilated patients. During an infusion, the half-life is 30 minutes.2 Propofol should be avoided in patients with hemodynamic instability as it induces peripheral vasodilation and decreases cardiac contractility. High doses of propofol (70 to 80 mg/kg/min) should not be administered for prolonged periods of since it may cause a serious condition known as propofol infusion syndrome, which is associated with mitochondrial dysfunction, bradiarrhythmias, decreased cardiac output, metabolic acidosis, fatty liver, pancreatitis, hyperkalemia, acute kidney injury, and rhabdomyolysis.16,17 The mortality rate of propofol infusion syndrome may be as high as 33%. There is no evidence that propofol causes congenital anomalies.18 DEXMEDETOMIDINE
Dexmedetomidine is a selective a-2 agonist that provides both sedation and www.clinicalobgyn.com
analgesia together with a sympatholytic effect without inducing respiratory depression. The half-life is 2 to 3 hours, and it is metabolized in the liver. Patients sedated with this medication in the ICU setting are commonly easily awakened with minimal stimulation, allowing frequent neurological evaluations if required. As dexmedetomidine decreases central nervous system output of catecholamines, it should not be used in patients with bradycardia or hemodynamic instability. A trial comparing dexmedetomidine and midazolam found the former to be associated with fewer days on the ventilator, less incidence of delirium, and fewer nosocomial infections.19 In the ICU, dexmedetomidine is commonly used as a continuous infusion of 0.2 to 1.5 mg/ kg/h and may be safely administered for a period of 1 week.19 The use of an initial bolus in the ICU may be associated with hemodynamic instability in critically ill patients. As no respiratory depression is associated with the use of this agent, dexmedetomidine is a great option for sedation during the extubation period in extremely agitated and uncooperative patients. There is no evidence that dexmedetomidine is teratogenic despite the fact that placental transfer is likely to occur.
Paralytic Agents The use of pharmacological paralysis is indicated in certain scenarios in the ICU, such as ARDS with a P/F ratio (partial pressure of oxygen/inspired fraction of oxygen)
