Anesthesia in the critical care unit and pain management

Critically ill patients in the intensive care unit (ICU) present with increased levels of anxiety, agitation, and pain. This often requires intense support and invasive monitoring. To ensure the comfort and safety of these patients, the use of sedative, analgesic, and paralytic therapies may be essential. In the ICU, however, options may be limited by several patient-specific contraindications such as the management of comorbidities, electrolyte abnormalities, and hemodynamic or cardiopulmonary instability.

In the past, pharmacologic therapies in the ICU were frequently used to keep patients motionless and reduce their recall of a traumatic stay. Revelations in research have ushered in a new paradigm that acknowledges the significant morbidity and mortality that heavy sedation and prolonged neuromuscular blockade can cause. This new model places emphasis on maximizing the comfort of patients while keeping them alert, awake, oriented, interactive, and able to follow instructions whenever possible. This model incorporates strategies such as daily interruptions of sedation, minimizing the use of paralytic agents and the use of sedation scales as a tool for clinical evaluation.

Significant progress has been made in improving the intensivist’s arsenal through refining treatment guidelines as well as through pharmacologic and nonpharmacologic innovation. This chapter seeks to summarize the knowledge, best practices, and future directions of anesthesia in the critical care unit. It will begin with a discussion around general principles surrounding the use of sedatives, analgesics, and paralytics in the ICU and will conclude with a detailed discussion of specific therapies, their dosages, and their indications for use.

Sedatives in the ICU

In at least 90 trials comparing sedative regimens, no sedative drug has proven to be clearly superior to all others. Sedatives that are commonly used in the ICU include benzodiazepines, opioids, anesthetics, α2 agonists, and antipsychotics. Variation in prescribing patterns among countries suggests that the sedative of choice is determined more by tradition and familiarity than by evidence-based practice. Reade et al. suggest that if minimizing the depth and duration of sedation is accepted as a desirable goal, then the use of a short-acting agent with an effect that can be rapidly adjusted should offer advantages over longer-acting agents or agents with active metabolites.

Sedatives and analgesics can be administered either by intermittent bolus dosing or by continuous infusion. Administration of the former may result in periods of both oversedation and undersedation and increased demands on the nursing staff. Hughes et al showed that benefits of continuous sedative infusions were shown to include a more consistent level of sedation with greater levels of patient comfort. Yet, continuous intravenous (IV) sedation has been associated with prolongation of mechanical ventilation, increased length of stay in the ICU and hospital, organ system failure, and elevated reintubation rates when compared with intermittent sedation strategies or no sedation. This study, however, carried an important limitation centered around the lack of randomization of patients observed. Although there is a paucity of data on prospective randomized trial of continuous sedative infusions versus intermittent bolus infusions, studies have alerted clinicians to the important and perhaps underrecognized complications accompanying both bolus and continuous sedative infusions in the ICU.

In the ideal situation, sedation of critically ill patients would be optimized if the pharmacokinetic and the pharmacodynamic profiles commonly observed in such patients were well understood, thereby providing specific guidance for drug administration. Unfortunately, critically ill patients frequently exhibit unpredictable alterations in their pharmacokinetic and pharmacodynamic profiles. In the ICU, patients often present with altered hepatic or renal function that impairs drug clearance, altered drug-drug interactions, altered protein binding, and circulatory instability. These altered profiles in response to sedatives typically cause abnormal results such as the tendency for accumulation in the peripheral compartment and a prolongation of their clinical effect.

A single drug can rarely achieve all the indications for sedation and analgesia in the ICU; therefore, a combination of drugs, each titrated to specific endpoints, is typically a more effective strategy. This can achieve adequate therapeutic effect with lower doses of individual drugs thereby reducing dose-dependent side effects and problems of drug accumulation.

Assessment and monitoring of sedation and delirium

Although ICU practice is characterized by close monitoring of carefully administered care, surveys that have been conducted in various countries have shown that the depth of sedation frequently goes unmonitored. This finding is surprising and unacceptable, as monitoring is simple and can improve patient outcomes. Physiologic variables, serum concentration of drugs, and neurophysiologic tools such as electroencephalogram (EEG) and the bispectral index (BIS) have all been evaluated as methods of monitoring sedation but have ultimately been found to be expensive and unreliable. Their use has been discarded for all but a few indications such as assessing the paralyzed patient. The best systems for monitoring sedation are clinically based.

Available sedation scales include the Richmond Agitation-Sedation Scale, Riker Sedation-Agitation Scale, (SAS) and the RAMSAY Sedation Score to monitor the target level of sedation. A comparison of these tools can be found in Tables 1 to 3 . These tools have significant utility because variations in metabolism and pharmacodynamics cause the dosages of commonly used sedative and analgesic drugs to vary widely between patients. Using a valid method or scoring system for monitoring sedation allows doses to be tailored to the individual while remaining simple, rapidly performed, noninvasive, and reproducible. Of the sedation scales described, the Riker Sedation-Agitation Scale and the Richmond Agitation-Sedation Scale are the most reported. While neither has been shown to be demonstrably superior in evaluation, the RASS has been validated in more populations.

TABLE 1

Richmond Agitation-Sedation Scale (RASS) and Riker Sedation-Agitation Scale (SAS)

Score	Term	Description
+4	Combative	Overtly combative, violent, immediate danger to staff
+3	Very agitated	Pulls or removes tube(s) or catheter(s); aggressive
+2	Agitated	Frequent nonpurposeful movement, fights ventilator
+1	Restless	Anxious but movements not aggressive vigorous
0	Alert and calm
−1	Drowsy	Not fully alert, but has sustained awakening (eye-opening/eye contact) to voice (>10 seconds)
−2	Light sedation	Briefly awakens with eye contact to voice (<10 seconds)
−3	Moderate sedation	Movement or eye opening to voice (but no eye contact)
−4	Deep sedation	No response to voice, but movement or eye opening to physical stimulation
−5	Unarousable	No response to voice or physical stimulation, does not communicate or follow commands

TABLE 2

Riker Sedation-Agitation Scale (SAS)

From Riker RR, Picard JT, Fraser GL. Prospective evaluation of the Sedation-Agitation Scale for adult critically ill patients. Crit Care Med 27:1325-1329, 1999.

Score	Term	Descriptor
7	Dangerous	Pulling at ET tube, trying to remove catheters, climbing over bedrail, striking at staff, thrashing side to side
6	Very agitated	Requiring restraint and frequent verbal reminding of limits, biting ETT
5	Agitated	Anxious or physically agitated, calms to verbal instructions
4	Calm and cooperative	Calm, easily aroused, follows commands
3	Sedated	Difficult to arouse but awakens to verbal stimuli or gentle shaking, follows simple commands but drifts off again
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

TABLE 3

Ramsay Sedation Scale

Score	Description
1	Patient is anxious and agitated or restless, or both
2	Patient is cooperative, oriented, and tranquil
3	Patient responds to commands only
4	Patient exhibits brisk response to light glabellar tap or loud auditory stimulus
5	Patient exhibits a sluggish response to light glabellar tap or loud auditory stimulus
6	Patient exhibits no response

Sessler CN, Gosnell MS, Grap MJ, et al: The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med 166:1338–1344, 2002.

The Riker Sedation scale ranges from 1 to 7, with scores of <4 indicating deeper sedation, a score of 4 indicating an appearance of calm and cooperativeness, and scores of ≥5 indicating increasing agitation. The RASS ranges from −5 to +4, with more negative scores indicating deeper sedation and more positive scores indicating increasing agitation, and with 0 representing the appearance of calm and normal alertness. For most patients undergoing mechanical ventilation in an ICU, an appropriate target is a score of 3 to 4 on the Riker Scale Sedation–Agitation Scale or a score of −2 to 0 on the Richmond Agitation–Sedation Scale.

The titration of the sedative dose to a defined endpoint is recommended with systematic tapering of the dose or daily interruption with retitration to minimize prolonged sedative effects. Patients who were woken up on a regular basis during their ICU stay had fewer days on ventilator. It is important to use titrated doses and infusions to prevent the occurrence of side effects. Oversedation in a patient with unprotected airway can be disastrous, leading to aspiration, unplanned intubations, raised intracranial pressure, and even death. Inadequate sedation can be very distressing for the patient leading to unwanted alteration in physiologic parameters, increased work of breathing, exhaustion, and increased myocardial oxygen demand. Institutions must devise their own sedation guidelines, depending upon the resources available, so that patient safety and comfort is not compromised.

Analgesia and pain management in the ICU

In the ICU, sedation may be incomplete without analgesia and vice versa. Inadequate pain control leads to increased ICU length of stay, higher hospital costs, and ultimately worse patient outcomes. However, adequate levels of comfort are rarely achieved in the ICU. Thus, improving current strategies of pain management may lead to improved patient outcomes. Categories of pain management include systemic, regional analgesics, and nonpharmacologic interventions.

Not only the correct agent needs to be chosen, but also its dose, route, side effect profile, and duration of dosing needs to be understood for all patients. An error at any stage of assessment or treatment can have far-reaching implications. A combined, multimodal sedative-analgesic regime may be preferable. The Society for Critical Care Medicine (SCCM) frequently reviews and updates its recommendations on ICU sedation and analgesia, which can be followed for better results. All ICU staff must remember the pneumonic “ABCDE,” as vital steps of critical care. “A” stands for “awakening,” “B” for “breathing,” “C” for “choice of sedative and analgesic,” “D” for “delirium monitoring,” and “E” for “early mobilization.” It is an evidence-based bundle shown to decrease morbidity and mortality in critical care units.

Systemic analgesics

Pain management has classically relied upon narcotic medications. Classically these drugs included morphine, meperidine, and hydromorphone. More recently fentanyl and its derivatives (remifentanil, sufentanil, alfentanil) have played a larger role. These drugs differ in terms of their pharmacokinetics, pharmacodynamics, potency, and context-sensitive half-lives. A multitude of formulations have been developed in terms of dosage (scheduled, patient-controlled analgesia) and routes of delivery (IV, oral, transdermal, epidural).

Each medication and method of delivery should be tailored according to the patient’s requirements and tolerance for side effects. The most severe and common side effects of this group of drugs include potential for addiction, nausea, vomiting, and constipation. Fear of addiction is one of the main reasons for the reluctance of physicians to prescribe narcotic analgesics in sufficient dosages; however, it has been clearly demonstrated that this potential for addiction is negligible in the setting of acute painful stimuli. The benefits of adequate pain control clearly outweigh the potential side effects.

Adequate levels of analgesia may be difficult to achieve in patients with substance use disorders. These patients have developed tolerance to narcotics and require extremely elevated levels of analgesics that physicians may be reluctant to administer. The added component of drug-seeking behavior may be difficult to distinguish from actual pain. The patient must be believed when they say they are in pain. Multimodal therapy is key. Elevated dosages are justified in the setting of patients who are tolerant and are experiencing acute pain.

Patient-controlled analgesia

One of the most effective methods of pain control in the acute postoperative period is via patient-controlled analgesia, which provides a superior level of pain control, patient comfort with decreased total medication, and consequently a decreased amount of side effects. A preset baseline infusion of the analgesic is given and supplemented with top-ups at the press of a button, at preset intervals. It gives a greater sense of control to the patient and improves their general well-being. Both parenteral (IV PCA pumps) and neuraxial (epidural PCA pumps) are available for use. Opioids and local anesthetic agents are the most commonly used agents in PCA.

Regional anesthesia

Acute and chronic pain are both amenable to treatment by regional techniques. Trauma and postoperative patients will be in severe pain due to multiple injuries or tissue trauma. Regional anesthesia can be a highly effective tool that can provide more than just improved pain management. Local therapy can decrease a clinician’s reliance on systemic medications with side effect profiles such as nausea, vomiting, constipation, urinary retention, and sedation that can prolong a patients’ ICU stay. Furthermore, achieving adequate pain control may not be possible with systemic therapies due to fears of cardiopulmonary suppression. Blockade of the various peripheral nerves and plexuses with local anesthetics (lidocaine and bupivacaine hydrochloride) is being practiced widely in surgical and trauma ICUs.

Potential risks from nerve blocks include bleeding, infection, nerve damage, and reaction to injected medication. Advisories from the American Society of Regional Anesthesia and Pain medicine offer specific evidence-based recommendations for clinical scenarios such as the patient receiving antithrombotic or thrombolytic therapy where bleeding risk is increased. To reduce the risk of intravascular injection, tests doses of anesthetic with epinephrine or isoproterenol can allow for objective measures of cardiovascular response to incidental intravascular injection. This reduces the reliance on self-report from patients, which can be variable and is particularly of use in the heavily sedated patient. When done successfully, the benefits of regional anesthesia can include a complete lack of all the side effects of systemic analgesics and a very high level of pain control in the specific target region. Several techniques can be used for locating the correct injection sites including using anatomical landmarks, electric impedance testing with muscle twitch monitoring, and ultrasound. Catheters may also be placed that offer the possibility of local anesthetic infusions for prolonged analgesia.

Nonpharmacologic interventions

Nonpharmacologic interventions represent an understudied and often forgotten tool that can be used to complement traditional management strategies. Interventions can be cognitive-behavioral (i.e., music therapy, distraction), physical (massage, physical/occupational therapy, early mobilization when possible), and emotional (i.e., presence of loved ones and even pet therapy). There is a paucity of randomized control data that have quantified their effect. Furthermore, blinding may be impossible to study these interventions. The theory behind these interventions, however, is rooted in modulating a patient’s experience of their environment. The sight of several lines leaving a patient’s body and the sound of alarms can be anxiogenic to someone unaccustomed to this environment and may even serve to reinforce/validate a patient’s pain.

Alleviation of sleep deprivation can have a major impact on a patient’s ability to recover. Constant monitoring and invasive procedures contribute to sleep deprivation, which can decrease pain threshold and increase the stress response. Significant attention should be focused on reducing undue discomfort or irritation to patients such as reducing noise or artificial lighting, ensuring patients are at a comfortable temperature, reducing traction on endotracheal tubes, helping patients reposition, or withdrawing unnecessarily induced neuromuscular paralysis.

Music therapy has been shown to have statistically and clinically significant reductions in anxiety, as well as sedative and analgesic frequency and intensity among ICU patients receiving acute ventilatory support for respiratory failure. Noise-canceling headphones were effective in reducing anxiety and analgesic frequency but not in reducing sedation intensity. Evidence suggests music can reduce heart rates, but no strong evidence was shown to influence oxygen saturation or blood pressure in these populations.

Animal-assisted therapy involves allowing pets to visit patients in the hospital. This intervention carries theoretical risks of transmission of zoonotic infections, yet reviews of the literature do not show this to be the case in practice. Vaccination, hygiene, and training of animals all play a role in mitigating this risk. Conversely, studies have shown benefit in reducing pain, anxiety, and fatigue. Literature in this area is still limited, and many hospitals are resistant due to theoretical risks and logistical challenges.

Virtual reality is a promising innovation in nonpharmacologic intervention for pain and anxiety control in the ICU, and so has been the use of virtual reality (VR) goggles. Several recent studies have evaluated the use of VR in the ICU, which demonstrated significant reductions in patient-reported pain and anxiety. There was also a significant effect on objective biomarkers such as pulse rate, mean arterial pressure, and respiratory rate without compromise of the patients’ blood-oxygen saturation. The feasibility of implementation has been demonstrated and the headsets are well received by patients. Randomized control trials are underway that seek to build the body of evidence of this promising field.

Assessing and monitoring pain control in the ICU

Regular assessment of pain control improves patient outcomes. Unmonitored, pain is often underestimated and undertreated. In a communicative patient, tools such as the Numerical Rating Scale, Visual Analog Scale, or the Verbal Rating Scale are simple and reliable tools to assess a patient’s current level of pain. In the critically ill, semiconscious or noncommunicative patient, behavioral observation serves as an invaluable tool for assessing pain. Fortunately, several standardized scales exist. This includes the Behavioral Pain Scale and the Critical Care Pain Observation Tool.

Ensuring pain is well controlled not only provides comfort to the patient, but also can aid in a patient’s recovery. Physiologic responses to pain include increased VO ₂ and metabolism, immune dysfunction, and a hypercoagulable state. These sequalae may contribute to morbidity and mortality as respiratory distress, infection, and thromboembolism are common in the ICU. Furthermore, pain control can prevent the development of chronic pain syndromes. Because of this, the authors recommend frequent assessment of patients’ pain and to be attentive to maximizing their comfort.

Muscle relaxants in the ICU

The neuromuscular blocking agents (NMBAs) have been used since time immemorial for critically ill patients on ventilatory support. They have since gone into disrepute as they are associated with prolonged mechanical ventilation, delayed awakening, residual deficits, and increased length of stay. For these reasons, the use of muscle relaxants in intensive care patients is rapidly declining. Nevertheless, they are important part of an intensive care.

The current recommendations are that muscle relaxants be used to decrease the work of breathing and facilitate intubation and mechanical ventilation in patients where sedation alone is inadequate in providing conditions for effective mechanical ventilation. Patients who are fighting the ventilator or require use of discomforting modalities such as the prone position, permissive hypercapnia, and high positive end-expiratory pressure levels are indications that muscle relaxants are needed.

The most basic problem is the creation of a paralyzed but inadequately sedated patient who cannot communicate their discomfort. It is always important to ensure that paralyzed patients receive adequate sedation. One of the ways this can be monitored is using BIS. BIS takes an electroencephalogram reading and summarizes the level of brain activity as a score that is representative of the patient’s level of sedation. Use of BIS is not widespread and thus clinicians should also be attentive to other signs of pain and discomfort such as heightened sympathetic activity. New-onset tachycardia or hypertension in a chemically paralyzed patient may be a sign of inadequate sedation and merits treatment. Additionally, there is the question of the dosing requirements (i.e., whether neuromuscular transmission needs to be completely or only partially abolished); however, some investigators have questioned the usefulness of monitoring degree of blockade, especially when short-acting agents are used.

Monitoring the degree of paralysis

Two methods are used for monitoring degree of paralysis. The first is the peripheral nerve stimulator (train-of-four [TOF]). TOF/peripheral nerve stimulation is the standard of care to monitor level of neuromuscular blockade. Appropriate paralysis using TOF monitoring is generally considered 85% to 90% blockade as indicated by one to two twitches out of four via the TOF monitoring. The consistent use of TOF will minimize drug accumulation but may not prevent prolonged paralysis or prolonged weakness seen in some patients after discontinuation of NMBAs. The physician should write the NMBA orders specifying the number of twitches desired (i.e., atracurium 2 to 15 ug/kg/minute, titrate to one to two twitches out of four on TOF). The second method is compliance with ventilatory support. The clinical indication of appropriate neuromuscular blockade is evident when the patient accepts ventilation without overbreathing or asynchrony. The patient will also have reduced airway pressures, absent gag/cough reflex during tracheal suctioning, and no visible extremity movements.

Procedures for monitoring patients during prolonged paralysis (24 or more hours) are as follows. All patients receiving around-the-clock neuromuscular blockade should be monitored with a peripheral nerve stimulator in addition to the clinical assessment of ventilator compliance. TOF must be assessed at least every 12 hours. Drug holidays (discontinuation of the infusion or holding of a scheduled dose for several hours) should be considered after 5 days of continuous administration, or after 48 hours if the patient is receiving concurrent steroids. The purpose of the drug holiday is to both assess if the indication for the NMBA still exists and to assess the time necessary for the patient to recover from the neuromuscular blockade. In general, if it takes a time equal to or greater than four t1/2 (half-life) of the NMBA to recover three to four twitches after the NMBA is held, then the dose or interval should be adjusted prior to restarting the NMBA. If the indication for neuromuscular blockade no longer exists after withdrawal, the NMBA should be discontinued. The following is an example of a drug holiday procedure:

1.
Consider a drug holiday for stable patients.
2.
Hold NMBA if patient has received 5 or more days of NMBA therapy without other interacting medications or if patient has received 2 or more days of therapy with concurrent steroids.
3.
Start checking TOF beginning 1 hour after the end of the last dosing interval or 1 hour after stopping an infusion.
4.
Check TOF every hour until three to four twitches are recovered.

Postparalytic syndrome occurs with all agents and is unpredictable. All the common NMBAs (i.e., vecuronium, atracurium) have been implicated with postparalytic syndrome/prolonged weakness. This weakness is caused by denervation of muscle or because of NMBA interaction with various medications. This can either result from drug accumulation or the development of acute quadriplegic myopathy syndrome, which includes critical illness myopathy, myopathy with selective loss of thick (myosin) filaments, and acute necrotizing myopathy of intensive care. It is characterized by acute paresis, myonecrosis, and abnormal electromyography findings. Sensory function generally remains intact. NMBAs should be avoided in patients at high risk for prolonged weakness and those receiving concurrent corticosteroids, aminoglycosides, or immunosuppressives. The occurrence of prolonged paralysis is unpredictable and may take weeks or months to reverse. The severity of this syndrome can range from mild weakness to quadriplegia. There is an increasing body of literature reporting prolonged neuromuscular dysfunction following the use of NMBAs. Several factors have been reported to potentiate the development of prolonged neuromuscular dysfunction, most notably the conjoined use of corticosteroids. Although most reports describe the use of high-dose corticosteroids in combination with a steroid-based NMBA, the benzylisoquinolinium agents have also been implicated. One mechanism responsible for this drug interaction is a decrease in thick filament proteins.

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