Management of Pain, Agitation, and Delirium in Mechanically Ventilated Oncology Patients Management of Pain, Agitation, and Delirium in Mechanically Ventilated Oncology Patients

Attention has heightened over the last several years to the importance of managing pain, agitation, and delirium in mechanically ventilated patients due to the multiple long‐ term adverse effects patients experience after an intensive care unit (ICU) admission. Furthermore, clinical practice is being molded not just by the guidelines and random‐ ized controlled trials, but also by the information gathered from real patient experiences to improve care at the bedside. The literature continues to remain sparse for providing guidance specifically in the oncology population. Therefore, several resources have been combined to better assist clinicians on making sound decisions for keeping patients comfortable on the ventilator while recognizing the differences in treatment that may need to be employed due to these patients’ medical condition.


Introduction
One of the leading causes of an intensive care unit (ICU) admission is acute respiratory failure where approximately 44-69% of patients with malignancies requiring mechanical ventilation due to the progression of cancer or chemotherapy toxicity [1]. Improved survival of critically ill oncology patients has been due to the advances in the treatment of malignancies and more appropriate triage of patients for ICU admission [2]. Thus, not all families of intubated patients are met with discussions for end of life or hospice care of their loved one. Goals of weaning and extubation to allow the resumption of cancer treatment have become more common.
agitation, and delirium is especially crucial for a population on chronic pain and anxiety medications prior to admission. However, national guidelines published by the Society of Critical Care Medicine (SCCM) in 2013 were primarily based on data from the nononcology population, which poses challenges in applying such concepts to these patients. Such protocol outcomes lack support from clinical trials in oncology patients. Studies involving ICU patients with cancer have largely focused on mortality outcomes, rather than improvement of care, due to these patients' overall poor prognosis. Thus, the concepts described in the SCCM guidelines must be applied simultaneously with literature on effective treatment of pain and agitation in noncritically ill oncology patients.
In addition to clinical trials, patient interviews conducted in the ICU are gaining more attention to help the clinician better predict the needs of the patient on mechanical ventilation. A prospective study, conducted in a medical ICU, evaluated the symptom experience of patients with a present or past diagnosis of cancer admitted during an 8-month period. The patients expressed the procedures associated with the greatest pain or discomfort were endotracheal suctioning, endotracheal and nasogastric tubes, mechanical ventilation, arterial puncture, and turning. The aspects of the environment reported to be most stressful were inability to communicate, communicate, sleep disturbances, and limited family visitation hours [2]. In this study, patients still experienced significant discomfort despite liberal administration of opioids and sedatives, along with the implementation of palliative care recommendations. This could be explained by the challenge of accurately assessing pain in mechanically ventilated patients, as well as the rate in which patients felt their stress was not relived by medications. For these reasons, it is imperative that a multidisciplinary team acquires a consistent and universal method by which these patients' pain, agitation, and delirium are managed. More importantly, the clinicians should have a strong understanding of the pharmacology of opioids and sedatives to ensure the safest agents are chosen.

Pain
The prevalence of pain has not been shown to differ between patients actively receiving anticancer treatment and those with an advanced-or terminal-phase disease. Studies have also published that on average 56-82.3% of cancer patients' pain is not adequately treated [3]. This emphasizes the importance of performing accurate and timely assessments of pain to ensure appropriate treatment. As recommended by SCCM guidelines, the gold standards for pain assessments in ICU patients are the numerical rating scale or visual analog scale (VAS) if a patient is communicative enough to express their level of pain. In some instances, such assessments can be challenging in ICU patients receiving high-dose sedatives during mechanical ventilation or those with altered level of consciousness [4]. If the patient is unable to selfreport his/her pain, then the most valid and reliable assessments for pain are the behavioral pain scale (BPS) and the critical pain observation tool (CPOT) outlined in Tables 1 and 2 [5], which are consistent with recommendations by NCCN guidelines for adult cancer pain. Vital signs alone are no longer recommended for detecting symptoms of pain. They only should be used as a cue to perform further assessments [4]. Chronic pain affects greater than 60% of oncology patients, with upwards of 66% experiencing failure of therapy [6]. Subsequently, the majority of these patients are opioid tolerant and on high doses of narcotics prior to being admitted. Upon ICU admission, many patients do not have oral access or have multisystem failure that can preclude them from receiving specific types of opioids. It becomes imperative that thorough medication reconciliations are performed to determine the amount of daily opioids the patient takes at home so that they can be converted to the most appropriate and safest formulation in the ICU. When performing such conversions, clinicians must consider incomplete cross tolerance if the patient is placed on an opioid they are not receiving prior to admission. Long-term exposure to one drug can result in the development of tolerance to those with similar structures. However, this tolerance is rarely complete with agents that bind to different receptors, thus the analgesic effect of the new agent is enhanced in the patient. Without appropriate conversions, the patient is at risk of withdrawal or overdose when rotating opioids. However, the heightened analgesic effect due to incomplete cross tolerance can also lead to excessive side effects such as respiratory depression, nausea, sedation, and dysphoria [7]. The total daily dose of the patient's regimen, both IV and oral, should be converted to the opioid to be initiated in the ICU using Table 3 and reduced by 20-30% for cross intolerance. Persistent or chronic pain should be controlled using a combination of long-acting agents, either extended or sustained release oral formulations or continuous IV infusions, in conjunction with short-acting agent. Long-acting opioid typically comprises 50% of the total daily requirement [11].

Upper limb movements
No movement 1 Partially bent 2 Fully bent with finger flexion 3

Permanently retracted 4
Compliance with mechanical ventilation Tolerating movement 1 Coughing but tolerating ventilation for most of the time 2
Society of Critical Care Medicine Guidelines emphasize that many sources of pain have been identified in ICU patients related to not only surgery, trauma, burns, or cancer but also procedures. In a comparative, descriptive study, data were obtained from over 6000 patients to describe pain intensity and procedural distress. Procedures were defined as wound dressing changes, turning, tracheal suctioning, and wound drainage removal. The average pain score was 5-7, and the most distressful procedures were turning and wound care. Unfortunately, less than 20% of these patients actually received opiates before the procedures. With procedures performed so frequently in the ICU, this remains one of the areas that is poorly managed [12]. Therefore, it is highly encouraged patients are pre-treated with bolus doses of opioids.
Unrelieved pain leads to long-term negative outcomes, such as patients recalling traumatic memories of pain during their ICU admission. It has also been shown that inadequately treated pain is associated with physiological consequences such as increase in catecholamines leading to arteriolar vasoconstriction, impaired tissue perfusion, catabolic hypermetabolism resulting in hyperglycemia, lipolysis, and breakdown of muscle [4].  Managing pain in ICU patients, especially the mechanically ventilated, is almost always in conjunction with managing agitation and delirium. Therefore, pain can be managed more effectively and appropriately with several simple concepts employed: 1. Nurses should perform consistent and accurate pain assessments using the tools validated in ICU patients with reassessments performed after analgesics are administered to evaluate response to therapy.

Intermittent boluses versus continuous IV infusion strategies should be selected based on
the frequency and severity of pain and/or patient's mental status. The use of patientcontrolled administration (PCA) should be highly considered for patients responsive and cognitive to control delivery of boluses.

3.
The type of opioid selected for each patient should be based on the drug pharmacokinetics/ pharmacodynamics including any risks for altered clearance if the patient has evidence of organ dysfunction (see Tables 4 and 5).

4.
Oral formulations should be limited to those patients with adequate gastrointestinal absorption.

5.
Regional or neuraxial (spinal or epidural) modalities can be considered for postoperative analgesia.

7.
Analgesic agents should be started prior to sedative agents if there is any suspicion of pain. After sedatives are initiated, pain assessments can be harder to perform and less accurate in ensuring the patient is comfortable.

8.
Pain medications should be titrated upward by 10-25% and doses selected based on the pain assessments using nursing driven scales. Opioid rotation should be considered if pain is inadequately controlled or persistent adverse effects are experienced [11].

9.
Use of nursing-driven protocol with effective multidisciplinary discussions for adjustment of such medication orders should occur on a routine basis.

Route of administration/formulation
The route of administration preferred for non-ICU patients is often oral, whereas for critically ill patients, intravenous is optimal when there is known or suspected altered gastrointestinal (GI) tract absorption. Furthermore, other routes such as intramuscular (IM), subcutaneous, or transdermal requiring systemic absorption are frequently avoided in critically ill patients due to erratic and unpredictable absorption [13]. Risks of changes in perfusion due to hemodynamic instability and fluid shifts can lead to potentiated or subtherapeutic effects. Table 4 illustrates the comparison of the most common analgesics used in ICU mechanically ventilated patients, with the exception of meperidine, which is discouraged in an ICU setting due to the high risk of neurotoxicity. Methadone is occasionally avoided due to the risk of QT prolongation, interaction with common ICU medications, and difficulty dosing. In the oncology setting, patients taking methadone at home can be encountered, and due to its multiple side effects, it should be converted to alternative opioids if the patient is unstable or lacks oral access. Methadone should not be discontinued abruptly without adequate alternative opioids initiated as replacement therapy to prevent withdrawal.

Pharmacokinetic/pharmacodynamic properties and side effect profile
When the patient is hemodynamically unstable or has renal insufficiency, then fentanyl or hydromorphone is recommended as first line agents. Either of two agents, in addition to morphine, can be used for patients with no renal insufficiency or those who are stable [24].
Clinicians should also be cognitive of possible inadequate metabolism and/or clearance of medications in patients with renal and hepatic cancers which may not be evident by laboratory values.

Nonopioid analgesics
Opioid analgesics are most often the first line agents employed in general ICU patients with the ease of administration and ability to titrate. However, in patients with cancer, nonopioid agents provide a novel approach to better controlling their pain long term and helping to reduce opioid requirements. The WHO analgesic ladder provides guidelines for the treatment of cancer pain by suggesting a sequential three step approach based on severity of pain.
Nonopioids are recommended for mild pain, weak opioids for moderate pain, and strong opioids for severe pain with fixed scheduled dosing according to the pharmacokinetic properties of the drugs. Typically, the nonopioids initiated in step 1 should be continued in conjunction with opioids added in the next step to allow for agents with different mechanisms of actions to improve analgesic control. There are several common nonopioid agents used to treat cancer pain that can be continued in an ICU if the patient has appropriate access. Table 5 compares the various classes of nonopioid agents and pharmacokinetics as well as common toxicities of which to be aware when using such agents in the ICU setting. Other nonopioids found to effective in the oncology population are bisphosphonates for bone metastases and medicinal cannabinoids that are not encouraged in the ICU due to their unsafe profile.

Unconventional modes of administration
Breathlessness is often a distressing symptom in oncology patients especially during end of life. Alternative routes of opioid administration, via inhaled nebulization and intranasal, have been studied. Unfortunately, data are still lacking on the efficacy of such routes of administration. However, benefit has been seen due to the short onset of action with these modes of delivery. Both morphine and fentanyl have been administered through nebulization, and fentanyl is preferred intranasally due its lipophilic properties allowing for better absorption [21].

Protocolized management of pain
In mechanically ventilated patients, use of protocols can greatly reduce the delay in treating pain, ICU length of stay, high dose analgesics, and duration of mechanical ventilation. It is advised to initiate orders that allow nurses to select the appropriate dose of an analgesic agent based on the pain scale score. Minimal data exist on the incremental doses that should be administered with various pain scores. However, orders for the analgesic agent of choice have been applied to our current practice in an oncology ICU and proven to be effective which are listed as follows: • Fentanyl 25 mcg IV every 15 min as needed for numeric pain score 1-2, critical pain observation tool (CPOT) 0-2, and/or Richmond agitation-sedation scale (RASS) +1.
Initial doses are defaulted but can be changed by the prescriber if more aggressive or more conservative doses are needed.
Pain should be assessed routinely especially after analgesic agents are administered. Most nursing standards expect pain to be reassessed within 15-30 min after treatment, and thus, the frequency of analgesic medications should be written to allow redosing in a timely manner if needed [4].

Analgesia-First Sedation
Recent literature now emphasizes the importance of adequately treating pain prior to use of sedatives. The most common source of agitation identified in intubated patients is pain. If agitation is treated immediately with sedatives, then the patient is at risk of experiencing the physiologic consequences previously discussed because pain remains untreated. Therefore, it may be beneficial to have intermittent analgesic medication orders written to PRN RASS scores in addition to incremental pain scores to allow the nurse to adequately use such medications for agitation (as shown in example above).
If pain is ruled out as the cause of agitation, then other causes should be promptly considered such as hypoxemia, hypoglycemia, hypotension, or withdrawal from alcohol or other drugs [4]. Aside from treating such underlying causes, strategies should be used to help reduce agitation by maintaining comfort for the patient, frequent reorientation, and optimization of the environment to maintain normal sleep patterns. After addressing such issues, sedatives only then should be considered if the patient remains agitated with a goal sedation level established: light for goals of extubation (i.e. the patient is alert, calm, arousable, and able to follow commands) or deep sedation with goals of synchronization with the ventilator, or the prevention of movement in severe trauma/burns/paralysis (i.e. patient is unresponsive to painful stimuli, unable to follow commands) with goals of synchronization with the ventilator, or the prevention of movement severe trauma/burns). Most patients should have goals of light sedation as many studies have demonstrated increased ICU length of stay, mechanical ventilation, delirium, and muscle deconditioning with deep, prolonged sedation [25][26][27].
Agitation should be assessed as frequently as pain is assessed using the RASS or SAS scales (Tables 6 and 7). Recommendations for options to treat agitation are in Table 8.  Table 6. Richmond agitation sedation scale (RASS) [28].  hypotension; propylene glycolrelated acidosis (rare); nephrotoxicity evident by an osmolar gap greater than 10-12 mOsm/L; accumulates in hepatic dysfunction; emergence from lorazepam after prolonged infusions will be longer than midazolam due to its greater potency and slower clearance; drug has potential to accumulate in adipose tissue with continuous infusions t ½ , half-life of elimination; MOA, mechanism of action.

Delirium
Delirium is defined as a syndrome with acute onset of cerebral dysfunction due to a change or fluctuation in baseline mental status, inattention, or disorganized thinking [4]. Two forms of delirium can exist: hyperactive (agitated, associated with hallucinations or delusions) or hypoactive (calm, lethargic, confused, and sedated). With delirium now being shown to be a strong predictor of negative long-term outcomes, it is imperative that regular assessments are performed to identify incidences of delirium and implementing preventative measures [24,31]. Such strategies include early mobilization, maintenance of light sedation while avoiding benzodiazepines in those with underlying risk factors for delirium, promoting sleep in adult ICU patients by optimizing environmental factors such as light, noise, clustering patient care activities, and decreasing stimuli at night.
Medication-induced delirium is not well studied and the exact onset, duration, or severity has yet to be confirmed. Delirium is multifactorial and, therefore, medications should not be solely considered as the cause in a patient experiencing changes in mental status. Most common causes of delirium are in Table 9. Benzodiazepines have been studied extensively as a possible risk factor for delirium. The data concerning benzodiazepines and outcomes with causing delirium remain controversial. The MENDS and SEDCOM studies had similar results showing higher delirium free days with or without coma when dexmedetomidine was administered compared to midazolam or lorazepam. Furthermore, both have similar results in showing no difference in mortality and the length of ICU stay [33,34]. However, another meta-analysis including six trials comparing benzodiazepine versus nonbenzodiazepine sedatives found opposite results. The ICU length of stay and duration of mechanical ventilation were significantly higher in the benzodiazepine group with no difference found in delirium prevalence or all-cause mortality [35]. Until further research can clarify such effects, caution is still warranted when using these sedatives and other risk factors shown in Table 10 should be considered as well.

Iatrogenic
Exposure to sedative and opioid medications

Environmental
Prolonged physical restraints Immobilization Disorientation to time and space

Other
Drug or alcohol withdrawal

Medication induced Anticholinergics
Benzodiazepines Opiates Antipsychotics Antispasmodics Anticonvulsants Corticosteroids Table 9. Two scales for assessing delirium with the highest psychometric (e.g., validity and reliability) scores are the CAM-ICU and the ICDSC [37]. Delirium should be assessed every 8-12 hours, only after sedatives are decreased or interrupted and preferably during daytime hours.  Treatment of delirium should be directed at the probable underlying causes (e.g., alcohol or drug withdrawal, infection, dehydration, discomfort) and consider pharmacologic agents only if needed. SCCM guidelines provide a Grade C recommendation that "atypical antipsychotics may reduce the duration of delirium in adult ICU patients." No evidence exists on the efficacy of haloperidol in reducing delirium and is associated with higher incidences of extrapyramidal and cardiac side effects [38]. The atypical antipsychotics, which have been studied and shown to be beneficial, are listed in Table 11. If such agents are initiated, it is crucial to ensure they are discontinued upon discharge or follow-up strategies are in place in the outpatient setting. Patients should also be monitored carefully for the adverse effects listed.
The fundamental component of implementing successful protocols to manage pain, agitation, and delirium in mechanically ventilated patients is a multidisciplinary team. Developing a comprehensive protocol can help reduce costs, improve ICU outcomes, and create more consistent practices. As presented earlier, the SCCM PAD Guideline concepts can be employed but the basic principles established in cancer patients for managing pain and anxiety must also be considered to achieve optimal outcomes.

Author details
Trisha Patel * and Mark E. Lewis *Address all correspondence to: trisha.patel@ctca-hope.com Cancer Treatment Centers of America at Eastern Regional Medical Center, Philadelphia, USA