Brief introduction
This article examines the challenges of sedation and analgesic treatment for patients with sepsis and advocates an individualized approach. Sedation is an essential part of the treatment of patients in intensive care to reduce stress and anxiety and improve long-term outcomes. Patients with sepsis have particular difficulties due to the risk of a range of complications, such as multi-organ failure, neurological deficits, septic shock, ARDS, celiac syndrome, vasodilatory shock, and myocardial dysfunction. The development of any one complication can lead to rapid deterioration of the patient, and each complication has different considerations in terms of appropriate and safe forms of sedation. Therefore, this article reviews the sedative and analgesic drugs commonly used in the intensive care unit, with particular emphasis on their strategic use in patients with sepsis, and proposes a set of analgesic recommendations aimed at improving the prognosis of these patients. These recommendations represent a shift from a simple approach such as simple avoidance of benzodiazepines to "goal-directed sedation" that considers the patient's major pathology as well as any comorbidities, and makes the most of currently available treatments to achieve personalized, patient-centered treatment goals.
introduce
Sedation of critically ill patients is a complex and rapidly changing field in the medical field. Several recent articles have raised questions about some of the widely used sedatives, such as propofol and single-dose etomidate. In the case of the latter, it has been removed from the arsenal of drugs used for prolonged sedation due to concerns about adverse effects. At the same time, there is an increasing trend to limit the use of narcotic drugs due to their harmful side effects, and environmental concerns are increasingly crowding out research on once-promising fluoride inhalation sedatives.
Of course, the need for sedation is indisputable, especially for patients in the intensive care unit (ICU). These patients are likely to experience pain, anxiety, and restlessness as a result of various invasive monitoring and other procedures. Sedation of ICU patients should have several simultaneous goals, including minimizing their oxygen consumption, allowing them to comfortably connect to the ventilator, and reducing stress and anxiety while performing any necessary procedures, while avoiding clinical deterioration of the patient's condition and preventing the occurrence of physical or psychological harm. Achieving all these goals in daily practice is far from easy, especially in the early stages of rehabilitation of septic surgery or neurocritically ill patients, or in patients associated with intra-abdominal hypertension or acute respiratory distress syndrome (ARDS).
In critically ill patients, patients with septic shock present with a very specific set of problems. A clinical syndrome in which dysregulated systemic inflammation due to underlying infection may lead to infection or septic shock, which is defined by the Sepsis-3 definition as "life-threatening organ dysfunction due to dysregulated host responses." Septic shock is characterized by the widespread release of cytokines, proteases, and reactive oxygen species that cause direct and indirect cellular damage. This is followed by vasodilation and capillary leakage, resulting in relative and absolute intravascular hypovolemia, which may then be significantly increased by resuscitation. Impaired microcirculatory blood flow leads to uneven organ perfusion, mitochondrial dysfunction, cellular hypoxia, and subsequent organ dysfunction and failure. The extent to which these changes occur depends on the extent of the complex interaction between infectious factors, patient factors, and treatment factors.
The basic approach to sepsis can be summarized as prompt identification, elimination of the source of infection, and early initiation of adequate antimicrobial therapy, volume resuscitation, vasopressor, and treatment in shock. In addition to this, clinicians are at risk of multiple organ dysfunction syndrome (MODS). MODS is not a single event, but a series of processes characterized by a continuous and incremental physiological attack on individual organs. Almost all organs are affected, but the degree of damage varies from mild to completely irreversible. One of the many fascinating paradoxes about sepsis is that its effects on body organs are variable. The most commonly affected organs are the lungs (ARDS is the most severely affected form), the brain (which manifests itself as a clinical feature of encephalopathy, including irritability, confusion, and coma), the hepatoenteric system (clinical features of hepatic dysfunction usually appear later in the sepsis process and, if present, predict a worse outcome), the kidneys (acute kidney injury), and the heart (cardiomyopathy).
Sepsis causes a variety of pathophysiological changes that alter drug distribution, the effects of which can be significant. Redistribution of blood from surrounding tissues elsewhere, sometimes accompanied by a decrease in cardiac output, may reduce the volume of distribution of some fat-soluble drugs, resulting in increased plasma concentrations. This is particularly important in intensive care, for fast-acting drugs with concentration-dependent adverse effects, such as intravenous anesthetics, analgesics, or sedatives.
This means that there are many factors to consider when choosing the best analgesic medication for each patient, such as the cardiovascular effects of a particular drug, the pharmacokinetics or pharmacokinetics that may be variable, or the drug interactions that may occur in polypharmacy patients. Therefore, it is essential to evaluate all possible combinations of medication alternatives to prevent physical and psychological harm associated with critical care. In addition, to consider patients with sepsis in particular, it is important to emphasize that each individual has a unique clinical background, so an individualized approach to treatment is essential.
In this paper, we examine the key features of sedatives and analgesics widely used in the ICU, with particular emphasis on strategic dosing and monitoring in patients with sepsis. In this way, we propose a series of interventions that address the above sedation goals and the specific needs of this patient population.
Monitor analgesic sedation status
Effective patient management with sepsis requires subjective and/or objective monitoring of three key variables: pain, agitation, and level of consciousness (LOC). When evaluating these three variables, it is necessary to (1) set a predetermined set of goals; (2) use tools that are both effective and precise, but also easy to implement so that they can be used flexibly (at least one assessment per shift); and (3) provide a well-defined protocol for the assessment and management of analgesia, sedation, and delirium. To this end, and to promote the multimodal approach needed in critically ill patients, certain initiatives have been proposed, such as the ABCDEF (A2F) bundle (assessment, prevention and management of pain; Spontaneous arousal and breathing tests are performed at the same time; choice of analgesia and sedative; delirium assessment, prevention, and management; early exercise and exercise; Family Involvement/Empowerment). This beam is designed to ensure that ICU patients receive comprehensive care, better pain control, and, importantly, early recovery of advanced physical and mental abilities during their recovery from critical illness. Another initiative concerns the so-called eCASH approach (Early Comfort Use of Analgesics, Minimal Use of Sedatives and Maximum Humane Care), which proposes the integration of light sedation, while adopting a series of measures aimed primarily at pain and the promotion of sleep. In both cases, appropriate tools exist for both the A2F bundle and the eCASH method to evaluate each element of the relevant scheme.
Assess and monitor pain
When assessing pain levels and analgesic needs, a scale based on patient-reported information is recommended, if possible. For this purpose, two such scales exist: the visual numerical scale (VNS) and the visual analogue scale (VAS), where VNS has a lower non-response rate (2%) and VAS (11%). When the patient is unable to provide the required information, physiological and behavioral pain indicators can be referenced, using the Behavioral Pain Scale (BPS) and the Intensive Care Observation Tool (CPOT). A limitation of BPS is that sedation has been observed to reduce responsiveness, particularly affecting the cooperative dimension with mechanical ventilation, leaving only facial expressions and upper limb movements to assess pain.
Specific pain assessment scales (COMFORT, FLACC) have also been developed for pediatric patients, and a few others are rarely used due to complexity and the few additional benefits they provide for pain assessment in the intensive care setting. In addition, although there are currently no existing guidelines recommended for use in the management of critically ill patients, in recent years, various methods have been developed to monitor pain response during surgery, such as the Nociception Level Index (NOL), Med-Storm Innovation AS, pupillometry, cardiac index, and analgesic pain index (ANI).
Assess and monitor the effect of sedation
关于镇静监测，目前临床实践指南中最广泛使用和推荐的两个评估标准分别是 Sedation-Agitation Scale (SAS) 和 Richmond Agitation Sedation Scale (RASS)。 这是因为它们具有极佳的可靠性和评估者间的一致性。
When inhalation sedation is performed with a halogen anesthetic, the concentration of the inhaled substance in the exhaled breath can be monitored using appropriate equipment and the resulting values are compared with the minimum alveolar concentration (MAC) associated with this anesthetic drug. There are multiple MAC values that are defined; However, the one used to administer sedation in the intensive care unit is the MAC-awake state, which for sevoflurane the value is between 0.5% and 1%. For a given sedative, the MAC value decreases with the patient's age and with concomitant use of other sedatives or opioids.
Diagnosis of delirium
The clinical diagnosis of delirium can be made by several validated scales, such as the ICU Confusion Assessment Method (CAM-ICU) and the Intensive Care Unit Delirium Screening Form (ICDSC), both of which are able to identify patients presenting with a form of hyperactive delirium. An assessment for delirium should be completed at least once per shift and should be performed whenever a change in the patient's conscious status is observed (e.g., before or after sedation has stopped). The state of consciousness is an important factor in assessing delirium; Therefore, an appropriate level of sedation must always be ensured and can be assessed by RASS when using the CAM-ICU Delirium Scale. For patients who are unable to communicate, the ICDSC is considered the most appropriate because it includes data obtained during routine observation by the care team responsible for caring for the patient.
THERE ARE THREE MODELS THAT CAN PREDICT THE OCCURRENCE OF DELIRIUM, INCLUDING THE PRE-DELIRIC MODEL; EARLY PREDICTION MODEL, E-PRE-DELIRIC; There is also the Lanzhou model. These models are invaluable to the health care team and can help them take measures, especially non-pharmacological interventions, to prevent delirium from occurring.
Electroencephalography (EEG) is also a potentially useful tool to assess delirium. Inflammatory mediators can cross the blood-brain barrier and increase vascular permeability, which in turn produces changes in brain activity that can be seen on EEG. However, the difficulty of implementing and interpreting EEG data prevents it from being a routine tool in ICU settings. Intensive Care Continuous Electroencephalogram (CCEEG) refers to the simultaneous recording of EEG and clinical behavior (video) in critically ill patients over a longer period of time (hours to weeks). CCEEG is usually performed in an ICU setting, but this varies from hospital to hospital and some patients may be in a stepper unit or a general medical or surgical unit. The goal of CCEEG is to identify changes in brain function, such as nonataxia seizures or ischemia, that may not be evident on neurological examination alone, in order to facilitate early recognition and management of these abnormalities. However, in patients with sepsis, prompt use of EEG may be recommended to identify nonataxia seizures due to the high frequency of delirium, which may be an indication of delirium.
The current literature strongly suggests that there is a neutral correlation between bispectral index (BIS) measurements and RASS and SAS, two clinical scoring instruments for assessing sedation. Therefore, BIS can be used in cases where it is not possible to assess patients using these clinical scoring tools. However, some important questions regarding the routine use of BIS are unclear in patients treated with neuromuscular blocking agents (NMBAs). Specifically, the optimal range of BIS values in these cases is unclear, as NMBAs themselves reduce EMG activity, which is one of the main indicators of obtaining BIS values; Therefore, BIS does not reliably reflect whether these patients are awake or not. In addition, there is a lack of high-quality studies on the effect of BIS monitoring on length of stay in intensive care unit or ventilator-free days. Therefore, it is not currently recommended as a routine tool and should be used in preference to clinical scoring tools. Table 1 summarizes the different tools currently used to assess pain, sedation, and delirium.
Intravenous sedation
Propofol
Propofol is highly fat-soluble and has a very short elimination half-life, making it ideal for administration by infusion while being able to quickly restore sedation. Unlike benzodiazepines, which are excreted by the kidneys, propofol is mainly metabolized by the liver (partially in the kidney) to form inactive metabolites. This means that there is no need to adjust the dose for patients with renal or hepatic insufficiency. However, in patients with septic shock, liver function is reduced threefold, which can lead to dose buildup and excessive sedation. In fact, studies have shown that this can occur in up to 60% of ICU admissions. Propofol consists of highly fat-soluble molecules with broad protein binding (98% binding to albumin). In severe infections, the volume distribution is initially reduced due to the concentration of blood flow. This, combined with a decrease in serum albumin, leads to significantly higher free plasma concentrations, leading to significant cardiovascular effects. Decreased cardiac output also prolongs anesthesia induction and requires dose reduction, slow administration, and adjustment to the response.
In addition to the above considerations, the main adverse effects of propofol are related to prolonged sedation. The main problem is related to the fact that the drug is formulated as a lipid emulsion, so long-term use can lead to hypertriglyceridemia; At the same time, it also means that the drug must be considered a source of calories as part of the nutritional care of critically ill patients. Another potential complication is the syndrome associated with propofol infusion (PRIS), which, although rare, is potentially fatal with a mortality rate of about 20-80%. Although there is no standard definition of the performance of PRIS, it is related to prolonged infusion (>48 hours) and dose (>80 micrograms/kg/min), or cumulative dose (>300 mg/kg), the latter of which is more important than the total infusion time. PRIS is more common in younger patients, particularly those who are taking catecholamines or corticosteroids, and those with severe disease. Unfortunately, severe disease can also delay or hinder the diagnosis of PRIS, especially in the setting of septic shock.
Propofol works by acting on GABA-A receptors, which activate the symptoms of delirium caused by sedation. The mechanism is the same as that of benzodiazepines; However, propofol is quickly cleared from the nervous system, meaning that it may cause more transient episodes of delirium compared to benzodiazepines.
Particular attention needs to be paid here to the development of intra-abdominal hypertension syndrome (IAH) and its final stage, abdominal compartment syndrome (ACS). Once IAH is diagnosed, non-surgical measures are immediately required to reduce intra-abdominal pressure (IAP), which may include attempts to create a negative fluid balance through diuresis or dialysis, assessment of intra-abdominal contents, and optimization of sedation. Although mechanical ventilation should be avoided as much as possible due to its potential to increase IAP, the use of deep sedation or even neuromuscular relaxants can help improve abdominal compliance and thus decrease IAP when necessary. In this case, propofol is the preferred intravenous sedative because it reduces respiratory drive and thus does not increase IAP. The use of neuromuscular relaxants is reserved only for cases that do not respond to this treatment and as a last resort prior to surgical intervention.
Dexmedetomidine
Dexmedetomidine (DEX) is a highly selective α2-adrenergic receptor agonist that can strongly inhibit the sympathetic nervous system and reduce heart rate and myocardial oxygen consumption. Its use may lead to biphasic arterial blood pressure responses, particularly in older patients, where arterial pressure is reduced at low doses and hypertension is caused at high doses (up to 0.7 micrograms/kg/hour).
The dose required to achieve optimal sympathetic inhibition and preserve organ function is unknown. However, it must be noted that hepatic dysfunction can hinder the elimination of dexmedetomidine from the body. In addition, it is not recommended as a sedative in patients with severe neurological disorders, especially in the acute phase, due to decreased cerebral blood flow, or in patients with autonomic nervous system disorders.
The use of DEX is also contraindicated in sustained bradycardia or in the presence of symptoms of second- or third-degree heart block, and indeed, if these symptoms occur after administration, the use should be discontinued. Similarly, DEX is not recommended if hypothermia is suspected or occurs as a result of use. There are insufficient data to determine the maximum time limit for the use of this drug; However, continuous dosing is recommended for no more than seven days. Abrupt cessation after a prolonged infusion may cause withdrawal symptoms, so a gradual dose reduction is recommended.
Deep sedation with DEX is difficult, which complicates management in patients with sepsis, especially if propofol or benzodiazepines may be required for the first 48 hours. However, it can also be said that the use of DEX helps to reduce the necessary dose for these other drugs. In addition, DEX improves the quality and duration of sleep without eliminating non-REM sleep, meaning that its effect mimics natural sleep, resulting in a stable sleep-wake circadian rhythm. This is very helpful for critically ill patients who often experience poor quality sleep and non-restorative, unorganized sleep patterns. This factor may also contribute to a lower risk of delirium caused by DEX compared to other sedative medications; However, the evidence currently available is uncertain.
Antipsychotic medications
Although there is conflicting evidence for the efficacy of antipsychotic drugs in the treatment of delirium, and the identification of significant adverse side effects in patients with non-critical illness, these drugs are widely used to treat the condition in the intensive care unit setting. Atypical antipsychotics (quetiapine, aripiprazole, ormitiz, and risperidone) are becoming increasingly popular due to their lower risk of adverse side effects than typical antipsychotics; Specifically, they are associated with a lower incidence of arrhythmias, QT interval prolongation, and neuropathic malignant syndromes, which are particularly intractable in older patients.
Currently, there is some controversy about the need for treatment of suppressed delirium, and as the current trend is to avoid pharmacological treatment, it is recommended to use only non-pharmacological measures. Similarly, there are currently no clear recommendations for any pharmacological treatment for hyperactive delirium. There is little evidence that any medication reduces the incidence of delirium or even the duration of delirium episodes. However, the use of DEX is a reasonable measure for intubated patients, and for patients with hyperactive delirium, the use of DEX in combination with antipsychotic medications is also a reasonable measure. In addition, propofol is also the drug of choice in situations where rapid reduction of delirium-related agitation is required. At the same time, benzodiazepines (especially midazolam and lorazepam) should always be avoided.
analgesic
Pain management in critically ill patients should always be a priority, as long-term immobilization of patients can be uncomfortable and the need for a variety of potentially painful routine procedures in the intensive care unit setting, such as insertion of vascular cannulation, insertion and removal of drains, repositioning, and aspiration of endotracheal secretions. In fact, analgesia should even take precedence over the choice of sedative. In this regard, opioids remain the main mainstay of pain treatment, and opioid analgesics are recommended in intensive care units. While the use of synthetic opioids such as remifentanil has increased, their duration of action is very short, and the most commonly used opioids in critically ill patients are morphine and fentanyl, which have very different pharmacological properties. Of the two drugs, fentanyl has a shorter onset of action; It is also rapidly transported to fat-rich body tissues and metabolized in the liver. Its half-life is greatly affected by the environment, and long-term infusion can prolong the drug's effect. In contrast, morphine is rapidly broken down into active metabolites that accumulate, especially in the case of renal insufficiency, prolonging its active effects. There are few studies comparing these two opioids; However, there does not appear to be much difference in terms of ventilator-free days or length of stay in the intensive care unit. However, for patients with creatine levels greater than 1.7 mg/dL, there is a reasonable preference for fentanyl. Elevated creatine levels are a common symptom in patients with sepsis with kidney damage, in which case intravenous morphine should be used with caution. On the other hand, fentanyl tends to have a lower rate of elimination in older patients, and the elimination half-life is prolonged, which has an impact on ventilator-free days.
Remifentanil is the drug most consistently associated with opioid-induced hypersensitivity pain (OIH) and must be distinguished from acute opioid withdrawal symptoms, particularly in younger patients with prolonged high-dose opioid use. This condition may require the use of additional analgesic medications and therefore prolonged mechanical ventilation. The onset of OIH usually occurs within 45 minutes of stopping the drug and in most cases, it only becomes a significant problem within the first few hours of stopping the drug. However, increased pain sensitivity has also been reported to last up to three months. For patients with renal insufficiency, liver failure, and critically ill nerves, remifentanil can be considered as a treatment to facilitate neurological examination.
Similarly, a multimodal approach can help reduce opioid use. Therefore, paracetamol is recommended as an adjunct to opioids for the treatment of postoperative pain, especially after abdominal surgery where the iliac is at risk or where nausea and/or vomiting is present. In patients with sepsis, the antipyretic effect of paracetamol may be useful in some cases, but care must be taken because taking paracetamol may mask the presence of a peak fever. For cases of neuropathic pain, gabapentin, carbamazepine, and pregabalin are recommended; However, proper precautions must be taken to avoid escalating doses in the setting of renal insufficiency, and these drugs may have an impact on cognitive performance and sedation in some patients. Other adjuvant therapies such as COX-1 selective NSAIDs (due to increased risk of bleeding and kidney injury), ketamine (due to potential neurotoxicity and increased risk of delirium), or lidocaine (due to associated hemodynamic changes) are not recommended.
Choice of medication: combination and rotation of intravenous sedative medications
Sedation in critically ill patients must be constantly adjusted to the needs and goals of their treatment. Modern intravenous agents are routinely used because of their short duration of action and the production of little or no persistent metabolites. However, problems may arise; For example, the level of sedation provided may be inadequate, or dose accumulation may occur, leading to longer weaning times or the occurrence of serious complications such as PRIS. Withdrawal symptoms may also occur when the drug is stopped. Therefore, it is necessary to prepare other treatment options and use them in combination with adequate analgesia, which can be used on a rotational basis or in combination.
SPICE III is the latest large-scale study comparing DEX and propofol in mechanically ventilated critically ill patients. In this study, high doses of two drugs were given (DEX: 1.0 μg/kg/h; Propofol: between 50 and 200 mg/hour), which means that the need for antipsychotics or midazolam is low. By comparing treatment outcomes in patients treated with different drugs, although the difference was not significant, patients treated with DEX had a higher incidence of adverse effects (9.6% vs. 1.8%), mainly hypotension and bradycardia, although in most cases these problems do not require treatment. Patients treated with DEX also required additional medication to achieve the required level of sedation, a result that was also confirmed in a study of MIDEX and PRODEX, where 43.8% and 72.5% of patients required intravenous medication, respectively.
Secondary Bayesian analysis of SPICE III data showed a significant reduction in mortality within 90 days in certain patient populations, particularly non-surgical patients younger than 65 years of age who were sedated with a combination of DEX and propofol, with propofol doses increased to achieve appropriate sedation. And this trend is even more pronounced if it is DEX that is added instead of propofol to provide a complete calming effect. To be sure, the combination of these two drugs can reduce the escalating need for a single drug dose, thereby reducing the risk of dose-related adverse side effects of either drug. However, the effect of the combination of these sedative drugs and their relative doses on mortality remains unknown, as well as the effects of their pharmacodynamic interactions and patient age are yet to be fully understood. Given that the combination of these agents in mechanically ventilated, critically ill patients increases the incidence of hypotension, the routine combination of these intravenous sedatives is not recommended at this time. Although DEX and propofol are the most widely used drugs with patients with sepsis, propofol is considered more appropriate due to the quality of the infusion; This is especially important during the first 48 hours of treatment, when the need is highest and it is difficult to achieve optimal levels of sedation with DEX alone. In addition, while the use of DEX sedation has been shown to significantly reduce the duration of mechanical ventilation and the occurrence of delirium in patients undergoing cardiac surgery, a similar benefit cannot be demonstrated in patients with sepsis compared with other drugs. However, it can be argued that sedation with DEX may be associated with a subpopulation of sepsis patients whose predictive scores show the highest risk of delirium.
Finally, drug selection and dosing have special considerations for obese patients, especially if the patient's BMI exceeds 40 kg/m2. In such cases, the dose regimen needs to be adjusted: propofol and DEX should be given at adequate doses based on the patient's ideal body weight, while antipsychotics such as haloperidol and quetiapine should be given at standard doses.
Effect of inhaled sedative medications
Elevated serum CPK (>5000 IU/L), high triglyceride levels (>400 mg/dL), creatinine, or aminotransferases in patients may be triggers to initiate a rotational regimen of propofol with other agents, or to consider inhalation anesthetics as an alternative.
Currently, there are several devices available for the administration of volatile anesthetics in the ICU: Sedaconda® (Sedaconda-ACD of Sedana Medical, Danderyd, Sweden) and MIRUS® systems (Pall Medical, Dreieich, Germany). Both devices use so-called reflectors to enable the reuse of the exhaled anesthetic in the subsequent inspiratory cycle. Sedaconda can be used for two anesthetics, isoflurane and sevoflurane; And Mirus is not only suitable for these two anesthetics, but also for desflurane.
The Sedaconda is a more basic device with only one infusion rate, which is determined by an electric syringe pump to supply the anesthetic. In contrast, the Mirus system allows the infusion rate to be adjusted by automatically controlling the peripheral concentration target. However, it must be said that Sedaconda has a more efficient reflex system.
In terms of the choice of anesthetic gases, isoflurane is considered most appropriate for long-term use in the intensive care unit (ICU). This result comes from a 2021 study that conducted a non-inferiority trial of isoflurane and propofol in 301 patients. This sample included a variety of patients admitted to the ICU and was not specifically studied in patients with sepsis. The results of the study showed that isoflurane reduced extubation time and opioid use compared to propofol and, crucially, provided evidence of the safety of isoflurane for long-term use, without the greater risk of expected adverse effects than propofol. Desflurane is usually used in anticipation of a longer anesthesia time, but not more than 48 hours, and is currently used less often, both because of the difficulty of administration and because of its higher price.
In addition to some work safety issues that are not discussed in detail here, the limitation of clinical use of inhalers is nephrotoxicity. These drugs are metabolized in the kidneys and are measured by an inorganic fluoride upper limit of 50 micromol/L established by experience with methoxyflurane. However, follow-up studies have failed to establish an association between this threshold and kidney damage. Isoflurane produces inorganic fluoride ions through conjugated metabolism and excretes them in the urine, and it must be emphasized here that the rate of metabolism of this drug is much lower than that of sevoflurane (0.2% vs. 5%); Therefore, in the case of isoflurane, fluoride toxicity is not related to the kidneys.
Clinicians often have the most experience with the Sedaconda device because it is much more widely used in the intensive care unit than other devices. Therefore, the following discussion will focus on the use of this device.
In this section, we aim to identify indications for inhaled sedative therapy based on the clinical status of patients with comorbidities and sepsis. However, it is important to emphasize that sedation cannot be considered as a therapeutic tool on its own, and that the first step in treatment is to provide effective analgesia according to the protocol developed by eCASH, from which we can further determine the minimum level of effective sedation. Next, we will consider the clinical context in which inhaled sedatives are appropriate.
Special circumstances to consider in patients with sepsis
Sepsis with ARDS
Pulmonary involvement is common in patients with sepsis, regardless of whether the cause of sepsis is respiratory or otherwise. In fact, the abdominal region is the second most common place of origin of sepsis associated with this complication.
In a live pig model, the use of sumaflurane improves oxygenation in patients with endotoxin-induced respiratory distress disorder compared to propofol. These models also show evidence of a reduction in levels of systemic inflammatory factors. It is thought that the pathophysiological explanation for the beneficial effects observed by volatile anesthetics in patients with sepsis is based on their immunomodulatory effects, especially on neutrophils, macrophages, T cells, B cells, and natural killer cells. In human patients with moderate or severe respiratory distress, an improvement in pO2/FiO2 values was seen at 48 hours after treatment with sumaflurane, along with a reduction in the level of markers of epithelial cell damage; However, there was no difference in mortality compared to patients treated with midazolam.
When the cause of respiratory distress is a primary infection of the respiratory tract, it is important to note that inhaled drugs have been shown to have antimicrobial effects against Streptococcus pneumoniae and Haemophilus influenzae. These drugs also exhibit antimicrobial effects against trauma-resistant strains of bacteria in liquid form, and their inhalation (especially isoflurane) has been speculated to protect against ventilator-associated pneumonia infection. In addition, inhaled medications, particularly sevoflurane, are considered bronchodilators and work very well in patients with asthma and have been proposed as a treatment option for patients with sepsis in respiratory distress. In a slightly different context, recent studies in patients with COVID-19 infection have shown that sedation with isoflurane is associated with improved arterial oxygenation and reduced opioid consumption.
The negative effects of ARDS related to inhalers are mainly related to the addition of dead space in the device used for drug administration. The dead space problem is a problem inherent to both Sedaconda and Mirus, and in the case of Sedaconda, in order to solve this problem, there are two improved devices: the L version and the S version. The most complex of these is the S version, which has a dead space size equivalent to that of a conventional HME filter, i.e. a minimum tidal volume of 200 ml. Comparing the S and L versions of the device under normal use conditions, gas monitoring showed that the former significantly reduced pCO2, while the reflectivity of the activated carbon film was only slightly reduced. Therefore, there is no doubt that the Sedaconda-S is the device of choice for patients with ARDS.
Currently, clinical trials are underway comparing sevoflurane and midazolam in patients with dyspnea. The study is expected to include 700 patients, and the primary objective of the trial is to assess the number of days without mechanical ventilation, followed by recording mortality to develop a set of guidelines on the use of inhaled sedatives.
Patients with sepsis have myocardial dysfunction
It is well known that myocardial dysfunction in patients with sepsis is associated with a 20% to 50% increase in mortality. The etiology is unknown, but it is associated with three mechanisms whose importance varies from patient to patient: myocardial ischemia, direct damage to inflammatory mediators, and mitochondrial dysfunction associated with sepsis. Clinical manifestations include wall contraction or diastolic dysfunction and dilation.
One of the most important and persistent mechanisms of myocardial dysfunction is ischemia, in the case of septic shock, high levels of markers of myocardial damage are observed, leading to the phenomenon of so-called myocardial dormancy. It is an adaptive phenomenon designed to protect the body from the adverse effects of ischemia, conceptually similar to cardiac post-processing. In this case, inhaled sedatives have a particularly beneficial effect; For example, studies in mouse models have shown that the combination of nitric oxide and sevoflurane can reduce myocardial damage. Regarding the elevation of markers of myocardial injury, sevoflurane, among other advantages, has been shown to have protective properties, especially in relation to the use of less vasopressors in cardiac surgery compared to intravenous sedation.
Therefore, the use of inhaled sedative drugs in sepsis patients with a history of myocardial ischemia is a reasonable choice. In fact, several guidelines, such as the American College of Cardiology or the American Heart Association, rank volatile anesthetics as Class IIA for maintenance anesthesia during noncardiac surgery due to their cardioprotective and vasodilatory effects. Once technology is able to administer and monitor inhaled drugs in the ICU as in the operating room, this recommendation for perioperative procedures can also be applied to the ICU. However, there are currently no recommendations for the use of volatile anesthetics to exert their cardioprotective effects.
Sepsis-associated encephalopathy
The central nervous system (CNS) is one of the earliest organs affected by sepsis, and its clinical manifestations are known as sepsis-associated encephalopathy (SAE). The incidence of SAE is about 50%. Its pathophysiology includes tissue damage due to neuroinflammation, vascular changes, and metabolic dysfunction. The affected central regulatory centers include autonomic control, arousal, consciousness, and behavioral centers, explaining the clinical features of SAE, ranging from disease behavior to impaired consciousness (i.e., from delirium to coma).
SAE refers to the combination of extracranial infection with the clinical presentation of neurological dysfunction. Clinical manifestations of SAE include impaired consciousness, ranging from delirium (50%) to coma (46%). Sepsis-associated delirium (SAD) is one of the symptoms of SAE.
Delirium states often develop in intensive care units, and the prevalence of each phenotype, defined by clinical risk factors, has been studied. Of the 1040 patients, 71% were diagnosed with a state of confusion at some point during their hospital stay: 64%, 56%, 51%, 25%, and 22% of sedative-related, hypoxic, septic, metabolic, and unclassified disorders, respectively.
There are many risk factors for SAD and SAE: older age, history of chronic alcohol abuse, neurological disorders, pre-existing cognitive dysfunction, long-term use of psychoactive drugs, acute renal failure, hyperglycemia, hypercapnia, hypernatremia, and Staphylococcus aureus sepsis. With regard to pharmacological measures, studies have published the association between benzodiazepine use and one-year mortality in hospitalized patients on mechanical ventilation for more than 48 hours. Benzodiazepines are associated with the development of delirium, which in turn is associated with prolonged duration of mechanical ventilation, prolonged admission to the intensive care unit, and increased risk of death, disability, and long-term cognitive impairment. Therefore, current guidelines do not recommend the use of benzodiazepines in settings other than alcohol withdrawal syndrome.
Benzodiazepine is not recommended as the treatment of choice for sedation, however, the risk of SAD with other sedatives remains unclear. A recent systematic review evaluated the efficacy and safety of DEX with other sedatives in adults mechanically ventilated in the ICU and found that DEX significantly reduced the risk of delirium, duration of mechanical ventilation, and length of ICU stay; However, DEX did not reduce the risk of dying within 30 days compared to other sedatives.
Post-intensive care syndrome (PICS) is currently the focus of research focusing on the long-term prognosis of patients after clinical treatment, and includes three main components: physical dysfunction, psychiatric disorder, and cognitive dysfunction. Cognitive dysfunction is directly affected by delirium and is produced through nerve damage. The occurrence of delirium was identified as an independent risk factor for long-term and permanent cognitive dysfunction in ICU patients, including those with sepsis. Therefore, taking some measures, such as avoiding benzodiazepines that may be beneficial for the development of delirium, may help improve the prognosis of PICS.
Continuous renal replacement therapy and extracorporeal membrane oxygenation
There is a very limited literature of references and recommendations in this area, particularly with regard to extracorporeal membrane oxygenation (ECMO). Midazolam is mainly metabolized by CYP3A enzymes to produce 1-OH-midazolam, and a small amount to 4-OH-midazolam. After hydroxylation, 1-OH-midazolam is further metabolized to its main metabolite, 1-OH-midazolam glucoside, which is excreted by the kidneys. Previous studies have shown that 1-OH-midazolam and 1-OH-midazolam glucoside have 60-80% and 10% sedative efficacy compared to midazolam, and therefore may result in unexpectedly sustained sedative effects when used in patients with renal failure. Midazolam and 1-OH-midazolam are not highly effective in continuous renal replacement therapy (CRRT), with approximately 43% of 1-OH-midazolam glucoside cleared by CRRT. The treatment mode of CRRT, filter patency, and CRRT line downtime all affect the clearance of the pharmacologically active metabolite 1-OH-midazolam glucoside. Therefore, the use of midazolam during CRRT should prompt a reduction in the midazolam dose to minimize the adverse consequences of excessive sedation.
A retrospective study of 74 patients showed that patients treated with propofol during continuous renal replacement therapy (CRRT) required a higher total dose and longer infusion duration to maintain good sedation. Clearance of propofol and stable maintenance of plasma concentrations were the same in both CRRT and non-CRRT groups. Previous studies in 10 patients showed no increase in propofol consumption, but the initial introduction of cardiopulmonary bypass led to a decrease in plasma concentrations in most patients. Several cases of early CRRT circulating clots have been reported in the context of the use of propofol and accompanied by hypertriglyceridemia. The exact pathophysiology of CRRT clots due to hypertriglyceridemia has not been fully elucidated.
Preliminary investigations suggest that the introduction of ECMO may significantly alter the pharmacodynamics of drugs in three ways: (1) the drug is immobilized in the circuit; (2) the volume of distribution increases; and (3) changes in drug clearance. For propofol, DEX, and midazolam, a higher than usual daily dose is recommended, suggesting significant intra-circuit drug fixation. However, field studies that have been conducted have not shown an increase in the need for sedatives, especially propofol and DEX.
Based on these data, the only firm recommendation that can be made in this case is close clinical monitoring.
Conclusion and future directions
Clinicians are fully aware of the importance of proper sedation and analgesia to ensure the best possible outcome for patients. This has become clear from changes in practice, such as the avoidance of benzodiazepines in critically ill patients due to their association with a high risk of death. However, different members of the intensive care unit team responsible for caring for a particular patient may have different priorities for sedation goals, so ensuring good communication between team members is critical to achieving consensus on the basis of each patient. In addition, there is a significant nursing workload associated with infusion and administration of sedation and analgesia; Therefore, nurse involvement and training are essential in the sedation procedure, and they must not only be trained in the infusion of the relevant medications, but also learn to use a variety of scoring scales for clinical assessment of analgesia, sedation, and delirium.
The purpose of this article is to convey the importance of personalizing sedation and analgesia to the needs of individual patients with pathology and comorbidities. For critically ill patients, as with other medical procedures they receive in the intensive care unit, such as haemodynamic monitoring or ventilation, individualized sedation and pain relief is the only right way to achieve the best possible outcome for all patients. In fact, we must move beyond simply avoiding certain drug classes to the concept of "goal-oriented sedation" and make the most of the treatments currently available.
With all this in mind, Table 2 presents a series of recommendations regarding sedation in patients with sepsis. These recommendations are intended to summarize the information presented in this article and should be interpreted flexibly and reassessed frequently with each progression of the patient's condition. We recognise the limitations of our recommendations, as some of them are based on limited evidence to support them. However, we are willing to risk criticism as long as we can draw attention and instill the notion that the best analgesic and sedative regimen should be sought on a case-by-case basis.
Based on current evidence, propofol should be the preferred sedation option in most clinical settings, particularly in cases where deep sedation is required for ARDS with hypercapnia and cardiomyopathy, and the dose should be carefully titrated. In cases of cardiomyopathy and the need for prolonged sedation, isoflurane may be considered as an alternative. We must distinguish cardiomyopathy from those with high demand for vasopressors, which may be shown to have a more beneficial effect than propofol when inhaled. We should take full advantage of the anti-inflammatory properties of inhaled drugs for hypoxic ARDS, making them the treatment of choice. In mildly sedated patients with delirium, DEX should be the drug of choice, and propofol can be used if agitation occurs.
In the context of hepatic insufficiency, and given the poor reproducibility of the pharmacokinetic model of propofol, we recommend looking for alternatives, such as the choice of isoflurane. For cases of renal insufficiency, sevoflurane is not suitable, and propofol and isoflurane should be considered as the main options for prolonged sedation.
Alternating between propofol and inhaler should be considered during prolonged sedation to minimize the side effects associated with prolonged infusions. Based on current evidence and options, benzodiazepines should only be used in specific settings, such as alcohol withdrawal symptoms.
Finally, the number of publications on sedation is growing exponentially every year, which has contributed to the rapid development of the field of clinical practice. It is therefore likely that, over time, many of the doubts raised by the recommendations made in table 2 will be resolved.