In 1955, the pioneer dedicated Pediatric Intensive Care Unit (PICU) was established in Europe, and pediatric critical care medicine has only been accepted as a distinct specialty since 1981 (1). Many pediatric critically ill patients in these units require life-saving measures, including mechanical ventilation (MV), continuous renal replacement therapy, and extracorporeal membrane oxygenation therapy. These interventions are associated with a protracted PICU stay and the need for analgosedation (2).

Unfortunately, several essential analgesic and sedative agents have been depleted globally primarily due to increased needs and the disruption of manufacturing and supply chains (3). In 2016, the World Health Organization proactively took a stand about the lack of essential medicines, reported in low, middle, and high-income countries. The scarcity of drugs poses risks to the patient's health due to non-treatment, undertreatment, and failure to find suitable alternatives (4).

This review aims to: (1) provide the reader with information regarding drug supply chain issues; (2) highlight the levels of service for dispensing medicines: conventional, contingency and crisis, emphasizing the role of pharmacists in the rationing of them; (3) address the relevance of appropriate management of analgesia and sedation in the PICU; and (4) present dose optimization strategies regarding analgo-sedative choices in addition to considering different approaches to preventing medication overuse.

Numerous definitions for drug shortages have been widely used, as shown in Table 1. Unfortunately, there is a lack of a standardized definition. Moreover, the low and middle-income countries have the absence of an official description (5).

Drug shortages are recognized as a global issue (4) and are usually due to several factors. Drug shortage affects high, middle, and low-income countries. In high-income countries, it has more attention when compared to other regions of the globe. The supply chain for delivering raw materials to patient use is complex and involves multiple entities, including manufacturers, group purchasing associations, wholesalers, and healthcare systems. On the manufacturing side, drug shortages occur due to lack of raw materials, regulatory problems, manufacturing interruptions, voluntary and involuntary recalls, promotion reduction (such as patent expiration or generic drug profitability), or manufacturer consolidations. Moreover, drug shortages also occur due to improper stocking practices, changes in clinical practice (resulting in increased demand), and even supply chain disruption due to natural disasters. Otherwise, low-middle income countries have some novel reasons for drug shortage, comprising licensing of manufacturers/products, shortage of raw material for a local producer, drug smuggling, and lodging tax government practices. These countries have insufficient research and lack policies to deal with this problem (5–7).

During a major disaster, such as a pandemic or war, for example, it is necessary to forecast and manage the shortage of drugs essential to critical care from global, national, regional, and institutional perspectives. Drug shortages can be expected to coincide with an interruption of other necessary resources such as personnel, availability of personal protective equipment, and medical devices. Supplies for drug preparation and administration can also be scarce (3).

Burry et al. summarized the main strategies that stakeholders must consider for future steps during a global disaster from the worldwide level to the institutional approach:

Given this situation, the role of pharmacists in alleviating the current crisis and future challenges is a central one. Notably, among the pharmacist's actions is advocacy for implementing the Interagency Drug Shortage Task Force recommendations by participating in dedicated drug shortage task forces or rationing committees to guide management strategies and keeping informed regarding drug shortages (9).

Finally, Ammar et al. suggest that drug escalation capacity and response be measured based on three levels: conventional care, contingency care, and crisis care. Contingency care comprises all the practices that may be outside usual care notwithstanding they attempt to keep traditional care. On the other hand, crisis care approaches are outside of standard of care, however, provide the best feasible care when resources are severely limited (10).

Children have unique illnesses and are at a singular developmental stage that may need specific medications for which there may not be therapeutic alternatives. Additionally, the evidence supporting the use of substitutes may be limited in pediatric patients and may raise concerns for adverse events. Therefore, a comprehensive and multidisciplinary approach is necessary to ensure that drug shortages do not lead to unfavorable patient outcomes (11).

Alleviating pain and anxiety in critically ill children may be quite challenging. Patient admission and daily care processes within PICUs can be frightening and painful for pediatric patients and their families. Pain can result from the underlying disease or trauma and can be exacerbated by anxiety and emotional stress, two common elements of the PICU stay. The condition in which children find themselves in this environment, surrounded by strange people and machines, separated from their parents, in a hostile, noisy, and bright place most of the time, leading to the interruption of the circadian cycle, causes more anxiety and vulnerability to pain. Pain may also result from diagnostic and therapeutic interventions to which patients are submitted during the hospitalization period. In intensive care, children, and newborns (NB) are often subjected to numerous potentially uncomfortable or painful procedures, such as arterial and venous punctures, thoracic drainage, and endotracheal intubation. These therapeutic interventions place an enormous burden on these patients, affecting the successful performance of these procedures and the patient's recovery (12–16).

An effective analgesia approach facilitates invasive procedures or interaction with invasive equipment such as MV and enhances rehabilitation of the critically ill patient (12). Accurate assessment of pain and comfort using validated scales with targeted, measured goals is central to excellent clinical management (13).

Adequate analgesia and sedation minimize the stress response and improve clinical and psychological outcomes. When inadequate, negative outcomes include undertreated pain or persistent agitation leading to accidental removal of invasive devices. On the other hand, oversedation results in prolonged PICU and hospital stay, prolonged MV, and the development of tolerance, physical dependence, iatrogenic withdrawal syndrome (IWS), and delirium. Accurate assessment of pain, distress, IWS, and delirium in critically ill children can be challenging as these conditions often overlap. The use of validated assessment scales as outlined in the recent PANDEM guidelines facilitates assessment guiding proper care and mitigating their development (12, 17).

The 2018 Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU (PADIS Guidelines) have recommended the approach to sedation as “analgesia first” (before sedation) or analgesia-based sedation, which implies that an analgesic (usually an opioid) is used before a sedative to achieve the desired sedative goal. Institutions should have protocols that include periodic evaluations of pain and sedation using validated tools and provide clear guidance on the choice and dose of the drug, ensuring that pain treatment is a priority over the administration of sedatives (18). Recently, Smith et al. developed Society of Critical Care Medicine (SCCM) clinical practice guidelines for critically ill pediatric patients, including pain, sedation/agitation, iatrogenic withdrawal, neuromuscular block, delirium, PICU environment, and early mobility. Key areas included the need for routine monitoring of pain, agitation, withdrawal, and delirium using validated tools in children; improved use of protocol sedation and analgesia, and recognition of the importance of non-pharmacological interventions to improve patient comfort and provision of comprehensive care (17).

The SCCM developed a multicomponent and evidence-based six-step strategy to liberate patients from the ICU. This approach, called “the ABCDEF bundle,” represents A: Assess, prevent, and manage pain; B: Both Spontaneous Awakening Trials (SATs) and Spontaneous Breathing Trials (SBTs); C: Choice of sedation; D: Delirium assessment, prevention, and management; E: Early mobility and exercise; and F: Family engagement and empowerment. The conceptualization of the proposed “ICU Liberation” achieved notable recognition in adult critical care research and has become prominent in PICU. In a recent survey of 161 PICUs in 18 countries, Ista et al. observed that, unfortunately, the A-F bundle items have been adopted with substantial variability internationally (19).

We should emphasize that providing analgosedation is not restricted to the PICU environment. Currently, with the exponential growth in the number of procedures in children and adolescents experience outside the operating room, there has been a greater need for awareness and guidance on procedural sedation by professionals who are not anesthesiologists, including emergency departments, wards, outpatient clinics, imaging centers, and dental offices (20, 21).

Regarding drug shortages, in the specific case of analgosedation, one of the recommended approaches to conserving intravenous analgesic supplies during contingency care is to implement protocols where clinicians would initially use intermittent analgesic boluses before patients transition to continuous infusion. In addition, enteral delivery of opioids and analgesics may help to conserve the supply of intravenous (IV) agents. However, this strategy should be limited to patients with adequate gastrointestinal motility and function. Other situations can also be considered. For example, ketamine has analgesic properties and may spare the use of IV opioids. Furthermore, it is not known to cause significant respiratory depression at moderate doses, and this is advantageous when trying to transition the child off MV (10).

With regard to benzodiazepines, they can also be administered in intermittent doses or as a continuous infusion to obtain mild sedation. However, they should only be considered as first-line sedatives in contingency care settings. When used, IV lorazepam, midazolam, or diazepam in scheduled doses or as needed, can help to conserve drug stocks in the scenario of ongoing shortages. This approach can limit overall sedative exposure while still providing appropriate light sedation, preserving the need for high doses and continuous infusions known to be associated with accumulation. However, if this is not sufficient for adequate sedation, continuous infusion of benzodiazepines can be started. Still intermittent doses may be reconsidered again when continuous infusion is no longer needed and transition from continuous infusion to a less aggressive dose is appropriate (10).

Analgo-sedative regimen selection should take into consideration patient-specific risk factors, targeted level of sedation, anticipated duration, analgesic needs, physician familiarity, and institutional formulary availability. The following strategies that ensure comfort and optimize dosing of analgesics and sedatives. Applying these strategies can be challenging for teams unfamiliar with these measures, particularly when human resources are scarce, and family presence is restricted.

Care of critically ill children during conditions of scarcity of analgesic and/or sedative drugs has presented numerous challenges globally. Effective approaches to managing drug shortages, implementing evidence-based guidelines for evaluating pain and delirium, and understanding alternative pharmacological and non-pharmacological options for analgesia and sedation will ensure safe and effective management of pain and delirium in the setting of limited resources or future disasters.

RC conceptualized and wrote the first draft of the review. MR-R, MM-B, AP-B, and JH made substantial contributions to the conception, design, literature data, and content of the tables. PK and AS drafted the article and revised it critically for important intellectual content. All authors approved the final version to be published.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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