Complications and Pharmacologic Interventions of Invasive Positive Pressure Ventilation During Critical Illness

Abstract

Objective: To review the fundamentals of invasive positive pressure ventilation (IPPV) and the common complications and associated pharmacotherapeutic management in order to provide opportunities for pharmacists to improve patient outcomes. Data Sources: A MEDLINE literature search (1950-December 2017) was performed using the key search terms invasive positive pressure ventilation, mechanical ventilation, pharmacist, respiratory failure, ventilator associated organ dysfunction, ventilator associated pneumonia, ventilator bundles, and ventilator liberation. Additional references were identified from a review of literature citations. Study Selection and Data Extraction: All English-language original research and review reports were evaluated. Data Synthesis: IPPV is a common supportive care measure for critically ill patients. While lifesaving, IPPV is associated with significant complications including ventilator-associated pneumonia, sinusitis, organ dysfunction, and hemodynamic alterations. Optimization of pain and sedation management provides an opportunity for pharmacists to directly affect IPPV exposure. A number of pharmacotherapeutic interventions are related directly to prophylaxis against IPPV-associated adverse events or aimed at reduction of duration of IPPV. Conclusions: Enhanced knowledge of the common complications, associated pharmacotherapy, and monitoring strategies facilitate the pharmacist’s ability to provide increased pharmacotherapeutic insight in a multidisciplinary intensive care unit setting.

Introduction

Invasive positive pressure ventilation (IPPV) is a supportive care modality utilized in over 750 000 patients annually with an associated estimated cost of $27 billion, or 12% of all hospital costs. Moreover, these patients are critically ill with in-hospital mortality estimated as high as 35%.^1,2 From a pharmacist perspective, pharmacotherapy regimens are highly complex with up to one third of patients in an intensive care unit (ICU) having more than 20 medications prescribed. In the same study, 70% of patients were prescribed more than 13 medications at any given point.³

IPPV is a complex therapeutic intervention that requires both theoretical understanding of the principles in addition to practical knowledge of how this intervention interplays with patient assessment and management. Pharmacotherapy and IPPV management are interdependent, and pharmacist knowledge of IPPV will enhance the ability to provide high-quality interventions that improve patient outcomes. Indeed, IPPV creates opportunities for pharmacist interventions that reduce length of stay (LOS) and duration of mechanical ventilation.^1,2

Indications for IPPV can be broadly categorized into hypoxemic respiratory failure, hypercapnic respiratory failure, and apnea.⁴ The 5 causes of hypoxemia are categorized as hypoventilation (eg, central nervous system [CNS] depression, obesity hypoventilation), ventilation-perfusion mismatch (eg, obstructive lung disease, interstitial disease), right-to-left shunt (eg, anatomic shunts, physiologic shunts such as atelectasis or pneumonia), diffusion impairment (eg, pulmonary fibrosis, exercise-induced), or reduced fraction of inspired oxygen (eg, high altitudes).⁵ Common causes of hypercapnic respiratory failure include chronic obstructive pulmonary disorder (COPD), severe asthma, neuromuscular skeletal diseases such as myasthenia gravis or traumatic brain injury, and situations of decreased respiratory-motor drive such as CNS infections or malignancy.⁶ Increased work of breathing (WOB), which is assessed by facial signs, accessory muscle recruitment, tachypnea, and abnormalities in chest wall movements, may also be an indication for IPPV. Another common indication is increased WOB: while WOB accounts for approximately 1% to 3% of total oxygen consumption in healthy adults, studies of patients with acute hypoxemic respiratory failure and shock demonstrate that respiratory muscles account for 20% of total oxygen consumption, ultimately a nonsustainable physiologic state.⁷

The goals of IPPV management follow the 3 general principles of critical care: to reverse the indication for IPPV, to provide supportive care to allow for reversal of the underlying indication, and to minimize risks and complications to the patient during the first 2 processes. Specific objectives of IPPV include ensuring adequate oxygenation and ventilation while also minimizing ventilator-induced lung injury, patient-ventilator asynchrony and discomfort, and duration of IPPV.⁴

All pharmacists play an essential role in each of these goals. Indeed, a commonly used ICU mnemonic recommends that evaluation of “FAST HUGS BID” be performed twice daily on all critically ill patients (Feeding, Analgesia, Sedation, Thromboembolic Prophylaxis, Head of Bed Elevation, Ulcer [Stress] Prophylaxis, Glycemic Control, Spontaneous Breathing Trial, Bowel Regimen, Indwelling Catheter Removal, and De-escalation of Antibiotics).^8,9 Strikingly, 8 of the 11 parameters are medication related, and a recent trial showed that pharmacists positively improve adherence to spontaneous breathing trial (SBT) protocols as well.^2,10,11 The purpose of this review is to discuss the fundamentals of IPPV and the complications and pharmacologic interventions commonly associated with IPPV to provide increased insight into the role pharmacists play in this common supportive care modality.

Data Sources

A literature search identified clinical trials, case reports, and reviews that evaluated IPPV. The PubMed database was searched for English-language reports published between 1950 and December 2017 using the key search terms invasive positive pressure ventilation, mechanical ventilation, respiratory failure, ventilator associated organ dysfunction, ventilator associated pneumonia, ventilator bundles, and ventilator liberation. Additional references were identified from a review of literature citations.

Study Selection and Data Extraction

All English-language original research and review reports were evaluated.

Data Synthesis

Fundamentals of IPPV

Essential knowledge of the fundamentals of IPPV allows the pharmacist to incorporate IPPV as a medication monitoring parameter. A summary of IPPV terminology is provided in Table 1.⁴ IPPV refers to specific form of mandatory ventilation (MV) involving the use of positive pressure and an invasive airway device such as an endotracheal tube (ETT) or tracheostomy. IPPV may be broken into discussion of control variables, phase variables or targeting schemes, breath sequence, and mode of ventilation.

Table 1.

Mechanical Ventilation Terminology.

Ventilator variables

Control variable: a predetermined variable within the equation of motion for the respiratory system

Phase variable: a variable that is measured and used to start, sustain, and end each phase of respiration

Trigger variable: a variable that is measured and results in the initiation of inspiration

Target variable: a variable that the ventilator attempts to achieve and maintain before the end of inspiration

Cycle variable: a variable that is reached and used to end inspiration

Ventilator settings

Tidal volume (VT): a volume of gas inhaled and exhaled during a respiratory cycle (mL)

Respiratory rate: number of breaths per minute (breaths/minute)

Fraction of inspired oxygen (FiO2): the percentage of oxygen that is administered to the patient (%)

Positive end expiratory pressure (PEEP): a pressure setting that maintains airway pressures above atmospheric pressure during the exhalation phase of a breath (cm H2O)

Ventilator modes

Continuous mandatory ventilation (CMV): a mode that provides only mandatory breaths and does not allow for any spontaneous breaths

Intermittent mandatory ventilation (IMV): a mode that allows for the patient to take spontaneous breaths between mandatory breaths

Synchronized intermittent mandatory ventilation (SIMV): a form of IMV that synchronizes mandatory breaths by triggering the breath with patient effort

Continuous spontaneous ventilation (CSV): indicates that all breaths are spontaneous and dictated by the patient

Volume control (VC): a volume-targeted, time-cycled mode in which the machine delivers the same VT during every inspiration, whether initiated by the machine or the patient

Pressure control (PC): a pressure-targeted, time-cycled mode of ventilation with maximal airway and alveolar pressures limited by the cap of preset pressure; VT, flow, minute ventilation, and alveolar ventilation are dependent on impedance of the respiratory system

Pressure regulated volume control (PRVC): a pressure-limited, time-cycled mode of ventilation that targets average VT; like PC, a constant pressure is applied throughout inspiration regardless of whether it is a control or assist breath; the system adjusts the pressure from breath to breath based on changes in the patient’s airway resistance in order to deliver the preset VT; PRVC compares each VT with the preset VT so that if the delivered volume is to low it increases the inspiratory pressure on the next breath or vice versa to stay within the preset ranges

Pressure support (PS): a mode of pressure-targeted partial ventilator support that is flow-cycled with each breath patient-triggered and machine supported; utilized to facilitate ventilator weaning

Airway pressure release ventilation (APRV): a pressure-limited, time-cycled (Thigh and Tlow), lung protective mode that that allows for unrestricted spontaneous breathing independent of ventilator cycling; ventilation occurs between the time-cycled switching between 2 set pressure levels (Phigh and Plow) in a CPAP circuit; a very similar setting to BIPAP, APRV is more frequently associated with lung-protective modes and more extreme I:E ratios

Biphasic positive airway pressure (BIPAP): see APRV; indistinguishable from APRV when the same I:E settings are used and often used interchangeably due to minor differences based on largely proprietary differences

Proportional assist ventilation (PAV): a synchronized mode of ventilation that generates pressure support in proportion to instantaneous patient effort; there is no target flow, VT, or airway pressure targets

High-frequency ventilation (HFV): a lung-protective mode that uses high respiratory rates and low VT that are less than the dead space in the lung

High-frequency percussive ventilation (HFPV): a form of HFV that combines high-frequency ventilation and conventional pressure-cycled ventilation (also known as volume diffusive respirator or VDR)

High-frequency oscillation ventilation (HFOV): a form of HFV that accomplishes gas transport with quasi-sinusoidal flow oscillations and that acts as a mixing device that rapidly blends high oxygen/low carbon dioxide content air with air from the alveoli

High-frequency jet ventilation (HFJV): a form of HFV frequently used in pediatric patients that uses high-velocity (“jet”) flow to achieve high respiratory rates with low VT

Ventilator terminology

Mandatory breath: a breath that is triggered and cycled by the ventilator

Spontaneous breath: a breath that is triggered and cycled by the patient

Minute ventilation: the amount of air that a person breaths per minute (MV = RR × VT)

Rapid shallow breathing index, Tobin-Yang index (RSBI): screening index utilized to assess patient readiness for extubation; RSBI < 105 breaths/min/L associated with extubation success (RSBI = RR/VT)

Mean airway pressure (MAP): the pressure applied during MV and correlates with alveolar ventilation and oxygenation

Control Variables

From a mechanical perspective, ventilation is a function of force (or pressure), displacement (or volume), and the rate of changes of displacement (or flow).⁴ The relationship among these variables is described by the equation of motion for the respiratory system.¹² The 2 primary control variables are pressure and volume, where one is the independent variable while the other is the dependent variable.

Phase Variables

The respiratory cycle can be divided into 4 phases: inspiration, the change from inspiration to expiration, expiration, and the change from expiration to inspiration.¹³ Phase variables, including pressure, volume, flow, and time, are measured and used to start, sustain, and end each phase (see Figure 1A). In an IPPV system, one breath is defined as one cycle of inspiration (positive flow) and expiration (negative flow) and may be classified by the start (trigger) and stop (cycle) of inspiration (see Figure 1A). For example, the patient or machine may trigger a breath based on various criteria such as time elapsed since the last breath or patient generated negative inspiratory pressure.

Figure 1.

Phases and types of respirations.

(A) The 4 phases of the breathing cycle are depicted and defined by the trigger, cycle, and target variables. The trigger variable is the measured variable that results in the initiation of inspiration. A target variable is what the ventilator attempts to achieve and maintain before the end of inspiration. Of note, this is not the variable that signals the end of inspiration. A target is used because although it is the aim of the ventilator, the ventilator does not always achieve this target; instead, the target variable can be thought of as an average objective achieved over time. The variable that is reached and then used to end inspiration and begin expiration is called the cycle variable. (B) In patient-triggered breaths, the machine senses negative inspiratory effort and initiates a breath. In the absence of a patient-triggered breath, the machine will deliver a breath after a certain time period has elapsed.

Breath Sequences

Three possible breath sequences exist that may be a combination of spontaneous breaths, assisted breaths, and mandatory breaths, with various combinations creating the 3 basic breath sequences: continuous mandatory ventilation (CMV), intermittent mandatory ventilation (IMV), and continuous spontaneous ventilation (CSV). In a spontaneous breath, the patient determines both the timing (eg, when inspiration is started and ended) and the volume, with the machine registering a patient initiated breath by the negative pressure or flow generated. An assisted breath occurs when the ventilator provides some support, through an increase in airway pressure above baseline during the inspiration or below baseline during expiration. In contrast, a mandatory breath is triggered and cycled by the ventilator (see Figure 1B). With synchronized IMV (SIMV), the mandatory breath is triggered by the patient through the setting of the trigger variables and ultimately works to minimize dyssychrony.⁴

Mode of Ventilation

The mode of ventilation is defined as the preset pattern of patient-ventilator interactions that are designed to achieve various goals and objectives. The most common modes of ventilation include pressure support (PS), volume control (VC), pressure control (PC), and pressure-regulated volume control (PRVC; see Figure 2A). PS is a pressure-targeted, patient-triggered mode of ventilation that provides partial respiratory support synchronized with the patient’s (preserved) respiratory drive, and PS trials are the cornerstone of IPPV weaning. In VC, the tidal volume (V_T) is constant while pressure will steadily increase throughout inspiration, while in PC, the V_T will vary in order to obtain constant pressure throughout inspiration (see Figure 2A). PRVC aims to provide volumes within a target range while also maintaining pressures within a target range by adjusting the delivered V_T after every breath.⁴ In this way, PRVC has a flat pressure curve (denoting constant pressure through the breath) similar to PC but maintains a V_T in a prespecified range similar to VT (see Figure 2A).

Figure 2.

Flow, pressure, and volume curves VC, PRVC, PC, and inverse-ratio ventilation.

(A) Flow, pressure, and volume patterns for volume control (VC), pressure-regulated volume control (PRVC), and pressure control (PC). Decelerating flow allows for constant pressures to be achieved in PC and PRVC. Inverse ratio ventilation alternates between 2 pressures (P_high and P_low) over 2 time intervals (T_high and T_low). (B) Inverse ratio ventilation achieves elevated mean airway pressure (MAP), helpful for lung recruitment and oxygenation, through maintaining a prolonged T_high or prolonged inspiratory period. In airway pressure release ventilation (APRV), the patient can breathe spontaneously throughout all phases of the breathing cycle, which contributes to minute ventilation and mitigates carbon dioxide accumulation.

The limitations of traditional modes of ventilation have spawned the next stages of IPPV, and additional modes include, but are not limited to, adaptive support ventilation, airway pressure release ventilation (APRV), proportional assist ventilation, mandatory minute ventilation, and neurally adjusted ventilator assistance.¹⁴ Although the novel nature of these modes has made their place in practice far from solidified, they likely represent the next phase in ventilator technology. In particular, APRV is an advanced mode of ventilation that alternates between 2 pressures (P_high and P_low) over 2 time periods (T_high and T_low) while allowing the patient to breath spontaneously at any phase in this cycle.⁴ APRV uses an inverse inhalation to exhalation (I:E) ratio characterized by long inspiration times and short expiration times.¹⁵ Spontaneous respirations contribute to increasing minute ventilation and can reduce the risk of hypercapnia. Because patients may breath at any time, APRV may reduce the need for sedation and even paralysis; however, if APRV is used in the absence of spontaneous breathing activity, the mode simply becomes a time-cycled inverse I:E ratio ventilation strategy with a risk of subsequent hypercarbia.¹⁶ Spontaneous breathing activity in APRV not only contributes to minute ventilation but also has demonstrated beneficial effects on airflow dynamics and lung recruitment.^15,17,18 APRV is an option when traditional modes of ventilation fail to achieve oxygenation goals in refractory hypoxemic respiratory failure and acute respiratory distress syndrome (ARDS).^19,20 Of note, refractory ARDS may be managed with multiple interventions including APRV and neuromuscular blocking agents (NMBA); however, NMBAs and the associated deep sedation required often inhibit spontaneous respirations occurring in APRV, and it may be reasonable to transition to a different mode of ventilation with the initiation of NMBA.²¹

For a pharmacist evaluating IPPV therapy, some clinical pearls include the following:

• The set respiratory rate (RR) and the patient’s RR may be different. The patient may be “over-breathing” the preset RR, in which case this is the value to use when analyzing RR. Alternatively, the patient may not be “over-breathing” the machine secondary to a variety of reasons including altered mental status or over sedation.

• In general with IPPV modes, PS provides the least amount of support followed by the modes of PC, VC, and PRVC. APRV and other advanced modes of IPPV indicate high levels of respiratory support and acuity of the patient’s respiratory status.⁴

• The fraction of inspired oxygen (FiO₂) is generally set at 40%. Higher percentages indicate a patient’s struggle to oxygenate with levels >60% placing the patient at higher risk for oxygen toxicity.⁴

• Positive end expiratory pressure (PEEP) is the amount of pressure that remains in the lungs at the end of expiration. Standard ranges are approximately 5 to 10 cm H₂O, with higher values indicating the need for alveolar recruitment or difficultly oxygenating.⁴

• Minute ventilation is the product of RR and V_T and is inversely related to carbon dioxide (CO₂). As such, respiratory acidosis (resulting from elevated CO₂ levels) may in part be corrected by increasing minute ventilation. Conversely, a high minute ventilation may result in respiratory alkalosis.⁴

• Low tidal volume ventilation (LTVV) or protective lung ventilation is a cornerstone to management of patients with ARDS and hypoxic respiratory failure and should be targeted whenever possible. This strategy targets lower V_T (6-8 cc/kg) and lower overall airway pressures to reduce ventilator-associated lung injury. Furthermore, emerging evidence suggests benefit in many other IPPV patient populations and has been incorporated as a component in several pharmacist driven quality improvement protocols.^11,22

• Ventilator dyssychrony is a common occurrence and IPPV parameters should be assessed and modified whenever clinically feasible due to the highly individual nature of the ventilator-patient interaction in addition to the evaluation of analgesia and sedation needs. Indeed, patients may tolerate one form of IPPV well and not another.

Case Example

An example of a pharmacist utilizing IPPV information to inform pharmacotherapy could be a patient placed on IPPV secondary to community-acquired pneumonia. Empiric antibiotics are initiated with ceftriaxone and azithromycin. The initial ventilator settings show the mode of PRVC with the following settings: RR 15, V_T 450 mL, FiO₂ 40%, and PEEP 5. The following day the patient has an increased leukocytosis, worsening fevers, and new ventilator settings that include PRVC with RR 15, V_T 450 mL, FiO₂ 80%, and PEEP 10. A possible explanation is that this patient has worsening oxygenation (as evidenced by increased FiO₂ and PEEP settings) secondary to worsening pneumonia, potentially indicating that the antibiotic coverage is not appropriate. As with all information available to the pharmacist, each data point must be taken into a patient-specific context and a myriad of explanations exist within this short vignette for worsening leukocytosis, fevers, and ventilator settings. Regardless, we recommend incorporating IPPV settings as one of the monitoring parameters for pharmacotherapy regimens.

Infectious Complications of IPPV

Impaired airway and host defense mechanisms, combined with critical illness, enhance the risk of invasive infection secondary to colonization.²³ Within 24 hours of ETT insertion, biofilm formation occurs on all lumen surfaces serving as a reservoir for nasopharyngeal and oropharyngeal colonization.²⁴ A shift in oral flora from community acquired respiratory microorganisms to more virulent, hospital-acquired organisms, including Staphylococcus aureus, Enterobacteriaceae, Pseudomonas species, and Acinetobacter species, ensues over the first 48 hours. As a result, infectious complications of IPPV are relatively common and associated with increased mortality: the incidence rate of ventilator associated pneumonia (VAP) is 13 cases per 1000 ventilator days with an associated mortality of approximately 10%, and the incidence rate of ventilator associated sinusitis (VAS) was observed to be 17.4 and 19.8 per 1000 patient days and nasoenteric tube days, respectively.^25-27

Ventilator-Associated Pneumonia

VAP diagnosis requires the presence of a new lung infiltrate at least 48 hours after ETT placement with concurrent signs and symptoms consistent with an infectious cause, including fever, purulent sputum, leukocytosis, and decreased oxygen saturation.²⁸ The risk of developing VAP is correlated with factors that promote an increased risk of microaspiration, including route and duration of intubation, ETT cuff underinflation, orogastric or nasogastric tube placement, medications or disease states altering mentation, exposure to antimicrobial agents or gastric acid suppressants, and underlying comorbidities.²⁸

Microbiology Evaluation and Treatment

The infectious etiology of VAP is dependent on the complex interaction of factors altering nasopharyngeal and oropharyngeal flora, including duration of hospitalization, previous antimicrobial therapy, and comorbid conditions.^29,30 Lower respiratory samples in patients with suspected VAP should be obtained and sent for Gram stain and culture. Culture of tracheal secretions and induced sputum are of limited use due to upper respiratory tract colonization, even in the absence of VAP. Guidelines support obtaining specimens noninvasively via endotracheal aspirate, with semiquantitative cultures rather than invasive sampling or quantitative cultures (eg, mini-BAL).²⁸ Historically, quantitative cultures were believed to be more specific in identifying VAP; however, these cultures did not affect duration of MV, ICU LOS, antimicrobial therapy, or mortality compared to semiquantitative cultures.^31,32 Additionally, semiquantitative cultures can be performed more readily with less laboratory personnel expertise.²⁸ However, invasive sampling may decrease the risk of contaminating lower respiratory tract specimens, leading to more narrow antimicrobial therapy and quicker de-escalation, though sampling of the incorrect lung segment may produce false positives or false negatives.^32-34 Due to lack of superiority and requirements for specialized expertise, invasive sampling should be reserved for patients clinically worsening with negative endotracheal aspirate cultures on empirical antimicrobial therapy or with positive cultures on targeted therapy.²⁸

Gram staining of endotracheal aspirates may identify polymorphonuclear leukocytes and macrophages supporting the presence of lower airway inflammation in addition to identifying the bacterial morphology.³⁰ Negative Gram stains suggest a low possibility of VAP, with a negative predictive value of 91%. While negative Gram stain may be useful, positive predictive value of Gram stain is low, and results from Gram stains are insufficient to inform narrowing of antimicrobial spectra.³⁵

The nosocomial nature of VAP necessitates the use of broad-spectrum antibiotics with coverage of Staphylococcus and Pseudomonas species with a recommended duration of 7 days. Ideally, antibiotic coverage is narrowed based on microbiologic results. Clinical course may dictate longer durations of therapy based on clinical, radiologic, and laboratory findings.²⁸

Ventilator-Associated Pneumonia Prevention

Prevention of VAP utilizing bundles is a commonly accepted approach despite varying evidence.^36,37 The Institute for Healthcare Improvement (IHI) defines bundles as “groupings of best practices with respect to a disease process that individually improve care, but when applied together may result in substantially greater impact.”³⁸ Bundles target a standard approach to implementing evidence-based strategies. In particular, the IHI recommends the use of a particular ventilator bundle to decrease VAP: head of bed (HOB) elevation, daily sedative interruptions and assessment of readiness to extubate, stress ulcer prophylaxis (SUP), and daily use of chlorhexidine gluconate (CHG); however, many bundles exist and include a variety of other interventions including but not limited to oral hygiene, hand hygiene, and specialized ETTs, whose design is intended to reduce aspiration or development of biofilm.^28,39-41

HOB elevation between 30° and 45° is perhaps the simplest of the prevention strategies.⁴² Two meta-analyses have found that HOB elevation nonsignificantly decreased VAP development by 26% (relative risk [RR] 0.74, confidence interval [CI] 0.35-1.56) and 63% (RR 0.47, CI 0.19-1.17), respectively.^42,43 A 0.12% or 0.2% solution of CHG applied to the mouth and tongue of ventilated patients as oral hygiene up to 4 times daily throughout the period of intubation reduces VAP: a meta-analysis evaluating 18 randomized controlled trials determined that the use of CHG reduced VAP significantly, with a number needed to treat of 17 (RR 0.74, CI 0.61-0.89).⁴⁴ Due to the relatively small acquisition cost and minimal adverse effect profile in addition to the efficacy profile, CHG is a core component of VAP bundles. The most common adverse effects reported include dysgeusia and mouth discoloration.⁴⁵ The most concerning adverse effect would be the development of acquired resistance with antiseptic use though risk is thought to be relatively low.⁴⁶ Though various regimens have been studied, a commonly used regimen is 0.12% chlorhexidine gluconate 15 mL (available as unit dose cups) applied to the mouth twice daily for the duration of mechanical ventilation.^47,48

Probiotics, including Lactobacillus, Bifidobacterium, and Bacillus species, have been utilized in the prevention of ventilator-associated tracheobronchitis (VAT). Although some studies have demonstrated reduced rates of VAT, the effect of probiotics on mortality, LOS, or duration of MV remains unclear.⁴⁹ Studies showing a reduction in VAT were largely performed in patients with lower severity of illness, thus making it difficult to extrapolate these results to a more critically ill population.⁴⁹ Additionally, multiple case reports have reported bacteremia secondary to probiotics.^50-52 Based on the proposed risks and a lack of clear benefit from these agents, the use of probiotics warrants further investigation prior to adoption.

Ventilator-Associated Sinusitis

VAS is a frequently unrecognized cause of fever and infection due to the rigorous diagnostic requirements of identifying mucosal thickening, opacification, or air fluid level on computed tomography.²⁷ Risk factors include IPPV, placement of a nasogastric tube (orogastric tubes are preferred), nasal colonization with Gram-negative organisms, and sedative medications.^27,53 Most often, the infectious etiology is polymicrobial with one third being Gram-positive, including S aureus, and the remainder being Gram-negative, predominantly Pseudomonas species. Aspiration and culture of sinus fluid is preferred for pathogen identification over nare or oral cavity secretions.²⁷ Complications of untreated sinusitis in patients receiving IPPV include bacteremia, meningitis, tracheobronchitis, and pneumonia with the causative organism frequently identified in the sinuses.²⁷ Because of the nosocomial nature of VAS, broad spectrum antibiotics are recommended empirically with the goal to narrow coverage based on microbiology results.²⁷

IPPV-Related Organ Dysfunction

Hemodynamic Changes and Assessment

For pharmacists, understanding how hemodynamic measurements are altered by IPPV can be helpful in interpretation of acute changes in a patient’s hemodynamic status. Blood pressure is the product of systemic vascular resistance (SVR) and cardiac output (CO), which is a function of stroke volume and heart rate. Afterload is the force against which the left ventricular pushes when it contracts, of which SVR is a primary component.⁵⁴ Preload is the filling pressure of the ventricles at the end of diastole and is directly related to volume status, which may be evaluated in numerous ways including central venous pressure (CVP), pulmonary capillary wedge pressure (PCWP), dynamic indices such as stroke volume variation (SVV), and fluid responsiveness to fluid challenges.

Despite data describing poor correlation with predicting volume responsiveness, CVP is still routinely used in practice but must be interpreted cautiously in the setting of IPPV.^55-57 PEEP, acting as a direct application of positive pressure, can influence the CVP leading to inaccurate interpretation.⁵⁸ When used, CVP should be incorporated into the larger clinical picture and used in relation to overall trends. In addition to directly affecting the CVP by altering intrathoracic pressure, PEEP and mean airway pressure can also alter CO by limiting venous return (or preload) during inspiration.⁵⁸ Pulmonary artery occlusion pressure (PAOP), also commonly referred to as pulmonary capillary wedge pressure (PCWP), has also been used to guide intravascular volume optimization via pulmonary artery catheter. Utility of PAOP has fallen out of favor due to lack of benefit over CVP monitoring and complications with placement and maintenance including perforated pulmonary artery and development of tachyarrhythmias.^59,60 Fluid challenges are used to identify patients whose hemodynamic parameters may improve with fluid administration. Definitions of “fluid responsive” vary by study but a commonly used challenge is 500 mL of crystalloid with an improvement in cardiac index by 15%.⁶¹

Recent sepsis guidelines now recommend use of dynamic indices over static indices for assessment of hemodynamic status and fluid responsiveness.⁶² Dynamic measures, such as pulse pressure variation or stroke volume variation (SVV), utilize the concept of pulsus paradoxus. Pulsus paradoxus describes the reduction in blood pressure observed during inspiration. For euvolemic patients, the appropriately full vessels are only minimally collapsible when the lungs push against the vessels as they expand during inhalation. In contrast, a hypovolemic patient has less pressure in the vessels, and those vessels collapse more readily during inspiration, and more variation is observed. Thus, larger SVV is associated with hypovolemia. IPPV interferes with pulsus paradoxus due to the application of varying levels of positive pressure and can thus confound assessment. Use of SVV was validated using V_T of at least 8 cc/kg and controlled respirations.^57,63 A pharmacist should interpret SVV values outside of these conditions with caution.

The net result of how IPPV effects hemodynamic includes the complex interplay of IPPV with preexisting cardiac function, volume status (or preload), presence of dynamic hyperinflation, and disease states such as sepsis. For example, in the case of dynamic hyperinflation, wherein a patient with airflow limitations (eg, asthma or COPD) inhales prior to complete exhalation, the resulting increased end expiratory lung volume leads to elevated intrathoracic pressures. These elevated intrathoracic pressures reduce right ventricular venous return and left-ventricular afterload; however, the net effect is largely dependent on preexisting cardiac function. Patients with reduced CO likely benefit from reductions in afterload, while patients with normal CO may show reduced function as a result of reduced venous return or preload.⁴

When a patient has a sudden change in cardiac indices, static or dynamic, pharmacists should evaluate clinical correlation in the setting of concomitant recent changes in mean airway pressure and PEEP.⁴⁵ An example may be a patient whose arterial blood pressure acutely drops. A plausible interpretation and corresponding action would be acute deterioration of the patient and to trial a fluid bolus or use of vasoactive agents; however, this drop in blood pressure could, in part, be explained if the PEEP was recently adjusted from 5 cm H₂O to 15 cm H₂O for a recruitment maneuver. Another example includes that a low SVV in the presence of a spontaneously breathing patient with V_T higher than 8 cc/kg does not necessarily indicate the need for more fluid or hemodynamic instability.

Altered Pharmacokinetics

Hemodynamic and neurohormonal effects of IPPV may alter hepatic and renal function. These alterations in organ function may subsequently play a role in the altered pharmacokinetics observed in critically ill patients. The application of positive pressure through IPPV creates a positive intrathoracic pressure gradient during inspiration, and the application of PEEP creates positive intrathoracic pressure during both inspiration and expiration. This increased pressure subsequently results in decreased venous return, especially notable with hypovolemia, which activates homeostatic responses. These responses can be classified as short-term (vasoconstriction, elevated heart rate [HR], etc), aimed at increasing intravascular pressure, and long-term neurohormonal responses, aimed at increasing intravascular volume, all with the common goal of maintaining CO. Increased antidiuretic hormone secretion, reduction of atrial natriuretic peptide, activation of the renin-angiotensin-aldosterone system, and increased sympathetic outflow have all been implicated in this complex neurohormonal response system.⁶⁴ Reductions in blood flow, in combination with alterations in intraabdominal pressure, may decrease hepatosplanchnic perfusion. Studies demonstrate these effects may be minimal at lower ventilation intensity; however, higher inspiratory pressures, V_T, and PEEP may have a more significant effect.⁶⁵ Observational studies of both animals and humans suggest that IPPV may decrease urine output, lead to sodium and water retention, and reduce renal perfusion, potentially reducing renal clearance. Mechanisms associated with reduced renal function include increases in CO₂ and decreases in oxygen leading to renal vasoconstriction and ischemia, PEEP reducing CO and ultimately renal perfusion, inflammatory cytokine release secondary to large V_T resulting in nephrotoxic effects, and the above-mentioned neurohormonal changes.^66-68

Generally, critical illness may result in a hypermetabolic state, liver or renal dysfunction, use of renal replacement therapy, and altered volume of distribution (V_D). Though it appears that patients are at more risk of suboptimal drug levels secondary to drug underdosing as opposed to adverse effects from overdosing, the complex relationships of critical illness, patient-specific factors, and IPPV make managing fluid balance and drug dosing in this patient population a common challenge. Therapeutic drug monitoring and critical illness specific drug dosing should be used whenever available.⁶⁹

Stress-Related Mucosal Disease (SRMD)

Critical illness results in gut ischemia and impaired mucosal defense mechanisms increasing the risk of SRMD and resultant clinically important bleeding (CIB).⁷⁰ Mucosal injury occurs nearly ubiquitously in critical illness; however, the rates of CIB are approximately 1.5% to 3.5%.^70-72 Because of the nearly 50% associated mortality rate of CIB in SRMD, SUP has historically been recommended in all critically ill patients with risk factors.⁷² IPPV is 1 of 2 of the strongest risk factors for SRMD based on the results of the 1994 Cook et al study both before and after multiple regression (odds ratio [OR] 25.5, P < .001, OR 15.6, P < .001, respectively).⁷² Indeed, SUP has been consistently a key component of ventilator bundles and has been generally accepted as mainstay of therapy for patients on IPPV.^70,73

Both histamine-2 receptor antagonists (H2RA) and proton pump inhibitors (PPIs) have demonstrated superiority over alternative acid suppression agents, but PPIs have yet to demonstrate superiority over H2RAs in a well-designed randomized controlled trial.^70,74 A meta-analysis in 2013 concluded that PPIs did reduce CIB over H2RAs but cautioned readers due to significant limitations of the study including overall poor quality of included trials and publication bias.⁷⁵ Notably, PPIs have been associated with significant cost burden and increased rates of infection including pneumonia and Clostridium difficile.^74,76

Recent evidence has called into question the role of SUP highlighting the low overall incidence of SRMD, questionable effect of SRMD on mortality, efficacy of SUP to reduce CIB, low quality of evidence supporting SUP, and complications associated with acid suppression therapy including increased rates of VAP and other infections.^77-79 Trials are actively being conducted to reevaluate the nearly universal role of SUP.^80,81

For the pharmacist, agent selection should be tailored to patient specific factors (ie, history of gastrointestinal bleeding necessitating PPI use, home agent use, etc) and should aim to minimize potential harms of SUP. Furthermore, inappropriate continuation of SUP once a patient is liberated from IPPV in both the hospital and outpatient settings is a rampant issue.^74,82,83 Pharmacist intervention to discontinue inappropriate SUP through the use of a pharmacy-driven protocol has been shown to significantly reduce inappropriate use without increasing adverse effects. Indeed, inappropriate use was reduced in ICU patients by 58.3% (P < .001), in general ward patients by 83.5% (P < .001), and on hospital discharge from 36.2% to 5.4% (P < .001) after protocol implementation with an estimated yearly institutional cost savings exceeding $200,000.⁸⁴

Adjunctive Therapies

Various pharmacotherapeutic interventions are utilized to optimize IPPV with the goal of improving oxygenation and ventilation or promoting ventilator liberation.

Bronchodilators

Beta-2 agonists enhance mucociliary clearance, optimize lung mechanics, decrease WOB, and reduce pulmonary edema, while anticholinergic agents decrease mucous hypersecretion.^85-88 Patients with primary indications such as COPD or asthma have continued rationale for use of inhaled agents when on IPPV; however, IPPV as a primary indication for bronchodilator use remains uncertain. Albuterol was found to significantly decrease end inspiratory and expiratory alveolar pressures; however, this improvement in lung mechanics has not necessarily translated to reduced duration of MV or ICU LOS.^89-91 β-2 agonists have the theoretical potential to cause tachycardia and arrhythmias. Matthay et al found statistically significant higher HR in patients receiving inhaled albuterol versus placebo (+4 beats per minute [bpm]), but the clinical relevance of this finding remains unclear. Notably, no difference existed in rates of atrial fibrillation.⁸⁹ Levalbuterol does not carry reduced risk of tachycardia in adults.^92,93 Khorfan et al found no significant change in HR from baseline when treating critically ill adult patients with albuterol 2.5 mg or levalbuterol 0.63 mg (0.89 ± 4.5 bpm vs 0.85 ± 5.3 bpm, P = .89).⁹⁴ Thus, in the majority of patients no statistically significant benefit for using levalbuterol exists regarding a decrease in tremor, arrhythmias, or overall HR.^94,95

Both metered dosing inhalers (MDIs) and nebulizers can be equally effective in critically ill patients.^96,97 MDIs are easy to administer, provide reliable doses, and have decreased risk of bacterial contamination as they can be administered through an inline spacer without disconnecting the ventilator circuit.⁹⁸ However, MDIs do require a spacer for optimal drug deposition, and the optimal dose is unknown though it appears that at least 2 to 6 puffs of a short-acting β-2 agonist may be necessary to achieve maximal effects. Nebulizers are potentially easier to use though they may have increased infectious risks.⁹⁹ Medication-specific acquisition costs and personnel costs associated with administration makes the selection between MDIs and nebulizers very institution-specific.^100,101

Role of Neuromuscular Blocking Agents

NMBAs have been used to improve oxygenation in refractory patients though the specific mechanism of benefit is unknown.¹⁰² NMBAs reduce ventilator asynchrony (and likely the resultant elevated airway pressures and lung stress), decrease the inflammatory response in the lung, and increase PaO₂:FiO₂ ratios in ARDS.^102-104 Papazian et al evaluated a cisatracurium bolus (15 mg) followed by a 48-hour continuous infusion of 37.5 mg/hour in patients with moderate to severe ARDS managed on VC and demonstrated a significant difference in 90-day mortality (0.68, 95% CI 0.48-0.98, P = .04) in a prespecified subanalysis. Barotrauma was also significantly reduced in the NMBA group (0.43, 95% CI 0.20-0.93, P = .03), potentially indicating that NMBA reduce ventilator-induced lung injury in ARDS.¹⁰⁵ Notably, cisatracurium is the only NMBA studied to show a mortality benefit and whether this benefit is a class effect is unknown.¹⁰² The Hoffman elimination of both atracurium and cisatracurium is a significant benefit due to minimal risk for accumulation in critically ill patients, though specific agent selection is largely based on institutional practices and patient specific characteristics.¹⁰⁶

All patients receiving NMBAs should be managed by the most recent guidelines.¹⁰² These guidelines include 1 strong recommendation, 10 weak recommendations, and 6 good practice statements. The only strong recommendation is the use of scheduled eye care with lubricating drops or gel and eyelid closure for all patients receiving NMBAs to avoid corneal abrasions and exposure keratitis.¹⁰² Other recommendations essential for pharmacists include utilizing a consistent dosing method (ie, ideal body weight or adjusted body weight), using peripheral nerve stimulation (PNS) only in conjunction with a clinical exam, achieving deep sedation with analgesics and sedatives, and discontinuing any NMBA prior to a brain death exam. Because the role of NMBA has largely shifted to a last line therapy for most disease states and their use necessitates IPPV, pharmacists should consider all patients receiving NMBA therapy to be critically ill requiring thorough pharmacotherapeutic review (ie, analgesia and sedation optimization, SUP, thromboembolic prophylaxis, bowel regimens, etc).^8,102,107 Awareness during paralysis leads to significant patient distress and great care should be exercised to avoid this scenario because while the patient is aware of their surroundings and can perceive pain or psychological distress, they will be unable to communicate.¹⁰⁸ Deep sedation should be achieved prior to paralysis including the use of analgesia (ie, continuous infusion fentanyl) and sedatives (ie, continuous infusion propofol or midazolam). Due to the light nature of sedation and lack of amnestic properties achieved with dexmedetomidine, this agent should generally be avoided.^92,108,109

PNS, commonly referred to as train-of-four (TOF) monitoring, is utilized for assessment and titration of NMBAs with a commonly accepted goal of 2 out of 4 twitches, correlating to blockade of approximately 90% of receptors.^102,110 A study by Rudis et al found that using TOF decreased NMBA doses, with a quicker recovery of neuromuscular function and spontaneous ventilation.¹¹¹ Other studies have shown no such benefit leading to guideline recommendations to utilize TOF monitoring only as one part of a more inclusive clinical assessment. When evaluating patients on NMBA, pharmacists should look for signs of efficacy (ie, improved oxygenation or ventilator synchrony) and signs of overblockade (ie, low TOF) or lack of appropriate analgesia and sedation (ie, lacrimation, diaphoresis, etc).¹⁰²

Hypophosphatemia

Hypophosphatemia is a relatively common electrolyte disorder in ICU patients occurring in approximately 30% of patients and is associated with respiratory muscle dysfunction and potentially IPPV weaning failure.¹¹² Phosphorous replacement, with mean phosphorous levels of 4 mg/dL has been shown to improve diaphragmatic activity.¹¹³ A linear relationship has been observed between hypophosphatemia and respiratory muscle weakness, especially in those patients with levels <2.5 mg/dL. Notably, after replacement, mean phosphorous levels increased to 3.5 mg/dL and improvement in maximal inspiratory and expiratory pressure was observed.¹¹⁴ In 2010, a study observed successful weaning at phosphorous levels >3.6 mg/dL and failure to wean at <3.2 mg/dL further supported by a recent observational study that showed increased rates of weaning failure in patients with phosphorus levels <2.7 mg/dL.¹¹⁵ Although large, randomized studies are lacking that show interventional benefit of phosphate repletion to a specific goal, the relationship of phosphorous with respiratory failure and poor outcomes in critically ill patients has caused many clinicians to view aggressive phosphorous replacement as a reasonable intervention to foster IPPV liberation. Aggressive, weight-based replacement recommendations include at least 0.16 to 0.32 mmol/kg for levels 2.3 to 2.9 mg/dL, 0.32 to 0.64 mmol/kg for levels 1.6 to 2.2 mg/dL, and 0.64 to 1 mmol/kg for levels <1.5 mg/dL of intravenous (IV) phosphorous.¹¹⁶ Though IV therapy has been traditionally preferred, a recent retrospective study observed no difference in duration of IPPV in patients receiving oral versus intravenous therapy. Though this study has numerous limitations due to its observational nature and the exclusion of multiple patient populations frequently seen in the ICU (ie, patients intubated for airway protection, chronic respiratory failure, tracheostomies, etc), oral administration of phosphorous may be advantageous to reduce volume overload and improve administration ease and may even be necessary in light of recent drug shortages.¹¹⁷

Role of Acetazolamide

Metabolic alkalosis is associated with hypoventilation and failure to wean, especially in patients with COPD. Acetazolamide, a carbonic anhydrase (CA) inhibitor, increases the urinary excretion of bicarbonate leading to reversal of metabolic alkalosis and has been assessed for its ability to reduce duration of IPPV with conflicting results.^118,119 The most recent study evaluating acetazolamide 500 to 1000 mg twice daily intravenously for 48 hours observed no difference in duration of MV (95% CI −36.5 to 4.0 hours; P = .17).¹²⁰ This study replicated previous results in reversing arterial blood gas values indicative of metabolic alkalosis, though these too have failed to demonstrate a difference in clinically meaningful outcomes.^121,122 Because acetazolamide is a nonspecific CA inhibitor with activity in both renal and pulmonary sites, administration of acetazolamide may result in a variety of physiological alterations, especially in a patient whose acid-base balance is likely already tenuous.¹²³ To avoid the inclination of “number fixing,” one recent review recommends that acetazolamide only be utilized in patients with significant alkalosis (pH > 7.5) with clinically important correlates such as reduced respiration rate.¹²⁴

Management of Postextubation Stridor

Postextubation laryngeal edema (PLE) and resultant postextubation stridor (PES) are complications of IPPV associated with increased rates of extubation failure but notably have pharmacologic interventions that can reduce incidence.¹²⁵ PES is defined as a high pitched sound produced by airflow through a narrowed airway that results from inflammation and edema from an ETT.¹²⁶ The 2017 clinical practice guideline “Liberation from Mechanical Ventilation in Critically Ill Adults” recommend evaluation of mechanically ventilated patients that meet extubation criteria and have high-risk features for PES through the use of a cuff leak test (CLT).¹²⁷ CLT evaluates the difference between expiratory tidal volumes with cuff inflation and deflation. Patients are considered high risk if they have at least one of the following criteria: traumatic intubation, female sex, endotracheal intubation ≥6 days, trauma to upper airway anatomy, re-intubated after unexpected extubation, or large endotracheal tube >8 mm.^127-129 Significant variation of cuff leak volume measurement and what constitutes failing a CLT exists across studies, but an absolute volume <110 mL is used most consistently.^125,130,131 Steroids are the mainstay of pharmacologic prevention, but the agents and regimens used in the literature vary widely with IV methylprednisolone (IVMP) demonstrating the most promising results.¹²⁹ Francois et al administered IVMP 20 mg every 4 hours starting 12 hours prior to extubation and showed significant reduction in laryngeal edema when compared to placebo (3% vs 22%, P < .0001) and need for reintubation (4% vs 8%, P = .02).¹³² Cheng et al conducted a comparative study of 2 dosing regimens of IVMP to placebo: 40 mg single-dose IVMP 24 hours prior to extubation versus IVMP every 6 hours for 4 doses. Although the 2 intervention arms significantly reduced incidence of PES compared with placebo, no difference between IVMP dosing regimens was observed.¹³³ Though dexamethasone has also been studied, results are inconsistent.^134,135 Current guidelines recommend administering systemic steroids at least 4 hours prior to extubation in patients that fail the CLT for preventions of PES, and protocolized management of mechanically ventilated patients at risk for PES may be a reasonable method to coordinate patient identification, testing, treatment, and extubation.^127,129,136 Strategies for the treatment of PES when it does occur vary widely and are largely based on extrapolated data in asthmatic patients but consistently include systemic steroids (ie, methylprednisolone 40 mg IV once) and nebulized epinephrine (ie, 2.25% racemic epinephrine 0.5 mL solution as needed for stridor).¹²⁵ Notably, lack of data for treatment of PES resulted in its omission from discussion in the most recent guidelines.¹³⁷

Pain, Agitation, and Delirium Management

Pain, agitation, and delirium management must be optimized throughout the entire ventilation process in order to facilitate IPPV liberation and must tailored to each specific patient.¹³⁸ Core components of analgesia and sedation management are discussed in detail in the Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit and include analgosedation and use of non-benzodiazepine agents (ie, propofol or dexmedetomidine), targeting light levels of sedation, delirium prevention, sedation interruption, and SBTs.¹³⁸ Analgosedation is defined as analgesia first sedation modality that has demonstrated decreased duration of mechanical ventilation and delirium.¹³⁸ Sedation should be evaluated using either the Richmond Agitation-Sedation Scale or Sedation-Agitation Scale with light levels targeted. Delirium has been associated with increased mortality, prolonged ICU LOS, and cognitive impairment. Delirium prevention requires a multifaceted approach including avoidance of benzodiazepines, promoting sleep wake cycles, early mobilization, and so on.¹³⁸ Both SBTs and spontaneous awakening trials (SATs) have been shown through multiple studies to help decrease time to extubation and ICU LOS, thus decreasing the time available to develop complications.^139-141 SATs are performed at least daily by aggressively minimizing sedation requirements. Because of the complex nature of interventions that must occur to optimize this management, the guidelines recommend a protocolized approach to integrate the many aspects of pain, agitation, and delirium management.¹⁴² Pharmacists have the opportunity to play a role in helping optimize analgosedation techniques and avoidance of benzodiazepines as a result of their detailed understanding of the mechanisms of action, effects, and pharmacokinetic profiles of the medications used.^107,143 Some common examples may include but are not limited to the following:

• Transitioning a patient’s from extended release (ER) formulations to immediate release formulations due to the inability to crush ER formulations (ie, OxyContin 20 mg BID to oxycodone 10 mg q6h).

• Incorporating a patient’s home medication regimen into the existing pain medication regimen (ie, a patient that uses a fentanyl 25 µg patch will likely need a higher starting rate of fentanyl infusion than an opioid naïve patient).

• Recognizing that repeated use of benzodiazepines for agitation may actually worsen agitation and delirium and recommending atypical antipsychotics for acute management and evaluation of causes of agitation including pain.

• Understanding the pharmacokinetic profiles of medications in order to optimize management (ie, a patient prescribed fentanyl 50 µg q4h as needed for pain that complains of the medication wearing off after an hour could be transitioned to a more frequent interval of fentanyl or a similar interval with morphine or hydromorphone based on the duration of action of fentanyl, morphine, and hydromorphone).

Additionally, pharmacists have the opportunity to be involved with protocol development, protocol adherence and monitoring, as well as patient specific medication recommendations. Indeed, pharmacists have shown significant impact on care in this role. One pharmacist-developed protocol was evaluated in a retrospective before-after study and showed a decrease in duration of mechanical ventilation from 6.39 ± 5.24 days to 3.78 ± 3.21 days (P = .259). Though not statistically significant, the study was likely limited by small sample size, and a reduction in duration of IPPV by 2 days likely has clinical significance.¹⁴⁴ Notably, 2 recent trials have highlighted the benefit of pharmacists in improving adherence to such protocols and reducing duration of mechanical ventilation, ICU LOS, and drug costs. Indeed, one recent study showed pharmacist-directed sedation management resulted in estimated cost savings of $1.2 million in direct hospital costs.¹⁴³ Stollings et al reported on a pharmacist-directed quality improvement program examining the daily adherence of SAT and SBT bundle in a medical ICU and observed significant improvements with adherence (58% vs 85%, P = .0001).¹⁰ Another even more expansive trial by Leguelinel-Blache et al evaluated pharmacist-driven adherence to multiple parameters including antimicrobial agent selection, sedation practices, use of protective mechanical ventilation, VAP prevention measures, and catheter evaluation. Significant reductions in hospital LOS (20.5 vs 16.8, P < .001), ICU LOS (7.9 vs 6.5, P = .004), and duration of mechanical ventilation (5.6 vs 4.4, P = .008) were observed.¹¹

Liberation From IPPV

Pharmacotherapy, including but not limited to analgesia, sedation, and diuretics, is integrally linked to patient liberation from IPPV. Pharmacists have the opportunity to play a vital role in the liberation of a patient from IPPV by evaluating how pharmacotherapy relates to key weaning parameters. For example, if a patient fails a SBT due to oversedation or fluid overload, these scenarios provide excellent opportunities for pharmacist-driven pharmacotherapy optimization. Various indices may be used to predict extubation success and failure while a patient is on an SBT. Broadly, an SBT simulates the conditions following extubation (minimal ventilator settings) and evaluates whether a currently intubated patient can tolerate those conditions. Minimal PS and PEEP settings are applied, and a patient is trialed for approximately 30 to 60 minutes, though ranges and settings vary. Clinical evaluation, including high RR, obvious signs of distress, or hemodynamic instability, along with objective measures are used to evaluate the patient’s readiness to extubate. The rapid shallow breathing index (RSBI) is the most commonly used objective tool and is calculated by dividing respiratory rate (RR) by V_T: [RR/V_T]. RSBI < 105 breaths/min/L is the accepted value for likelihood of successful extubation, with a positive predictive value 78% and negative predictive value 95%.¹⁴⁵ Other indices studied have either been less effective or their complexity limits clinical utility.¹⁴⁵ A patient with an elevated RSBI, or failed SBT, should be evaluated for medication related causes of failure. Examples include, but are not limited to, oversedation with opioids or benzodiazepines, which may need to be discontinued or given more time to be removed from the system; fluid overload, which may be rectified with diuretics or dialysis; agitation, which may be treated with anxiolytics; or airway constriction, which may be relieved with bronchodilators.

Conclusion

IPPV is a cornerstone to supportive care of critically ill patients, and pharmacists are integral members to the critical care health care team. One of the most notable aspects of the Leguelinel-Blache et al study was highlighting the role of pharmacists not only as siloed members of the health care team providing pharmacotherapy recommendations but also as overall quality of care experts providing comprehensive care in a multidisciplinary setting. Indeed, several parameters of the studied bundle did not strictly deal with medication therapy (ie, protective mechanical ventilation, urinary catheter use, etc) and underscore the need for pharmacists to have a working understanding of IPPV.¹¹ As vital members of the interdisciplinary health care team, comprehension of the essential principles of IPPV enables pharmacists to have further insight to patients’ clinical course, thus allowing for increasingly precision-based pharmacotherapy regimens that reduce associated risks of IPPV and improve patient outcomes.