Tropical Medicine & Surgery

Lung-Protective Ventilation for Adult Patients with ARDS in Intensive Care Unit: A Systematic Review and Evidence-Based Guideline

Yophtahe B. Woldegerima^1*, Tikuneh A. Yetneberk¹ and Habtamu K. Getinet^{2 1}Department of Anesthesia, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
²Department of Anesthesia, College of Medicine and Health Sciences, Debre-Tabor University, Debre-Tabor, Ethiopia
^*Correspondence: Yophtahe B. Woldegerima, Assistant Professor of Anesthesia and Critical Care, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia, Tel: 251912494282, Email:

Received: 31-Aug-2021 Published: 21-Sep-2021, DOI: 10.35248/2329-9088.21.9.250

Introduction

Acute Respiratory Distress Syndrome (ARDS) is a life-threating condition characterized by non-cardiogenic pulmonary edema, bilateral lung infiltrates and decreased lung compliance that leads to acute on-set of refractory hypoxemia. The two world wars brought evidences of edematous lungs after traumatic injuries and the condition with such features obtained the term “shocked lung.” Later on 1994, American-European Consensuses Conference has given the term “acute respiratory distress syndrome.” However, some debatable issues were persisted till the recent and current definition of ARDS was developed by international expert’s panel held in Berlin in 2011. Compared to other definitions, the Berlin definition has significant prediction ability for mortality (Table 1).

Table 1: Global distribution of deep samples positive for Candida spp.

However, still critical issues are being raised on the definitions of ARDS [1]. Wide spread inflammation of the lungs, diffuse alveolar injury to alveolar cells, endothelial injury, increased pulmonary capillary permeability, atelectasis, activation of complex local and systemic inflammatory and immune responses, surfactant dysfunction and disturbed coagulation are common features of ARDS. Usually, ARDS follows predisposing conditions that can be broadly classified as extra-pulmonary origin (sepsis, burn, and pancreatitis) and pulmonary origin (pneumonia, contusion, aspiration) [2,3].

Acute Respiratory Distress Syndrome (ARDS) is one of the commonest clinical problem for admission to Intensive Care Units (ICU). The annual incidence of ARDS in the western world is estimated to be 7.2-34 per 100,000 people [4,5]. Approximately, 5% of hospitalized patients meet the diagnosis criteria for ARDS. Acute Respiratory Distress Syndrome (ARDS) is responsible for 9% ICU admissions, 39% of mechanically ventilated patients [1,4]. Multiple studies from different parts of the world are still identifying pneumonia and sepsis as the leading causes for ARDS. Hepatic cirrhosis, compromised immunity, aspiration, different cardiac events, trauma, pancreatitis and metastatic cancer also are the commonest concomitant conditions in ARDS [5-8]. Due to severity of the condition 75% of patients has moderate to severe form of ARDS and only the remaining 25% has mild form. Short-term mortality is 45% and survivors have significant longterm morbidities, low quality of life, cognitive dysfunction and disabilities. Many studies have disclosed that “life is hardly the same after ARDS.”

These figures are expected to differ in the developing and resource limited countries due to many factors such as higher rate infectious disease including retro-viral infection, trauma, underdiagnosis and limited level of hospital and ICU care [1,3,4].

Providing care for a patient with ARDS is really one of the challenging conditions in medical practice. It needs multidisciplinary approaches that involve timely and effective resuscitation, handling of the predisposing condition, antimicrobial therapy and source control in sepsis, optimal ventilatory strategy, hemodynamic monitoring and management, and supportive care [1,3]. Regardless of some improvements in the incidence and prognosis of ARDS in the last decades due to better understanding of the syndrome and advancements in critical care, mortality rate in ARDS remains unacceptably very high (>40%) [1,9]. The determinants of outcomes in ARDS were age, risk factor for ARDS, comorbidity, severity of illness, multiple organ dysfunction syndrome (MODS), oxygenation index (OI), and ventilation strategies [4,5,8,10-18].

Additional to poor quality of life, thereafter surviving ARDS, the financial implications of ARDS have enormous burden. Cost analysis studies done nearly two decades ago have showed that, health care costs of initial hospital/ICU admission, readmission and inpatient rehabilitation are very high. Especially, in high risk patients (prognostic estimate to survive at least 2 months is less than 50%), the cost per Quality Adjusted Life Years (QALY) was exaggeratedly very high (>100,000 USD). The median (IQR) of health cost of 5 years survivors after discharge was found to be 58,500 USD (19,700-157,800 USD, 90 percentile: 328,083 USD). These costs are supposed to be increased due to high inflation, expensiveness of medical services and currency manipulations. Survivors of ARDS had dependence on activities of daily life, exercise limitation and poor QALY. As a result, they cannot generate income comparable to pre-ARDS life years. On the second year of survival, only 65% survivors had returned to work with high incidence of physical limitations. Acute Respiratory Distress Syndrome (ARDS) and Acute Lung Injury (ALI) are widespread diseases with massive socioeconomic impacts comparable with the burden from breast cancer, acquired immune-deficiency syndrome, asthma or myocardial infarction [7,19-22].

Lung protective ventilation is a strategy of mechanical ventilation targeting the delivery of optimal ventilation support without causing Ventilator Associated Lung Injury (VALI) secondary to barotrauma (pressure overload), volutrauma (volume overload), atelectrauma (shearing of collapsed lung while opening and closing) and biotrauma (release of inflammatory mediators). These injuries worsen the conditions of the sick lung and worsen the outcome [23,24].

The rationales of this systematic review and guideline

Mechanical Ventilation (MV) has a central and invaluable role in the complex management of patient with ARDS. However, it is associated with many unwanted events including VALI, ventilator associated pneumonia and hemodynamic instability. Especially, in patients with ARDS, the incidence and the burden of VALI is higher due to preexisting damage and inflammatory processes in the lungs that result in diminished uneven compliance [25]. To prevent VALI, multiple studies advocated to implement LPV strategies for ARDS patients [4,6,12]. Even though, LPV was primarily introduced for patients with ARDS, patient without ARDS also can be benefited from it [26-28]. Despite these recommendations, Under-use of LPV was reported in developed countries for many reasons [29-31]. Furthermore, there are literature concluded that LPV did not improve the outcomes of ARDS; especially, in-relation to long-term survival [5]. Equi-vocal results also were obtained [17]. The burden of critical illness is very huge world-wide and extremely very huge in the developing countries with limited capacity, well-trained personnel and infrastructures [32].

Developing concise and practicable clinical guideline according to current evidence may help to improve use of LPV strategies; hence, care provision and outcome of patients with ARDS in settings with human and material resource limitations. One of the resource limitations is human-resource scarcity. The developing world has a small numbers of well-trained clinicians and specialists. So provision of practicable clinical guideline based on current evidences can improve the situations. This facilitates early discharge from ICU hence, free ICU beds and other resources will be available for other patients. All of these have cost implications; specifically in the low-income countries. Our objectives were to review systematically current evidence and develop achievable clinical practice guidelines; hence we aimed to provide a working document for better applications of LPV for patients with ARDS in ICU especially in areas with human and material resource limitations. For the simplicity of implementing the guideline, it is presented in algorithmic approach.

Literature Review

The research question was constructed in PICOS (Population, Interventions, Comparisons, Outcomes and Study designs) model. Studies done on adult human patients with ARDS on mechanical ventilation were included. The interventions and comparisons were applications of lung-protective strategies. The outcome was measured in terms of morbidity, mortality, hospital stay and long-term outcomes. Most of studies included in this review were prospective randomized controlled trials and meta-analyses. Current evidence in the last ten years (2009- 2019) was collected using appropriate search engines and databases such as PubMed through HINARI, Google Scholars and Cochrane Library by setting appropriate filtering method. Terms such as “ARDS” “ventilation,” “mechanical ventilation,” “lung protection,” “lung protection in ARDS,” “lung-protective ventilation strategies,” “lung protective ventilation in ARDS” “VALI” and combinations of terms with Boolean operators (AND, OR, NOR) were used. Keywords, mesh-terms, Boolean operators, time bound and English language were used to limit literature searching. Animal studies, articles published other than English language, articles on mechanical ventilation in non- ARDS patients were excluded from the current review. Authors independently performed literature searching and critical appraisal was done with appropriate appraisal tools, presented for coauthors and consensus reached on the eligibility of the included articles. Data was extracted from articles according to the research question. Final conclusions and recommendations were done by balancing the benefits and downsides of the alternative strategies for LPV in adult patients with ARDS based on levels of evidence and classes of recommendation (Tables 2 and 3).

Table 2: Levels of evidence.

Table 3: Classes of recommendations.

The characteristics of included studies are illustrated Table 4. This systematic review was reported using PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta- Analyses). The guidelines are preferred for reporting items for systematic reviews and meta-analyses and developed by Cochrane Collaboration.

Table 4: Summary on characteristics of included studies.

Patient and public involvement statement

Patients and/or, the public were not involved in the design, conduct, reporting, or dissemination plans of this research.

Discussion

The four major components of LPV are limiting tidal volume (TV), end-inspiratory plateau pressure (Pplat) and FiOTsub, then providing optimal PEEP to prevent lung collapse [24]. Lungprotective ventilation (LPV) was found to decrease mortality by 22% (IB) [33]. A Cochrane review of RCTs that compared ventilation with TV ≤ 7 ml/Kg, Pplat ≤ 30 cm H₂O or combination versus TV 10-15 ml/Kg found use of low TV and Pplat has reduced hospital and 28-days mortality (relative risk=0.86). However, it had evidence insufficiency to conclude on morbidity and long-term outcomes [4] (IA). A prospective cohort showed that ventilation with TV ≤ 6.5 ml/Kg and Pplat ≤ 30 cm H₂O had benefit on two years survival [12] (IIC). The joint American Thoracic Society (ATS), European Society of Intensive Care Medicine (ESICM) and Society of Critical Care Medicine (SCCM); strongly recommended that ARDS patients should be ventilated with strategies that limit the tidal volume (4-8 ml/ Kg PBW) and inspiratory pressures (Pplat<30 cm H₂O) [23] (IA). Avoiding over-distention while MV can attenuate release of inflammatory mediators [34] (IB). A double-blind RCT in China concluded that ventilation with 6 ml/Kg of TV and 10 cm H₂O of PEEP could protective of VALI with less hemodynamic, stress and inflammatory effects [35] (IB). The low TV ventilation is associated with higher PaCO₂ that has potential benefits by increasing O₂ delivery (right-ward shift of O₂-hemoglobin dissociation curve), micro-circulatory vasodilatation and cardiac index. To achieve these, PaCO₂ as high as 66 mmHg and рH as low as 7.15 can be tolerable (or buffer with bi-carbonate) unless there are strong contra-indications such as raised intracranial pressure [3,36] (IA). In addition, low TV ventilation can result in patient-ventilator asynchrony and stacked breaths [37] (IIaC).

Applying PEEP is considered as a typical treatment for hypoxia by reopening the collapsed lung units. Despite improved oxygenation, the optimal settings of PEEP and its effect on the outcome remained controversial [24]. Adjustment of PEEP should balance alveolar recruitment and avoiding overdistention in consideration of hemodynamic adverse events [38]. Multiple studies including ALVEOLI trial have not found significant difference between use of higher and lower PEEP in terms of mortality [23,39-44] (IA). A Cochrane review found no difference in mortality and barotrauma between the groups. However, oxygenation was improved in higher PEEP group [43] (IA). A meta-analysis by Briel et al. showed that patients with moderate/sever ARDS had lower mortality and more ventilator free days with higher PEEP. Whereas, patients with mild ARDS tends to have non-significantly worsened outcome [45] (IA). An RCT by Mercat et al. suggested that higher PEEP can improve lung function, duration of MV and organ failure rather than mortality [40] (IB). Another meta-analysis has concluded higher PEEP ventilation combined with RM has reduced mortality [46] (IA). In contrast, decremental PEEP titration with Staircase Recruitment Maneuver (SRM) has improved lung compliance, shunt fraction, oxygenation and PaO₂/FiO₂ in 80% of patients [47] (IIaC). Ventilation with lower TV and PEEP is associated with increased mortality; especially, when PEEP is lower than 5 cm H₂0 [48,49] (IB). The joint of ATS, ESICM and SCCM; recommended that ARDS patients should receive higher rather than lower levels of PEEP [23] (IA). In unilateral lung diseases; higher PEEP may over-distend the healthy lung then worsen shunt and oxygenation [24] (IIaB). Regarding method of PEEP delivery, PEEP/FiO₂ protocols designed by ARDSnet and ARMA trials are favored till date [33,41,50] (IB). Whereas according to severity of the ARDS, Hess recommended to use PEEP of 5-10 cm H^₂O in mild, 10-15 cm H₂O in moderate and 15-20 cm H₂O in severe cases [38] (IIaA). Inverse ratio ventilation (I:E>1:1) can increase airway pressure and oxygenation, but can result in high intrinsic PEEP; then worsen gas exchange, volutrauma and hemodynamic instability [3] (IA).

Recruitment maneuver is transient use of high trans-pulmonary pressure to open atelectatic units and increase lung volume. It is expected to prevent atelectrauma and VALI. Like other LPV strategies, there are no consensuses on the techniques of RM and impacts on outcomes of ARDS [3,38,50,51]. A small size study by Villagar et al. has concluded that RM has no shortterm benefit on oxygenation; whereas it can result in regional alveolar over-distention and worsen intrapulmonary shunt [52-69] (IIbB). In contrast, other studies reported that RM can improve oxygenation and reduce need for rescue therapy and mortality [23,46,50] (IA). However, higher PEEP may be required to maintain the recruitment and increase the benefit [38,46,50] (IA). The commonest technique of RM is applying continuous positive airway pressure 30-40 cm H₂O for 20-40 seconds [38]. Another technique recently gaining popularity is SRM or step-wise increment of pressure up to 60 cm H₂O [3]. In a small size study, SRM with decremental PEEP titration had improved response in 80% of patients with transient reduction in mean arterial pressure and heart rate and increased central venous pressure but no barotrauma [47] (IIaB). The ARDSnet did not recommend the routine use of RM [38] (IB). But the recent article by the joint of ATS, ESICM and SCCM advised to use RM in ARDS patients [23] (IA). Supporting this, there is a Cochrane review that has found those ventilation strategies incorporated RM has improved oxygenation and reduced ICU mortality without risk of barotrauma [15] (IA). Close monitoring is highly recommended since transient hypotension (12%), desaturation (8%), barotrauma (1%) and arrhythmias (1%) can occur (IA), and use in caution or avoid RM in patients with circulatory compromises [47,50] (IB).

Volume assist-control is the most popular mode for lung protective ventilation. However till date there is no high quality evidence that proved its superiority over other modes [50] (IA). In accordance to this, a Cochrane review of RCTs with a total of 1089 patients failed to confirm or disprove whether pressurecontrolled or volume-controlled ventilation has benefit for ARDS patients [14] (IIA). Non-invasive ventilation modalities can be optionally use in patients with mild ARDS and immunecompromised with no other organ failure [50] (IA).

After introduced in 1970s, prone positioning (PP) has been constantly proven for its effectiveness to improve oxygenation in ARDS patients; particularly, when conventional measures have failed in sever hypoxemia. However, its impact on outcomes found to be inconsistent [3]. In the PROSEVA trial, mortality was reduced by 50% at 28th and 90th days (16% vs.32% and 23.6% vs. 41%, p<0.001) by PP compared with supine positioning [53] (IB). However, secondary analysis of this trial found that VAP (associated with higher mortality) was not minimized by PP [54] (IB). Two recent systematic reviews supported that PP can reduce mortality especially when combined with other LPV strategies, applied early and for longer duration (>12-16 hrs.) [55,56] (IA). A meta-analysis of RCTs also claimed PP can reduce mortality by 10% and prevent occurrence of sever ARDS in mechanically ventilated patients [57] (IA). Benefits of PP in ARDS have been explained by increased lung volumes, homogeneity of ventilation, providing regional recruitment, decreasing driving pressure and lung straining and displacing cardiac weight from the lungs [3,55,58,59] (IA). In addition to respiratory benefits, PP was known for hemodynamic advantages (reduce right ventricle pressure overload, incidence of cardiac arrest and stress response and increase cardiac index) [53,55,60,61] (IA). Complication rate such as skin necrosis, dislodgement of tubings and others were not significant; even lower in some studies [3,53,59] (IA). Despite efficiency and simplicity of PP, under-use was commonly reported [57,59] (IA).

There are no well-established agreements concerning the use of Neuromuscular Blocking Agent (NMBA) in ARDS patients [3,24,50,62-64] (IA). Spontaneous breathing may worsen ARDS, patient-ventilator asynchrony, breath stacking, lung straining,negative pressure pulmonary edema, and pendelluft (flow of gases between lung regions) especially in sever ARDS [64] (IB). In contrast, cessation of spontaneous breathing is criticized for ICU-acquired myopathy (dis-use and loss of muscles of respiration including the diaphragm) and increased time of recover from paralysis. So a review by Grawe et al. Recommended to avoid routine early use of NMBAs in ARDS patients [62] (IA). Use of NMBAs increases chest wall compliance; reduce oxygen consumption by skeletal muscles. Paralysis with NMBAs was reserved for refractory hypoxemia. Muscle weakness after NMBAs seems over-emphasized, even NMBAs have sedativesparing effect. Recent evidences suggested routine and early initiation in moderate-sever ARDS [3,50] (IA). As a relaxant of choice, the effects of Cis-atracurium are promising. In multiple studies including ACURASYS trial, early infusion (within 48 hrs.) of Cis-atracurium has increased oxygenation, ventilator-free days, patient-ventilator synchrony and reduced mortality without muscle weakness; especially if steroids and hyperglycemia are avoided. Its advantageous features are; it does not accumulate, no histamine release, no active metabolite, organ independency and non-steroid linked, but it is expensive [65-69] (IA). The cheaper drugs, Vecuronium was compared with Cis-atracurium and found to have no significant difference in terms of mortality; but ventilator days, ICU days and total hospital stay were less when Cis-atracurium used [65,69,70] (IB). Vecuronium had comparable effect with Cisatracurium when comorbidities and severity of illness were adjusted [65,70] (IB). With available equivocal evidences, we can recommend (moderate confidence in effect estimates) precautious intermittent use of Vecuronium at early-phase of ARDS as alternative to Cis-atracurium with close monitoring of peripheral neuromuscular function, circuit disconnection, malfunction and avoidance of steroids and hyperglycemia (Table 4, Figure 1).

Figure 1:An algorithmic approach to lung-protective ventilation in ARDS.

Key-points

• Apply Lung Protective Ventilation (LPV) strategies as early as possible.

• Maintain patient-ventilator synchrony (sedation and analgesia).

• Apply and follow with standard monitoring.

• Routinely use peripheral neuromuscular monitoring. Especially when NMBAs are used.

• Monitor for ventilator disconnections and malfunctions.

• High tidal volumes and high plateau pressures need to be avoided.

• Tidal volume should be calculated based on predicted body weight (PBW) rather than on actual body weight, according to gender and height.

• Predicted body weight can be calculated as 50+0.91 × (height in cm-152.4) for men and 45.5+0.91 × (height in cm-152.4) for women.

• Tidal volumes should be watchfully adjusted (from 4 to 7 mL/ Kg of PBW) and maintain a plateau pressure of 30 cm H₂O or less.

• The respiratory rate should be titrated as needed (in a range of 15 to 35/min) to maintain a pH of 7.15 to 7.35 and PaCO2=55– 65 mmHg unless contraindicated (e.g. raised ICP).

• Apply recruitment maneuver by increasing the pressure to 30–50 cm H₂O for 30–40 seconds, whilst monitoring for signs of hemodynamic adverse events.

• An appropriate combination of FiO₂ and PEEP should be used to achieve adequate oxygenation (PaO2 of 55 to 85 mmHg, or SpO2 of 90% or greater).

• Prone positioning and returning should be done with enough numbers of trained personnel.

• Pad and lubricate the eyes and pressure point

• With available equivocal evidences, we recommend precautious intermittent use of neuro-muscular blocking agents (NMBAs) at early-phase of ARDS.

• Avoid hyperglycemia and limit use of steroids since increase the risks of ICU-induced muscle weakness. Especially when steroid linked NMBAs (e.g. Vecuronium) are used (Table 5).

Table 5: FiO₂/PEEP combinations to achieve oxygenation goal (UMC Health System Respiratory ARDSNet Protocol, 2017).

Conclusion

Acute respiratory distress syndrome is a life-threatening condition with very high mortality>40%. Implementation of lung protective ventilation strategies may improve the outcomes in ARDS patients. With till date evidences, mechanical ventilation strategies in ARDS patients should include use of low tidal volume, limited plateau pressure, PEEP: FiO₂ titration protocols, recruitment maneuvers, prone positioning and neuromuscular blocking agents.

Acknowledgement

We would like to thank University of Gondar.

Conflict of Interest

The authors declared that they have no conflict of interests regarding this article.

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