Critical Care Medicine

Dear Editor, Extracorporeal membrane oxygenation (ECMO) has a significant impact on intensive care unit (ICU) patient costs. Human resources are a major cost driver for ECMO in severe acute respiratory distress syndrome (ARDS) [1]. However, recent developments in ECMO technology has allowed safe patient management by a single caregiver [2–4]. In the present report, we analyze the direct ICU costs of patients with influenza A (H1N1)-related ARDS supported with miniaturized ECMO systems and managed by a single caregiver. We performed an observational study of all patients (n = 10) with H1N1-associated ARDS treated with ECMO in Hospital S. Joao (Porto, Portugal), between November 2009 and April 2011. The clinical data and ECMO treatment details of this ICU patient cohort have been described in a previous report [5]. Patients were admitted in medical ICUs and managed by a single caregiver using miniaturized ECMO circuits (Rotaflow Centrifugal Pump plus Quadrox PLS and CARDIOHELP; Maquet Cardiopulmonary AG). In our single caregiver model, the ICU nurse primarily managed the ECMO patient under the coordination of 24/7 inhouse ICU physicians, with the backup of an on-call ECMO specialist. Our multidisciplinary ECMO specialist team (ICU physicians, ICU nurses, and cardiovascular perfusionists) is responsible for managing equipment and supplies, circuit preparation, patient transportation, troubleshooting, daily rounds, education, and service administration. Per patient ICU direct costs were analyzed retrospectively from clinical records and hospital databases using both top-down and bottom-up approaches. Bottom-up analysis was performed for all drugs, transfusion requirements, laboratory and imagiology exams. Regarding disposable items, bottom-up analysis was possible for ECMO-specific disposables and for renal replacement therapies. Costs with human resources were assessed using the top-down approach. Specific ECMO costs were also individualized for each ICU episode: (1) disposables devices; (2) laboratory tests; (3) transfusion requirements; and (4) drugs. The Ethics Committee of the Hospital S. Joao approved this study and waived the need for patients’ informed consent. Variables are reported as median and interquartile ranges, if not otherwise indicated. The cost drivers of H1N1-related ARDS patients treated with miniaturized ECMO are presented in Table 1. ECMO support corresponded to 63.6 (62.5–88.5) % of the ICU length of stay (LOS). The ICU LOS positively correlated (r = 0.97; p \ 0.001) with ICU patient costs [42,721 (33,358–56,801) €], but not with specific ECMO costs [r = 0.17; p = 0.63; 7,516 (5,599–7,736) €]. ECMO-specific costs represented 17.6 (13.1–18.1) % of the total ICU direct costs, mostly ECMO disposable devices [94.8 (87.1–96.1) %]. Daily ICU costs with antibiotics, sedation, analgesia and neuromuscular blockade, fluids and nutrition, vasoactive drugs, anticoagulation medications, and other unspecific drugs were higher during the period of ECMO support compared with the period without ECMO support. In conclusion, the use of miniaturized ECMO had a small impact on direct ICU costs in our cohort of H1N1-related severe ARDS patients managed by a single caregiver and did not correlate with the ICU LOS. Knowledge of the incremental costs associated with miniaturized ECMO will contribute to the clarification of its cost-effectiveness in severe ARDS.

Science, Medicine, and the Anesthesiologist

Extracorporeal Membrane Oxygenation: Opportunities for Expanding Nurses' Roles.

We aimed to evaluate the outcomes of post-traumatic acute respiratory distress syndrome (ARDS) in young patients with and without Extracorporeal membrane oxygenation (ECMO) support. A retrospective analysis was conducted for trauma patients who developed ARDS at a level I trauma facility between 2014 and 2020. Data were analyzed and compared between ECMO and non-ECMO group. We identified 85 patients with ARDS (22 patients had ECMO support and 63 matched patients managed by the conventional mechanical ventilation; 1:3 matching ratio). The two groups were comparable for age, sex, injury severity score, abbreviated injury score, shock index, SOFA score, and head injury. Kaplan Meier survival analysis showed that the survival in the ECMO group was initially close to that of the non-ECMO, however, during follow-up, the survival rate was better in the ECMO group, but did not reach statistical significance (Log-rank, p = 0.43 and Tarone-Ware, p = 0.37). Multivariable logistic regression analysis showed that acute kidney injury (AKI) (Odds ratio 13.03; 95% CI 3.17–53.54) and brain edema (Odds ratio 4.80; 95% CI 1.10–21.03) were independent predictors of mortality. Sub-analysis showed that in patients with severe Murray Lung Injury (MLI) scores, non-ECMO group had higher mortality than the ECMO group (100% vs 36.8%, p = 0.004). Although ARDS is uncommon in young trauma patients, it has a high mortality. ECMO therapy was used in a quarter of ARDS cases. AKI and brain edema were the predictors of mortality among ARDS patients. ECMO use did not worsen the outcome in trauma patients; however, the survival was better in those who had severe MLI and ECMO support. Further prospective study is needed to define the appropriate selection criteria for the use of ECMO to optimize the outcomes in trauma patients.

Aerosolized Prostacyclin Versus Inhaled Nitric Oxide in Children with Severe Acute Respiratory Distress Syndrome

In the treatment for severe acute respiratory distress syndrome (ARDS) from coronavirus disease 2019 (COVID-19), the World Health Organization (WHO) recommends prone positioning (PP) during mechanical ventilation for periods of 12-16 h/d to potentially improve oxygenation and survival. In this prospective observational study, we evaluated the ability of long PP sessions to improve oxygenation in awake intensive care unit (ICU) patients with moderate or severe ARDS due to COVID-19. The study was approved by the ethics committee of Galicia (code No. 2020-188), and all patients provided informed consent. In this case series, awake patients with moderate or severe ARDS by COVID-19 admitted to the ICU at University Hospital of Santiago from March 21 to April 5, 2020 were prospectively analyzed. Patients were instructed to remain in PP as long as possible until the patient felt too tired to maintain that position. Light sedation was administered with dexmedetomidine. The following information was collected: number and duration of PP sessions; tissue O2 saturation (StO2) and blood gases before, during, and following a PP session; need of mechanical ventilation; duration of ICU admission; and ICU outcome. Linear mixed-effects models (LMM) were fit to estimate changes from baseline with a random effect for patient. Seven patients with moderate or severe ARDS by COVID-19 were included. All patients received at least 1 PP session. A total of 16 PP sessions were performed in the 7 patients during the period study. The median duration of PP sessions was 10 hours. Dexmedetomidine was used in all PP sessions. Oxygenation increased in all 16 sessions performed in the 7 patients. The ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FIO2) significantly increased during PP (change from baseline 110 with 97.5% confidence interval [CI], 19-202) and, after PP, albeit not significantly (change from baseline 38 with 97.5% CI, -9.2 to 85) compared with previous supine position. Similarly, tissue oxygenation underwent a small improvement during PP (change from baseline 2.6% with 97.5% CI, 0.69-4.6) without significant changes after PP. Two patients required intubation. All patients were discharged from the ICU. We found that PP improved oxygenation in ICU patients with COVID-19 and moderate or severe ARDS. PP was relatively well tolerated in our patients and may be a simple strategy to improve oxygenation trying to reduce the number of patients in mechanical ventilation and the length of stay in the ICU, especially in COVID-19 pandemic.

The Emerging Role of Bivalirudin for Therapeutic Anticoagulation in Patients With Coronavirus Disease 2019 Requiring Extracorporeal Membrane Oxygenation Support: Is It Time to Change the Routine Practice?

To the Editor Management of patient sedation and analgesia to alleviate anxiety and pain and facilitate mechanical ventilation is one of the key roles of every intensivist. During the coronavirus disease 2019 (COVID-19) pandemic, unprecedented numbers of patients require sedation in intensive care units (ICUs) and other hospital locations due to their ventilator dependence. However, pharmacologic sedation in mechanically ventilated patients with COVID-19 has thus far received very little attention in the critical care literature, with minimal mention in the Society of Critical Care Medicine's COVID-19 guidelines or clinical reviews.1,2 We propose that sedation of mechanically ventilated patients with COVID-19 poses unique challenges and has multiple important implications that we would like to briefly outline: Unusually high sedation requirements in a large proportion of COVID-19 patients are observed in current clinical experience. These high sedation requirements are likely related to younger age and good health of many patients before the onset of COVID-19, high respiratory drive, and intense inflammatory responses previously linked to tolerance.3 This translates into the need to administer combinations of multiple agents (eg, propofol, ketamine, hydromorphone, dexmedetomidine, and midazolam), increasing potential risks of side effects (eg, QT interval prolongation, hypertriglyceridemia, hypotension, and delirium) and requiring vigilance of the ICU staff. When these are administered in combinations, the typical requirements to ensure patient comfort and ventilator synchrony in adult patients range between 25 and 50 µg/kg/min for propofol, 10 and 20 µg/kg/min for ketamine, 2 and 4 mg/h for hydromorphone, and 2 and 5 mg/h for midazolam. There are currently no sedation guidelines specific for this patient population requiring high doses and prolonged drug administrations. Deeper sedation levels may be required to facilitate ventilator synchrony in patients with severe acute respiratory distress syndrome (ARDS) and may also be favored by ICU staff to reduce risk of patient self-extubation, which is particularly problematic in this population given the need for emergent reintubation and risk of exposure to coronavirus. Subsequent tolerance to sedatives (eg, dexmedetomidine) from their use early in the course of illness and high doses will also limit the effectiveness of these drugs during ventilator weaning. Intermittent administration of certain drugs (eg, narcotics) tailored to individual needs of each patient may not always be feasible in situations of overwhelmed health care systems (eg, when one nurse is required to attend to multiple critically ill patients). In these situations, continuous infusions of sedative drugs are favored for their practicality, but this practice further increases the risks of side effects. A subset of patients with severe ARDS is likely to require prolonged sedation (often >2 weeks)4 to facilitate lung-protective mechanical ventilation or extracorporeal membrane oxygenation (ECMO) therapy and subsequent weaning. These prolonged periods of time may lead to drug accumulation (midazolam), tolerance and tachyphylaxis (dexmedetomidine), hypertriglyceridemia (propofol), QT interval prolongation (haloperidol), psychomimetic effects (ketamine), hyperalgesia or opioid dependence (fentanyl and/or hydromorphone), and delirium (midazolam). Increased precision in monitoring the depth of sedation (eg, processed electroencephalogram [EEG]) is required in patients with high sedation requirements who also require neuromuscular blockade to improve respiratory system compliance. While these neuromonitoring technologies exist,5 they may not be widely available given the number of patients who would benefit. Patient awareness under these conditions (eg, paralysis or prone position) may result in significant psychological trauma. Prolonged infusions of opioids that are often required to facilitate strict lung-protective ventilation are known to result in gut hypomotility, leading to intolerance to feeding, interruptions in feeding, and malnutrition during prolonged ICU stay. These gastrointestinal side effects of opioids may also result in abdominal distension, which can impair ventilation and/or contribute to nausea/vomiting, increasing the risk of aspiration. High doses of opioids, sometimes required to facilitate lung-protective ventilation in patients with ventilator dyssynchrony, may paradoxically complicate ventilation management by inducing breathing patterns with large tidal volumes that may further injure lungs. Prolonged infusions of high doses of sedatives and analgesics in large numbers of patients have already resulted in drug shortages at hospital, regional, and state levels. In these situations, providing sedation with less commonly used agents (barbiturates, methadone, clonidine, chlorpromazine, and propranolol) may need to be considered. The use of inhalational anesthetics (eg, isoflurane), at least in locations with appropriately designed scavenging systems, such as operating rooms converted to ICUs, may be a rational alternative that is supported by their documented safety6 and potential anti-inflammatory and lung-protective effects. Attention must be paid to the potential interaction between sedative drugs and other agents administered as part of clinical trials (there are >300 clinical COVID-19 trials currently ongoing worldwide). For instance, significant QT prolongations may result from combinations of hydroxychloroquine and haloperidol. Administration of barbiturates may increase metabolism of hydroxychloroquine. In patients with high fevers, dexmedetomidine may need to be discontinued to help delineate the cause of the fever. In summary, management of sedation in ICU patients with COVID-19 needs to reflect individual properties and side effect profiles of agents, unique patient characteristics (prolonged intubation and virus shedding), and health care system limitations (large numbers of patients, ICU patients in emergency rooms and operating rooms, and drug shortages). Potential for interactions with investigational drugs used in clinical trials (some blinded to ICU staff) needs to be considered. The collective clinical experience from the United States and from other highly affected areas around the world should be quickly leveraged to formulate recommendations and guidelines to increase patient safety and provider awareness of these unique challenges. Dusan Hanidziar, MD, PhDEdward A. Bittner, MD, PhDDepartment of Anesthesia, Critical Care and Pain MedicineMassachusetts General HospitalBoston, Massachusetts[email protected]

The Case for Prolonged ECMO for COVID-19 ARDS as a Bridge to Recovery or Lung Transplantation.

COVID-19 acute respiratory distress syndrome: intriguing haemodynamics of an intriguing syndrome.

The novel influenza A(H1N1) pandemic affected Australia and New Zealand during the 2009 southern hemisphere winter. It caused an epidemic of critical illness and some patients developed severe acute respiratory distress syndrome (ARDS) and were treated with extracorporeal membrane oxygenation (ECMO). To describe the characteristics of all patients with 2009 influenza A(H1N1)-associated ARDS treated with ECMO and to report incidence, resource utilization, and patient outcomes. An observational study of all patients (n = 68) with 2009 influenza A(H1N1)-associated ARDS treated with ECMO in 15 intensive care units (ICUs) in Australia and New Zealand between June 1 and August 31, 2009. Incidence, clinical features, degree of pulmonary dysfunction, technical characteristics, duration of ECMO, complications, and survival. Sixty-eight patients with severe influenza-associated ARDS were treated with ECMO, of whom 61 had either confirmed 2009 influenza A(H1N1) (n = 53) or influenza A not subtyped (n = 8), representing an incidence rate of 2.6 ECMO cases per million population. An additional 133 patients with influenza A received mechanical ventilation but no ECMO in the same ICUs. The 68 patients who received ECMO had a median (interquartile range [IQR]) age of 34.4 (26.6-43.1) years and 34 patients (50%) were men. Before ECMO, patients had severe respiratory failure despite advanced mechanical ventilatory support with a median (IQR) Pao(2)/fraction of inspired oxygen (Fio(2)) ratio of 56 (48-63), positive end-expiratory pressure of 18 (15-20) cm H(2)O, and an acute lung injury score of 3.8 (3.5-4.0). The median (IQR) duration of ECMO support was 10 (7-15) days. At the time of reporting, 48 of the 68 patients (71%; 95% confidence interval [CI], 60%-82%) had survived to ICU discharge, of whom 32 had survived to hospital discharge and 16 remained as hospital inpatients. Fourteen patients (21%; 95% CI, 11%-30%) had died and 6 remained in the ICU, 2 of whom were still receiving ECMO. During June to August 2009 in Australia and New Zealand, the ICUs at regional referral centers provided mechanical ventilation for many patients with 2009 influenza A(H1N1)-associated respiratory failure, one-third of whom received ECMO. These ECMO-treated patients were often young adults with severe hypoxemia and had a 21% mortality rate at the end of the study period.

EXTRACORPOREAL MEMBRANE OXYGENATION: A HOPE FOR THE SICKEST PATIENTS WITH COVID-19

This scoping review has identified 21 studies on care bundle use in critically ill patients in ICU with COVID-19, ARDS, viral influenza or pneumonia and severe respiratory failure. The data for patients with COVID-19 specifically are limited, derived mainly from observational quality improvement or clinical experiential accounts. Research is required, urgently, to further assess care bundle use and optimal components of these bundles in this patient cohort. The care bundles described were also varied, with guidance on ventilator settings described in 10 care bundles, while chest X-ray was part mentioned in one care bundle in one study only. None of the studies identified in this scoping review measured users' experience of adapting care bundles. Optimising care bundle implementation requires that the components of the care bundle are collectively and consistently applied. Data on challenges, barriers and facilitators to implementation are needed. A formal synthesis of the outcome data presented in this review and a critical appraisal of the evidence is required by a subsequent effectiveness review. This subsequent review should further explore effect estimates across the included studies.

ECMO: Commentary of the EOLIA trial on the use of Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome

Extracorporeal membrane oxygenation (ECMO) therapy for patients with influenza A (H1N1)-related acute respiratory distress syndrome (ARDS) has been described once all other therapeutic options have been exhausted. The current report reviews our institutional experience and lessons learned in 18 consecutive patients. Between December 2009 and March 2011, 18 patients underwent ECMO therapy for severe H1N1-related ARDS. Mean age was 40 ± 18 years (range 4-67 years). Ten patients (56%) received venoarterial cannulation (v-a ECMO) while venovenous cannulation (v-v ECMO) was initiated in the remaining patients (n = 8, 44%). To identify risk factors of adverse outcome, univariate analysis was performed for clinical parameters. Successful ECMO weaning was possible in 44% (n = 8) of patients and overall mortality was 61% (n = 11). Seven of the eight patients who could be successfully weaned from ECMO support fully recovered. Survival within the v-a ECMO group (60%) was superior to the v-v ECMO group (13%; p = 0.06). Two patients (11%) required re-exploration of the axillary artery cannulation site. No further adverse events associated with ECMO implantation occurred. Outcome was better when the time of severe deoxygenation (Pao2 < 70 mm Hg) despite maximally invasive respiratory support to ECMO implantation was less than 6 hours (odds ratio: 2.4; p = 0.05). ARDS associated with H1N1 remains a devastating clinical picture. In our hands, ECMO support offered survival to 40% of patients with otherwise fatal prognosis. While v-v ECMO remains the method of choice for patients suffering an isolated ARDS in the setting of stable hemodynamic conditions, v-a ECMO may be considered if the clinical picture of ARDS is aggravated by systemic inflammatory response syndrome with the requirement of high dose vasopressor support.