Management of respiratory failure in immune checkpoint inhibitors-induced overlap syndrome: a case series and review of the literature.

BACKGROUND: Checkpoint inhibitor-induced overlap syndrome ([OS] myocarditis, and myositis with or without myasthenia gravis) is rare but life-threatening. CASES PRESENTATION: Here we present a case series of four cancer patients that developed OS. High troponinemia raised the concern for myocarditis in all the cases. However, the predominant clinical feature differed among the cases. Two patients showed marked myocarditis with a shorter hospital stay. The other two patients had a prolonged ICU stay due to severe neuromuscular involvement secondary to myositis and myasthenia gravis. Treatment was based on steroids, plasmapheresis, intravenous immunoglobulin, and immunosuppressive biological agents. CONCLUSION: The management of respiratory failure is challenging, particularly in those patients with predominant MG. Along with intensive clinical monitoring, bedside respiratory mechanics can guide the decision-making process of selecting a respiratory support method, the timing of elective intubation and extubation.

Association of plasma volume status with outcomes in hospitalized Covid-19 ARDS patients: A retrospective multicenter observational study.

PURPOSE: To evaluate the association of estimated plasma volume (ePV) and plasma volume status (PVS) on admission with the outcomes in COVID-19-related acute respiratory distress syndrome (ARDS) patients. MATERIALS AND METHODS: We performed a retrospective multi-center study on COVID-19-related ARDS patients who were admitted to the Mayo Clinic Enterprise health system. Plasma volume was calculated using the formulae for ePV and PVS, and these variables were analyzed for correlation with patient outcomes. RESULTS: Our analysis included 1298 patients with sequential organ failure assessment (SOFA) respiratory score ≥ 2 (PaO2/FIO2 ≤300 mmHg) and a mortality rate of 25.96%. A Cox proportional multivariate analysis showed PVS but not ePV as an independent correlation with 90-day mortality after adjusting for the covariates (HR: 1.015, 95% CI: 1.005-1.025, p = 0.002 and HR 1.054, 95% CI 0.958-1.159, p = 0.278 respectively). CONCLUSION: A lower PVS on admission correlated with a greater chance of survival in COVID-19-related ARDS patients. The role of PVS in guiding fluid management should be investigated in future prospective studies.

Clinical Characteristics and Cause of Death Among Hospitalized Decedents With Cancer and COVID-19.

There is scant information on the clinical progression, end-of-life decisions, and cause of death of patients with cancer diagnosed with COVID-19. Therefore, we conducted a case series of patients admitted to a comprehensive cancer center who did not survive their hospitalization. To determine the cause of death, 3 board-certified intensivists reviewed the electronic medical records. Concordance regarding cause of death was calculated. Discrepancies were resolved through a joint case-by-case review and discussion among the 3 reviewers. During the study period, 551 patients with cancer and COVID-19 were admitted to a dedicated specialty unit; among them, 61 (11.6%) were nonsurvivors. Among nonsurvivors, 31 (51%) patients had hematologic cancers, and 29 (48%) had undergone cancer-directed chemotherapy within 3 months before admission. The median time to death was 15 days (95% confidence interval [CI], 11.8 to 18.2). There were no differences in time to death by cancer category or cancer treatment intent. The majority of decedents (84%) had full code status at admission; however, 53 (87%) had do-not-resuscitate orders at the time of death. Most deaths were deemed to be COVID-19 related (88.5%). The concordance between the reviewers for the cause of death was 78.7%. In contrast to the belief that COVID-19 decedents die because of their comorbidities, in our study only 1 of every 10 patients died of cancer-related causes. Full-scale interventions were offered to all patients irrespective of oncologic treatment intent. However, most decedents in this population preferred care with nonresuscitative measures rather than full support at the end of life.

Post-cardiac arrest PCI is underutilized among cancer patients: Machine learning augmented nationally representative case-control study of 30 million hospitalizations.

BACKGROUND: Cancer patients are less likely to undergo percutaneous coronary intervention (PCI) after cardiac arrest, although they demonstrate improved mortality benefit from the procedure. We produced the largest nationally representative analysis of mortality of cardiac arrest and PCI for patients with cancer versus non-cancer. METHODS: Propensity score adjusted multivariable regression for mortality was performed in this case-control study of the United States' largest all-payer hospitalized dataset, the 2016 National Inpatient Sample. Regression models of mortality and PCI weighted by the complex survey design were fully adjusted for age, race, income, cancer metastases, NIS-calculated mortality risk by Diagnosis Related Group (DRG), acute coronary syndrome, and likelihood of undergoing PCI. RESULTS: Of the 30,195,722 hospitalized adult patients, 15.43% had cancer, and 0.79% of the whole sample presented with cardiac arrest (of whom 20.57% underwent PCI). In fully adjusted regression analysis among patients with cardiac arrest, PCI significantly reduced mortality (OR 0.15, 95 %CI 0.13-0.19; p < 0.001) among patients with cancer greater than those without it (OR 0.21, 95 %CI 0.20-0.23; p < 0.001). CONCLUSIONS: This nationally representative study suggests that post-cardiac arrest PCI is underutilized among patients with cancer despite its significant mortality reduction for such patients (independent of clinical acuity).

Triage and Prognostication of Cancer Patients Admitted to the Intensive Care Unit.

Cancer remains a leading cause of morbidity and mortality. Advances in cancer screening, early detection, targeted therapies, and supportive care have led to improvements in outcomes and quality of life. The rapid increase in novel cancer therapies can cause life-threatening adverse events. The need for intensive care unit (ICU) care is projected to increase. Until 2 decades ago, cancer diagnosis often precluded ICU admission. Recently, substantial cancer survival has been achieved; therefore, ICU denial is not recommended. ICU resources are limited and expensive; hence, appropriate utilization is needed. This review focuses on triage and prognosis in critically ill cancer patients requiring ICU admission.

Risk factors and outcomes of critically ill patients with acute brain failure: A novel end point.

OBJECTIVE: To determine the incidence, risk factors and outcomes of acute brain failure (ABF) in a mixed medical and surgical cohort of critically ill patients and its effect on ICU & hospital mortality. DESIGN: Observational electronic medical record (EMR) based retrospective cohort study of critically ill patients admitted to the ICU between 2006 and 2013. SETTING: Tertiary academic medical center. PATIENTS: Consecutive adult (>18years) critically ill patients admitted to medical and surgical ICUs. Patients admitted to the Neuroscience, Pediatric and Neonatal ICUs were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: ABF was defined by the presence of delirium (positive CAM-ICU) or depressed level of consciousness (by abnormal GCS and FOUR scores) in the absence of deep sedation (RASS<-3). Severity of ABF was categorized as grade I if there was delirium with GCS consistently >8 and grade II if the GCS was ≤8 with or without delirium during the ICU hospitalization. ABF duration was not used for this study. Univariate and multivariable analyses were used to access the factors associated with the development of ABF and its effect on short and long term mortality. Of 67,333 ICU patients included in the analysis, ABF was present in 30,610 (44.6%). Patients with ABF had an isolated delirium in 1985 (6.5%) patients, isolated depressed consciousness in 18,323 (59.9%), and both delirium and depressed consciousness in 10,302 (33.6%) patients. When adjusted for comorbidities and severity of illness ABF was associated with increased hospital (OR 3.47; 95% CI 3.19-3.79), and at one year (OR 2.36; 95% CI 2.24-2.50) mortality. Both hospital and one year mortality correlated with the increased severity of ABF. The factors most strongly associated with ABF were pre-admission dementia (OR 7.86; 95% CI 6.15-10.19) and invasive ventilation (OR 2.32; 95% CI 2.24-2.40) but older age, female sex, presence of liver disease, renal failure, diabetes mellitus, malignancy and COPD were also associated with increased risk of ABF. CONCLUSIONS: ABF is a common complication of critical illness and is associated with increased short and long term mortality. The risk of ABF was particularly high in older patients with baseline dementia, COPD, diabetes, liver and renal disease and those treated with invasive mechanical ventilation.

The "Complex Restrictive" Pulmonary Function Pattern: Clinical and Radiologic Analysis of a Common but Previously Undescribed Restrictive Pattern.

BACKGROUND: Most patients with restriction have a pulmonary function test (PFT) pattern in which total lung capacity (TLC), FVC, and FEV1 are reduced to a similar degree. This pattern is called "simple restriction" (SR). In contrast, we commonly observe a pattern in which FVC percent predicted (pp) is disproportionately reduced relative to TLCpp. This pattern is termed "complex restriction" (CR), and we attempted to characterize its clinical, radiologic, and physiologic features. METHODS: This study reviewed PFT results of patients tested between November 2009 and June 2013 who had restriction (TLC less than the lower limit of normal). SR was defined as TLCpp-FVCpp ≤ 10%, and CR was stratified into four classes based on TLCpp-FVCpp discrepancy: Class 1 CR, TLCpp-FVCpp > 10% and ≤ 15%; Class 2 CR, TLCpp-FVCpp > 15% and ≤20%; Class 3 CR, TLCpp-FVCpp > 20% and ≤ 25%; and Class 4 CR, TLCpp-FVCpp > 25%. The medical records of 150 randomly selected patients with SR and 50 patients from each CR class were reviewed. RESULTS: Of 39,277 PFTs completed, we identified 4,532 patients (11.5%) with restriction: 2,407 (6.1%) with SR, 1,614 (4.1%) with CR, and 511 (1.3%) with a mixed pattern. Patients with CR were younger, were more often women, and had a higher prevalence of neuromuscular disease, BMI > 40 kg/m2 or < 18.5 kg/m2, diaphragmatic dysfunction, bronchiectasis, CT mosaic attenuation, and pulmonary hypertension (P < .0001, < .0001, < .001, .004, .0008, .002, .008, .009, .053, and .01, respectively) and a lower prevalence of interstitial lung disease (P < .0001). CONCLUSIONS: CR is a common PFT pattern with distinct clinical features. The associated clinical entities share impaired lung emptying (eg, neuromuscular disease, occult obstruction, chest wall limitation). Clinicians should be aware of this novel PFT pattern and how it shapes the differential diagnosis.

Identification of acute brain failure using electronic medical records.

PURPOSE: Up to 80% of critically ill patients have acute neurologic dysfunction syndromes. We evaluated interrater reliability between the examination by the investigator and the charted assessment by the nurse because the accuracy and reliability of detailed data sets extracted from the electronic medical records represents a keystone for creating EMR-based definitions. MATERIALS AND METHODS: We conducted a prospective observational study of intensive care unit (ICU) patients to assess the reliability of charted Confusion Assessment Method for the ICU, Glasgow Coma Scale (GSC), Full Outline of Unresponsiveness, and Richmond Agitation Sedation Scale (RASS) scores, and a composite measure of ABF defined as new-onset coma or delirium. Trained investigator blinded to nursing assessments performed the neurologic evaluations that were compared with nursing documentation. RESULTS: A total of 202 observations were performed in 55 ICU patients. Excellent correlation was noted for GCS and Full Outline of Unresponsiveness scores on Bland-Altman plots (Pearson correlation 0.87 and 0.92, respectively). Correlation for Confusion Assessment Method for the ICU was also high (κ= 0.86; 95% confidence interval [CI], 0.70-1.01). Richmond Agitation Sedation Scale had good agreement when scores were dichotomized as oversedated (less than -2) vs not oversedated, with κ= 0.76 (95% CI, 0.54-0.98). Investigator assessment and nurse charting were highly concordant (κ= 0.84; 95% CI, 0.71-0.99). CONCLUSION: Neurologic assessments documented on the EMR are reliable.

Fatal right ventricular failure and pulmonary hypertension after protamine administration during cardiac transplantation.

Protamine sulfate is the only Food and Drug administration approved medication for reversal of intraoperative heparin-induced anticoagulation during cardiac and vascular surgeries. One of the rare side effects of protamine sulfate is an idiosyncratic reaction resulting in acute pulmonary hypertension (APH) and right ventricular (RV) failure occurring after protamine administration. These reactions are rare but catastrophic with high mortality. A 36-year-old female with severe congestive heart failure was undergoing cardiac transplant surgery. After successful implantation of the donor heart, the patient was weaned off cardiopulmonary bypass. Protamine was then administered to reverse the heparin anticoagulation. She immediately developed APH and RV failure immediately after protamine infusion. The patient required immediate administration of inotropic agents, nitric oxide (NO), and subsequently required a number of mechanical support devices including an RV assist device (RVAD) and ultimately full veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Despite heroic efforts, the patient developed refractory multi-organ failure in the Intensive Care Unit and died after family requested discontinuation of resuscitative efforts. This case probably represents the first reported occurrence of fatal protamine-induced APH and ventricular failure in the setting of cardiac transplantation surgery. A number of interventions including inhaled NO, systemic vasopressors, RVAD, and ultimately VA-ECMO failed to reverse the situation, and the patient died of multi-organ failure.

Diffuse cholangiocarcinoma presenting with hepatic failure and extensive portal and mesenteric vein thrombosis.

A 64-year-old previously healthy man presented with a 4-week history of vague right upper quadrant abdominal pain. Imaging studies revealed extensive portal, splenic, superior and inferior mesenteric vein thrombosis with mosaic perfusion and wedge-shaped areas of liver perfusion abnormalities. An extensive thrombophilia workup including tests for factor V Leiden, prothrombin G20210A, lupus anticoagulant, paroxysmal nocturnal haemoglobinuria, protein C and S, homocysteine and antinuclear antibody titres were all negative. Other laboratory testing revealed an elevated alkaline phosphatase (340 IU/L). Surgical exploration and catheter-directed thrombolysis were not felt to be feasible given the extensive clot burden. He was started on anticoagulation therapy. Over the next 10 days, he required intensive care unit admission due to progressive hepatic encephalopathy and fulminant liver failure. He continued to decline and eventually died of multiorgan failure. Autopsy revealed extensive, diffuse intrahepatic cholangiocarcinoma that had almost entirely replaced his normal liver parenchyma.

Ketamine/propofol admixture (ketofol) at induction in the critically ill against etomidate (KEEP PACE trial): study protocol for a randomized controlled trial.

BACKGROUND: Endotracheal intubation (ETI) is commonly performed as a life-saving procedure in the intensive care unit (ICU). It is often associated with significant hemodynamic perturbations and can severely impact the outcome of ICU patients. Etomidate is often chosen by many critical care providers for the patients who are hypotensive because of its superior hemodynamic profile compared to other induction medications. However, recent evidence has raised concerns about the increased incidence of adrenal insufficiency and mortality associated with etomidate use. A combination of ketamine and propofol (known as ketofol) has been studied in various settings as an alternative induction agent. In recent years, studies have shown that this combination may provide adequate sedation while maintaining hemodynamic stability, based on the balancing of the hemodynamic effects of these two individual agents. We hypothesized that ketofol may offer a valuable alternative to etomidate in critically ill patients with or without hemodynamic instability. METHODS/DESIGN: A randomized controlled parallel-group clinical trial of adult critically ill patients admitted to either a medical or surgical ICU at Mayo Clinic in Rochester, MN will be conducted. As part of planned emergency research, informed consent will be waived after appropriate community consultation and notification. Patients undergoing urgent or emergent ETI will receive either etomidate or a 1:1 admixture of ketamine and propofol (ketofol). The primary outcome will be hemodynamic instability during the first 15 minutes following drug administration. Secondary outcomes will include ICU length of stay, mortality, adrenal function, ventilator-free days and vasoactive medication use, among others. The planned sample size is 160 total patients. DISCUSSION: The overall goal of this trial is to assess the hemodynamic consequences of a ketamine-propofol combination used in critically ill patients undergoing urgent or emergent ETI compared to etomidate, a medication with an established hemodynamic profile. The trial will address a crucial gap in the literature regarding the optimal induction agent for ETI in patients that may have potential or established hemodynamic instability. Greater experience with planned emergency research will, hopefully, pave the way for future prospective randomized clinical trials in the critically ill population. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02105415. 31 March 2014.

Transfusion-Related Acute Lung Injury After IVIG for Myasthenic Crisis.

BACKGROUND: A 26-year-old female with myasthenic crisis developed transfusion-related acute lung injury (TRALI) after she was treated with intravenous immunoglobulin. METHODS: Case report. RESULTS: Respiratory status markedly worsened with each intravenous immunoglobulin (IVIG) administration and progressing from a need to use bilevel positive airway pressure (BiPAP) to intubation. Pulmonary function tests improved during this episode. CONCLUSIONS: IVIG may cause TRALI and due to subtle clinical findings can be mistaken for neuromuscular respiratory failure.

Ketamine and propofol combination ("ketofol") for endotracheal intubations in critically ill patients: a case series.

BACKGROUND: Endotracheal intubation is a common procedure performed for critically ill patients that can have immediate life-threatening complications. Induction medications are routinely given to facilitate the procedure, but most of these medications are associated with hypotension. While etomidate is known for its neutral hemodynamic profile, it has been linked with increased mortality in septic patients and increased morbidity in trauma patients. Ketamine and propofol are effective anesthetics with counteracting cardiovascular profiles. No data are available about the use of this combination in critically ill patients undergoing endotracheal intubation. CASE REPORT: We describe 6 cases in which the combination of ketamine and propofol ("ketofol") was used as an induction agent for endotracheal intubation in critically ill patients with a focus on hemodynamic outcomes. All patients received a neuromuscular blocker and fentanyl, while 5 patients received midazolam. We recorded mean arterial pressure (MAP) 1 minute before induction and 15 minutes after intubation with the combination. Of the 6 patients, 5 maintained a MAP ≥ 65 mmHg 15 minutes after intubation. One patient was on norepinephrine infusion with a MAP of 64 mmHg, and did not require an increase in the dose of the vasopressor 15 minutes after intubation. No hemodynamic complications were reported after any of the intubations. CONCLUSIONS: This case series describes the use of the "ketofol" combination as an induction agent for intubation in critically ill patients when hemodynamic stability is desired. Further research is needed to establish the safety of this combination and how it compares to other induction medications.

A quality improvement project sustainably decreased time to onset of active physical therapy intervention in patients with acute lung injury.

RATIONALE: Rehabilitation started early during an intensive care unit (ICU) stay is associated with improved outcomes and is the basis for many quality improvement (QI) projects showing important changes in practice. However, little evidence exists regarding whether such changes are sustainable in real-world practice. OBJECTIVES: To evaluate the sustained effect of a quality improvement project on the timing of initiation of active physical therapy intervention in patients with acute lung injury (ALI). METHODS: This was a pre-post evaluation using prospectively collected data involving consecutive patients with ALI admitted pre-quality improvement (October 2004-April 2007, n = 120) versus post-quality improvement (July 2009-July 2012, n = 123) from a single medical ICU. MEASUREMENTS AND MAIN RESULTS: The primary outcome was time to first active physical therapy intervention, defined as strengthening, mobility, or cycle ergometry exercises. Among ICU survivors, more patients in the post-quality improvement versus pre-quality improvement group received physical therapy in the ICU (89% vs. 24%, P < 0.001) and were able to stand, transfer, or ambulate during physical therapy in the ICU (64% vs. 7%, P < 0.001). Among all patients in the post-quality improvement versus pre-quality improvement group, there was a shorter median (interquartile range) time to first physical therapy (4 [2, 6] vs. 11 d [6, 29], P < 0.001) and a greater median (interquartile range) proportion of ICU days with physical therapy after initiation (50% [33, 67%] vs. 18% [4, 47%], P = 0.003). In multivariable regression analysis, the post-quality improvement period was associated with shorter time to physical therapy (adjusted hazard ratio [95% confidence interval], 8.38 [4.98, 14.11], P < 0.001), with this association significant for each of the 5 years during the post-quality improvement period. The following variables were independently associated with a longer time to physical therapy: higher Sequential Organ Failure Assessment score (0.93 [0.89, 0.97]), higher FiO2 (0.86 [0.75, 0.99] for each 10% increase), use of an opioid infusion (0.47 [0.25, 0.89]), and deep sedation (0.24 [0.12, 0.46]). CONCLUSIONS: In this single-site, pre-post analysis of patients with ALI, an early rehabilitation quality improvement project was independently associated with a substantial decrease in the time to initiation of active physical therapy intervention that was sustained over 5 years. Over the entire pre-post period, severity of illness and sedation were independently associated with a longer time to initiation of active physical therapy intervention in the ICU.

Chronic pulmonary aspergillosis complicating bronchial atresia.

Bronchial atresia is a rare pulmonary developmental anomaly characterized by the presence of a focal obliteration of a segmental or lobar bronchial lumen. The lung distal to the atretic bronchus is typically emphysematous along with the presence of mucus filled ectatic bronchi (mucoceles). BA is usually asymptomatic but pulmonary infections can rarely develop in the emphysematous lung distal to the atretic bronchus. We present a unique case of chronic pulmonary aspergillosis (CPA) in a patient with BA with no evidence of immune dysfunction. The patient was treated initially with voriconazole and subsequently underwent surgical excision of the involved area. On follow-up, she has done extremely well with no evidence for recurrence. In summary, we describe the first case of chronic pulmonary aspergillosis in an immunocompetent patient with bronchial atresia.

Reducing deep sedation and delirium in acute lung injury patients: a quality improvement project.

OBJECTIVE: Deep sedation and delirium are common in the ICU. Mechanically ventilated patients with acute lung injury are at especially high risk for deep sedation, delirium, and associated long-term physical and neuropsychiatric impairments. We undertook an ICU-wide structured quality improvement project to decrease sedation and delirium. DESIGN: Prospective quality improvement project in comparison with a retrospective acute lung injury control group. SETTING: Sixteen-bed medical ICU in an academic teaching hospital with pre-existing use of goal-directed sedation with daily interruption of sedative infusions. PATIENTS: Consecutive acute lung injury patients. INTERVENTION: A "4Es" framework (engage, educate, execute, evaluate) was used as part of the quality improvement process. A new sedation protocol was created and implemented, which recommends a target Richmond Agitation Sedation Scale score of 0 (alert and calm) and requires failure of intermittent sedative dosing prior to starting continuous infusions. In addition, twice-daily delirium screening using the Confusion Assessment Method for the ICU was introduced into routine practice. MEASUREMENTS AND MAIN RESULTS: Sedative use and delirium status in acute lung injury patients after implementation of the quality improvement project (n = 82) were compared with a historical control group (n = 120). During the quality improvement vs. control periods, use of narcotic and benzodiazepine infusions were substantially lower (median proportion of medical ICU days per patient: 33% vs. 74%, and 22% vs. 70%, respectively, both p < 0.001). Further, wakefulness increased (median Richmond Agitation Sedation Scale score per patient: -1.5 vs. -4.0, p < 0.001), and days awake and not delirious increased (median proportion of medical ICU days per patient: 19% vs. 0%, p < 0.001). CONCLUSION: Through a structured quality improvement process, use of sedative infusions can be substantially decreased and days awake without delirium significantly increased, even in severely ill, mechanically ventilated patients with acute lung injury.

Physical rehabilitation of patients in the intensive care unit requiring extracorporeal membrane oxygenation: a small case series.

BACKGROUND AND PURPOSE: Neuromuscular weakness and impaired physical function are common and long-lasting complications experienced by intensive care unit (ICU) survivors. There is growing evidence that implementing rehabilitation therapy shortly after ICU admission improves physical function and reduces health care utilization. Recently, there is increasing interest and utilization of extracorporeal membrane oxygenation (ECMO) to support patients with severe respiratory failure. Patients receiving ECMO are at great risk for significant physical impairments and pose unique challenges for delivering rehabilitation therapy. Consequently, there is a need for innovative examples of safely and feasibly delivering active rehabilitation to these patients. CASE DESCRIPTION: This case report describes 3 patients with respiratory failure requiring ECMO who received physical rehabilitation to illustrate and discuss relevant feasibility and safety issues. OUTCOMES: In case 1, sedation and femoral cannulation limited rehabilitation therapy while on ECMO. In the 2 subsequent cases, minimizing sedation and utilizing a single bicaval dual lumen ECMO cannula placed in the internal jugular vein allowed patients to be alert and participate in active physical therapy while on ECMO, illustrating feasible rehabilitation techniques for these patients. DISCUSSION: Although greater experience is needed to more fully evaluate the safety of rehabilitation on ECMO, these initial cases are encouraging. We recommend systematically and prospectively tracking safety events and patient outcomes during rehabilitation on ECMO to provide greater evidence in this area.