Thrombotic events following tocilizumab therapy in critically ill COVID-19 patients: a Façade for prognostic markers.

BACKGROUND: Hospitals in the Middle East Gulf region have experienced an influx of COVID-19 patients to their medical wards and intensive care units. The hypercoagulability of these patients has been widely reported on a global scale. However, many of the experimental treatments used to manage the various complications of COVID-19 have not been widely studied in this context. The effect of the current treatment protocols on patients' diagnostic and prognostic biomarkers may thus impact the validity of the algorithms adopted. CASE PRESENTATION: In this case series, we report four cases of venous thromboembolism and 1 case of arterial thrombotic event, in patients treated with standard or intensified prophylactic doses of unfractionated heparin or low molecular weight heparin at our institution. Tocilizumab has been utilized as an add-on therapy to the standard of care to treat patients with SARS-CoV-2 associated acute respiratory distress syndrome, in order to dampen the hyperinflammatory response. It is imperative to be aware that this drug may be masking the inflammatory markers (e.g. IL6, CRP, fibrinogen, and ferritin), without reducing the risk of thrombotic events in this population, creating instead a façade of an improved prognostic outcome. However, the D-dimer levels remained prognostically reliable in these cases, as they were not affected by the drug and continued to be at the highest level until event occurrence. CONCLUSIONS: In the setting of tocilizumab therapy, traditional prognostic markers of worsening infection and inflammation, and thus potential risk of acute thrombosis, should be weighed carefully as they may not be reliable for prognosis and may create a façade of an improved prognostic outcome insteasd. Additionally, the fact that thrombotic events continued to be observed despite decrease in inflammatory markers and the proactive anticoagulative approach adopted, raises more questions about the coagulative mechanisms at play in COVID-19, and the appropriate management strategy.

Sustaining Life versus Altering Life-Saving Drugs: Insights to Explain the Paradoxical Effect of Extracorporeal Membrane Oxygenation on Drugs.

There has been a substantial increase in the use of extracorporeal membrane oxygenation (ECMO) support in critically ill adults. Understanding the complex changes that could affect drugs' pharmacokinetics (PK) and pharmacodynamics (PD) is of suitable need. Therefore, critically ill patients on ECMO represent a challenging clinical situation to manage pharmacotherapy. Thus, clinicians' ability to predict PK and PD alterations within this complex clinical context is fundamental to ensure further optimal and, sometimes, individualized therapeutic plans that balance clinical outcomes with the minimum drug adverse events. Although ECMO remains an irreplaceable extracorporeal technology, and despite the resurgence in its use for respiratory and cardiac failures, especially in the era of the COVID-19 pandemic, scarce data exist on both its effect on the most commonly used drugs and their relative management to achieve the best therapeutic outcomes. The goal of this review is to provide key information about some evidence-based PK alterations of the drugs used in an ECMO setting and their monitoring.

Etomidate and mortality in cirrhotic patients with septic shock.

BACKGROUND: Clinical effects and outcomes of a single dose etomidate prior to intubation in the intensive care setting is controversial. The aim of this study is to evaluate the association of a single dose effect of etomidate prior to intubation on the mortality of septic cirrhotic patients and the impact of the subsequent use of low dose hydrocortisone. METHODS: This is a nested-cohort study within a randomized double blind placebo controlled study evaluating the use of low dose hydrocortisone in cirrhotic septic patients. Cirrhotic septic patients ≥ 18 years were included in the study. Patients who received etomidate prior to intubation were compared to those who did not receive etomidate for all cause 28-day mortality as a primary outcome. RESULTS: Sixty two intubated patients out of the 75 patients randomized in the initial trial were eligible for this study. Twenty three of the 62 intubated patients received etomidate dose prior to intubation. Etomidate use was not associated with all cause 28-day mortality or hospital mortality but was associated with significantly higher ICU mortality (91% vs. 64% for etomidate and controls groups, respectively; p = 0.02). Etomidate patients who received subsequent doses of hydrocortisone required lower doses of vasopressors and had more vasopressor-free days but no improvement in mortality. CONCLUSIONS: In this group of septic cirrhotic patients with very high mortality, etomidate increased ICU mortality. Subsequent use of hydrocortisone appears to have no benefit beyond decreasing vasopressor requirements. The lowest mortality was observed in patients who did not receive etomidate but received hydrocortisone.

Impact of computerized physician order entry (CPOE) system on the outcome of critically ill adult patients: a before-after study.

BACKGROUND: Computerized physician order entry (CPOE) systems are recommended to improve patient safety and outcomes. However, their effectiveness has been questioned. Our objective was to evaluate the impact of CPOE implementation on the outcome of critically ill patients. METHODS: This was an observational before-after study carried out in a 21-bed medical and surgical intensive care unit (ICU) of a tertiary care center. It included all patients admitted to the ICU in the 24 months pre- and 12 months post-CPOE (Misys®) implementation. Data were extracted from a prospectively collected ICU database and included: demographics, Acute Physiology and Chronic Health Evaluation (APACHE) II score, admission diagnosis and comorbid conditions. Outcomes compared in different pre- and post-CPOE periods included: ICU and hospital mortality, duration of mechanical ventilation, and ICU and hospital length of stay. These outcomes were also compared in selected high risk subgroups of patients (age 12-17 years, traumatic brain injury, admission diagnosis of sepsis and admission APACHE II > 23). Multivariate analysis was used to adjust for imbalances in baseline characteristics and selected clinically relevant variables. RESULTS: There were 1638 and 898 patients admitted to the ICU in the specified pre- and post-CPOE periods, respectively (age = 52 ± 22 vs. 52 ± 21 years, p = 0.74; APACHE II = 24 ± 9 vs. 24 ± 10, p = 0.83). During these periods, there were no differences in ICU (adjusted odds ratio (aOR) 0.98, 95% confidence interval [CI] 0.7-1.3) and in hospital mortality (aOR 1.00, 95% CI 0.8-1.3). CPOE implementation was associated with similar duration of mechanical ventilation and of stay in the ICU and hospital. There was no increased mortality or stay in the high risk subgroups after CPOE implementation. CONCLUSIONS: The implementation of CPOE in an adult medical surgical ICU resulted in no improvement in patient outcomes in the immediate phase and up to 12 months after implementation.

Low-dose hydrocortisone in patients with cirrhosis and septic shock: a randomized controlled trial.

BACKGROUND: Recent studies have reported a high prevalence of relative adrenal insufficiency in patients with liver cirrhosis. However, the effect of corticosteroid replacement on mortality in this high-risk group remains unclear. We examined the effect of low-dose hydrocortisone in patients with cirrhosis who presented with septic shock. METHODS: We enrolled patients with cirrhosis and septic shock aged 18 years or older in a randomized double-blind placebo-controlled trial. Relative adrenal insufficiency was defined as a serum cortisol increase of less than 250 nmol/L or 9 µg/dL from baseline after stimulation with 250 µg of intravenous corticotropin. Patients were assigned to receive 50 mg of intravenous hydrocortisone or placebo every six hours until hemodynamic stability was achieved, followed by steroid tapering over eight days. The primary outcome was 28-day all-cause mortality. RESULTS: The trial was stopped for futility at interim analysis after 75 patients were enrolled. Relative adrenal insufficiency was diagnosed in 76% of patients. Compared with the placebo group (n = 36), patients in the hydrocortisone group (n = 39) had a significant reduction in vasopressor doses and higher rates of shock reversal (relative risk [RR] 1.58, 95% confidence interval [CI] 0.98-2.55, p = 0.05). Hydrocortisone use was not associated with a reduction in 28-day mortality (RR 1.17, 95% CI 0.92-1.49, p = 0.19) but was associated with an increase in shock relapse (RR 2.58, 95% CI 1.04-6.45, p = 0.03) and gastrointestinal bleeding (RR 3.00, 95% CI 1.08-8.36, p = 0.02). INTERPRETATION: Relative adrenal insufficiency was very common in patients with cirrhosis presenting with septic shock. Despite initial favourable effects on hemodynamic parameters, hydrocortisone therapy did not reduce mortality and was associated with an increase in adverse effects. (Current Controlled Trials registry no. ISRCTN99675218.).

A per-protocol initiation of sacubitril/valsartan in an advanced heart failure disease management programme in the Middle East Gulf Region.

AIMS: The aim of this study is to evaluate the utilization and success in therapy intensification after initiation of sacubitril/valsartan using a specified protocol within an advanced heart failure and transplant programme in the Middle East Gulf Region. METHODS AND RESULTS: We studied a single-centre, retrospective cohort in a 364-bedded multi-speciality hospital located in the United Arab Emirates (February 2016 to July 2017). The advanced heart failure and transplant programme formulated an institutional protocol for initiation of sacubitril/valsartan with defined criteria for switching from angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB). Prescribing this drug is intended for patients with heart failure with reduced ejection fraction with left ventricular ejection fraction ≤40%. We excluded patients (i) with age below 18 years or (ii) initiated on sacubitril/valsartan from an outside hospital with or without follow-up in our outpatient clinic. We included 102 patients with an average initial dose of 78.9 ± 44.2 mg twice daily. Only 17 patients were on target doses of ACEI or ARB prior to switching to sacubitril/valsartan. Up-titration was successful in 55 patients during the follow-up period. In addition, 6.9% patients were hospitalized with heart failure exacerbation. In patients with elevated baseline serum potassium prior to initiating this medication, the serum potassium levels decreased post-initiation by 0.5 ± 0.3 mmol/L (P = 0.0008). CONCLUSIONS: Initiating sacubitril/valsartan through a defined protocol selects for appropriate candidates and guides starting dose and titration. Overall, significant success can be achieved in replacing ACEI or ARB by sacubitril/valsartan in symptomatic heart failure with reduced ejection fraction patients.

Recombinant activated factor VII treatment of retroperitoneal hematoma in a patient with renal failure receiving enoxaparin and clopidogrel.

Enoxaparin is a low-molecular-weight heparin that has pharmacokinetic and therapeutic advantages over unfractionated heparin in certain clinical conditions. However, its administration is not without risk. We describe the case of a 70-year-old woman with numerous medical problems who developed severe retroperitoneal bleeding after receiving several therapeutic doses of subcutaneous enoxaparin that inadvertently were not adjusted for her renal function until day 14 of therapy. She had severe bleeding with hemodynamic instability and required massive transfusions of blood products. Her bleeding could be controlled only by administration of four doses of recombinant activated factor VII (factor VIIa) in addition to embolization of the bleeding sites through angiographic microcoiling. The patient's hemodynamic status improved, and her hemoglobin level stabilized. This case report provides evidence of the clinical effectiveness of factor VIIa use as part of the management of refractory enoxaparin-induced retroperitoneal bleeding. However, further studies are needed to validate the dose-response relationship and further support the clinical utility of factor VIIa in this life-threatening situation.

Knowledge of thromboprophylaxis guidelines pre- and post-didactic lectures during a venous thromboembolism awareness day at a tertiary-care hospital.

BACKGROUND: Didactic lectures are frequently used to improve compliance with practice guidelines. This study assessed the knowledge of health-care providers (HCPs) at a tertiary-care hospital of its evidence-based thromboprophylaxis guidelines and the impact of didactic lectures on their knowledge. METHODS: The hospital launched a multifaceted approach to improve thromboprophylaxis practices, which included posters, a pocket-size guidelines summary and didactic lectures during the annual thromboprophylaxis awareness days. A self-administered questionnaire was distributed to HCPs before and after lectures on thromboprophylaxis guidelines (June 2010). The questionnaire, formulated and validated by two physicians, two nurses and a clinical pharmacist, covered various subjects such as risk stratification, anticoagulant dosing and the choice of anticoagulants in specific clinical situations. RESULTS: Seventy-two and 63 HCPs submitted the pre- and post-test, respectively (62% physicians, 28% nurses, from different clinical disciplines). The mean scores were 7.8 ± 2.1 (median = 8.0, range = 2-12, maximum possible score = 15) for the pre-test and 8.4 ± 1.8 for the post-test, P = 0.053. There was no significant difference in the pre-test scores of nurses and physicians (7.9 ± 1.7 and 8.2 ± 2.4, respectively, P = 0.67). For the 35 HCPs who completed the pre- and post-tests, their scores were 7.7 ± 1.7 and 8.8 ± 1.6, respectively, P = 0.003. Knowledge of appropriate anticoagulant administration in specific clinical situations was frequently inadequate, with approximately two-thirds of participants failing to adjust low-molecular-weight heparin doses in patients with renal failure. CONCLUSIONS: Education via didactic lectures resulted in a modest improvement of HCPs' knowledge of thromboprophylaxis guidelines. This supports the need for a multifaceted approach to improve the awareness and implementation of thromboprophylaxis guidelines.

Advantages and disadvantages of etomidate use for intubation of patients with sepsis.

Etomidate is a potent imidazole hypnotic used widely in single doses in the rapid sequence intubation of critically ill patients with sepsis due to its presumed hemodynamic safety, fast onset, and short duration of action. However, the literature is conflicting regarding the hemodynamic advantages of etomidate over other induction agents, and its safety in this population is a matter of strong debate in the critical care community as the drug is associated with suppression of adrenal steroidogenesis, which can last up to 72 hours after a single dose, primarily through potent inhibition of the 11ß-hydroxylase enzyme. However, the clinical impact of this adrenal suppressive effect is not certain. The use of continuous-infusion etomidate in critically ill patients was abandoned more than 20 years ago due to reports of increased mortality. Nevertheless, mortality data of single-dose etomidate are still controversial, with no strong evidence of benefit over other agents and a tendency toward harm (keeping in mind the limitations of the available literature). Proponents of single-dose etomidate use in patients with sepsis suggest that the increased mortality associated with etomidate is merely a reflection of the patients' severity of illness and not related to the drug itself, whereas others believe that the drug causes true harm and increases mortality in this population. In view of the lack of a clear clinical advantage of etomidate over other agents used in rapid sequence intubation, it would be prudent to favor other agents until further conclusive evidence of etomidate safety is available in critically ill patients with sepsis.

Clinical experience with alteplase in the management of intracardiac and major cardiac vessels thrombosis in pediatrics: a case series.

BACKGROUND AND OBJECTIVES: Experience with alteplase in pediatric patients is limited and recommendations are extrapolated from adult data. Comprehensive guidelines on the management of thromboembolic events in this group are lacking. We assessed the efficacy and safety of alteplase (recombinant tissue plasminogen activator) in the management of intracardiac and major cardiac vessel thrombosis in pediatric patients. METHODS: All pediatric patients, 14 years of age and younger, with intracardiac or major cardiac vessel thrombus who were treated with alteplase from 1997 to 2004 at our tertiary care institute were identified through the pharmacy database. Patient data were retrospectively evaluated for the efficacy and safety of altepase. RESULTS: Five cases were eligible out of nineteen who received alteplase. Patient ages ranged from 40 days to 13 years. The initial dose of alteplase ranged from 0.3 to 0.6 mg/kg followed by a continuous infusion in three patients with a dosage range between 0.05 and 0.5 mg/kg/hr, while intermittent infusion was used in the other two patients. The duration of therapy ranged from 2 to 4 days. By the end of the treatment, two patients had complete resolution of thrombus and one had partial resolution. Two patients failed to respond and had "old" thrombus. Major bleeding events were reported in three patients. The rest had minor bleeding events. CONCLUSION: Alteplase may effectively dissolve intracardiac thrombi, particularly when freshly formed. Continuous infusion for a long duration appears to be associated with an increased risk of major bleeding. Optimal dose and duration of infusion are still unknown.