Dinesh Yogaratnam

Incidence of propofol-related infusion syndrome in critically ill adults: a prospective, multicenter study

IntroductionWhile propofol is associated with an infusion syndrome (PRIS) that may cause death, the incidence of PRIS is unknown. Determining the incidence of PRIS and the frequency of PRIS-related clinical manifestations are key steps prior to the completion of any controlled studies investigating PRIS. This prospective, multicenter study sought to determine the incidence of PRIS and PRIS-related clinical manifestations in a large cohort of critically ill adults prescribed propofol.MethodsCritically ill adults from 11 academic medical centers administered an infusion of propofol for [>/=] 24 hours were monitored at baseline and then on a daily basis until propofol was discontinued for the presence of 11 different PRIS-associated clinical manifestations and risk factors derived from 83 published case reports of PRIS.ResultsAmong 1017 patients [medical (35%), neurosurgical (25%)], PRIS (defined as metabolic acidosis plus cardiac dysfunction and [>/=] 1 of: rhabdomyolysis, hypertriglyceridemia or renal failure occurring after the start of propofol therapy) developed in 11 (1.1%) patients an average of 3 (1-6) [median (range)] days after the start of propofol. While most (91%) of the patients who developed PRIS were receiving a vasopressor (80% initiated after the start of propofol therapy), few received a propofol dose >83 mcg/kg/min (18%) or died (18%). Compared to the 1006 patients who did not develop PRIS, the APACHE II score (25 +/- 6 vs 20 +/- 7, P = 0.01) was greater in patients with PRIS but both the duration of propofol use (P = 0.43) and ICU length of stay (P = 0.82) were similar.ConclusionsDespite using a conservative definition for PRIS, and only considering new-onset PRIS clinical manifestations, the incidence of PRIS slightly exceeds 1%. Future controlled studies focusing on evaluating whether propofol manifests the derangements of critical illness more frequently than other sedatives will need to be large. These studies should also investigate the mechanism(s) and risk factors for PRIS.

Introduction to Drug Pharmacokinetics in the Critically III Patient

Despite regular use of drugs for critically ill patients, overall data are limited regarding the impact of critical illness on pharmacokinetics (PK). Designing safe and effective drug regimens for patients with critical illness requires an understanding of PK. This article reviews general principles of PK, including absorption, distribution, metabolism, and elimination, and how critical illness can influence these parameters. In the area of drug absorption, we discuss the impact of vasopressor use, delayed gastric emptying and feeding tubes, and nutrient interactions. On the topic of drug distribution, we review fluid resuscitation, alterations in plasma protein binding, and tissue perfusion. With drug metabolism, we discuss hepatic enzyme activity, protein binding, and hepatic blood flow. Finally, we review drug elimination in the critically ill patient and discuss the impact of augmented renal clearance and acute kidney injury on drug therapies. In each section, we highlight select literature reviewing the PK impact of these conditions on a drug PK profile and, where appropriate, provide general suggestions for clinicians on how to modify drug regimens to manage PK challenges.

Propylene Glycol-Induced Lactic Acidosis in a Patient Receiving Continuous Infusion Pentobarbital:

Objective: To report a case of probable propylene glycol (PG) toxicity in a patient receiving continuous infusion of pentobarbital for refractory status epilepticus. Case Summary: A 59-yoar-old woman with a declining mental status was admitted to the intensive care unit for management of status epilepticus. After failing to achieve the therapeutic endpoint of electroencephalogram burst suppression with a continuous infusion of propofol, the sedative regimen was changed to continuous infusion of pentobarbital. The patient received a loading dose of 450 mg (5 mg/kg), and the maintenance infusion was titrated to a dose of 10 mg/kg/h to achieve burst suppression. Twelve hours after the pentobarbital infusion was started, the patient developed an anion gap metabolic acidosis, elevated serum lactate level, hyperosmolality, and increased osmolal gap. The pentobarbital infusion was discontinued, and the patients acidosis and hyperosmolality resolved. Discussion: Pentobarbital contains 40% v/v of PG, which was thought to be a potential source of the patients metabolic derangements. Reports of toxicity with drugs containing PG. particularly intravenous lorazepam, have been well described in the literature. What we describe, however, is one of few reports involving intravenous pentobarbital. The Naranjo probability scale supports a probable drug-related adverse event in our patient. Conclusions: PG toxicity is a potential complication associated with intravenouspentobarbital. Practitioners should be aware of the PG content of pentobarbital and should be familiar with the signs and symptoms associated with PG toxicity.

Pirfenidone: A Novel Agent for the Treatment of Idiopathic Pulmonary Fibrosis

OBJECTIVE To evaluate the published clinical literature on the role of pirfenidone for the treatment of idiopathic pulmonary fibrosis (IPF). DATA SOURCES A systematic literature search was performed using the key words pirfenidone or Esbriet, alone and in combination, with IPF or idiopathic pulmonary fibrosis (expanded using MESH terminology). MEDLINE (1948-September 2012) was the primary database used for search purposes. In addition, all available articles and abstracts referenced by the articles identified via literature search were included. STUDY SELECTION AND DATA EXTRACTION The search was limited to English-language publications. All available clinical trials of pirfenidone pertinent to its pharmacology, pharmacokinetics, efficacy, and safety were included. DATA SYNTHESIS Pirfenidone is the first agent specifically developed for the treatment of IPF. It has been approved for use in Europe and Japan, but not in the US. Although Phase 3 trials have shown pirfenidone to improve certain clinical (6-minute walk test) and functional (change in forced vital capacity) outcomes in patients with IPF, an independent benefit on either mortality or acute exacerbation rates has yet to be demonstrated. Until more definitive supportive data are available, international guidelines have recommended against using pirfenidone to treat most patients with IPF. CONCLUSIONS Although pirfenidone appears to be an effective treatment for IPF, additional clinical trials are needed to better delineate its risk-benefit profile.

Idarucizumab for Reversal of Dabigatran-Associated Anticoagulation

Objective: To review clinical data on idarucizumab for the reversal of dabigatran-associated anticoagulation. Data Sources: Articles for this review were identified via PubMed using the MeSH term dabigatran combined with the keyword idarucizumab. Additional online searches via PubMed and Google Scholar were conducted for both prescribing and cost information. Study Selection and Data Extraction: English-language clinical trials published between 1946 and May 2016 were included for review. Bibliographies of selected articles were also manually reviewed for relevant publications that focused on reversal strategies for dabigatran-associated anticoagulation. Data Synthesis: The safety and tolerability of idarucizumab has been evaluated in 3 phase I clinical trials. The use of idarucizumab for reversing dabigatran-associated anticoagulation is also being evaluated in the phase III RE-VERSE AD study. Interim results of the RE-VERSE AD study have been published. Conclusions: Idarucizumab rapidly neutralizes the anticoagulant effect of dabigatran in healthy volunteers, in patients with life-threatening bleeding, and in patients requiring urgent surgery that cannot be delayed. These observations are largely based on laboratory assessments rather than clinical outcomes. Idarucizumab is well tolerated, and it does not appear to induce procoagulant or immunogenic adverse effects.

Nutrition as Medical Therapy

Recent data support the use of nutritional agents for use as targeted medical therapy. This article reviews some of the pharmacologic roles that parenteral nutritional ingredients (selenium, lipid emulsion, insulin, and levocarnitine) can play in the setting of critical illness.

Liver failure. Preface.

The liver is a complex organ responsible for myriad physiologic functions. Drug and toxin metabolism, protein synthesis, and glucose and nutrient regulation are just some of the crucial roles the liver plays in the human body. Not surprisingly, acute and chronic liver injury can lead to a plethora of both short-term and long-term adverse consequences. In this issue of Critical Care Nursing Clinics of North America, experts from a variety of disciplines discuss the challenges and controversies surrounding the care of the critically ill patient suffering from liver disease. Acute liver disease portends a very poor prognosis. Foston provides an overview of this devastating disease state and touches on a variety of topics that are further elucidated in the other articles in this issue. Infectious complications as a result of chronic liver disease can result in significant morbidity. Mehta and Lyon describe the risk factors associated with infection and provide a detailed discussion on specific pathogens, sites of infection, and issues surrounding antibiotic selection. They also describe the role of vaccinations and the impact of infectious disease on transplant considerations. Patients who are admitted to an intensive care unit will often require numerous medications during their acute illness. In the presence of liver disease, designing a pharmacotherapy regimen can become even more complicated. Lin and Smith discuss the consequences of altered liver function on the pharmacokinetics and pharmacodynamics of drugs. In addition, they provide general guidance on how to prospectively manage and evaluate drug therapy in the hepatically injured patient. Drug therapy can sometimes result in liver toxicity, which can occasionally be serious and fatal. Kim, Hattori, and Phongsamran discuss the epidemiology and risk factors associated with drug-induced liver disease. The pathophysiology associated with different toxic agents is discussed, and management and preventative strategies are put forth. Nutritional support is a vitally important component in the management in liver disease. Inappropriate supplementation can increase the risk of complications, such as hepatic encephalopathy. Zhao and Ziegler provide an in-depth discussion on the many complex issues surrounding macroand micronutrient support in liver disease.