Objectives: To assess the evidence and discuss the risks and clinical relevance of ketamine for the treatment of various disease states impacting the adult critically ill population. Data Sources: A literature review was performed using PubMed evaluating primary literature published until August 2018. Study Selection: Case reports, observational studies (cohort, case-control), and randomized controlled trials involving patients 18 years and older in a nonperioperative setting using either IV or intramuscular ketamine were included for analysis. Uses of ketamine discussed focused on critically ill patients in the ICU and emergency department settings. Data Extraction: Included studies were evaluated for dosing, outcomes, and adverse effects of ketamine. For each study, the design, population, intervention, investigated outcomes, and results were assessed. Data Synthesis: The evidence was organized according to use of ketamine, which included pain, sedation, status asthmaticus, alcohol withdrawal syndrome, status epilepticus, and acute behavioral psychologic disturbances. Evaluation of the evidence was based on the included primary literature along with any related guideline recommendations. Conclusions: Ketamine has suggested potential benefit in several disease states impacting critically ill patients including pain, alcohol withdrawal syndrome, status epilepticus, and acute agitation. Further supporting evidence is needed to validate its use in the setting of critical illness.

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Background: Essential to the coagulation pathway, vitamin K (phytonadione) is used to correct clotting factor deficiencies and for reversal of warfarin-induced bleeding. In practice, high-dose intravenous (IV) vitamin K is often used, despite limited evidence supporting repeated dosing. Objective: This study sought to characterize differences in responders and nonresponders to high-dose vitamin K to guide dosing strategies. Methods: This was a case-control study of hospitalized adults who received vitamin K 10 mg IV daily for 3 days. Cases were represented by patients who responded to the first dose of IV vitamin K and controls were nonresponders. The primary outcome was change in international normalized ratio (INR) over time with subsequent vitamin K doses. Secondary outcomes included factors associated with response to vitamin K and incidence of safety events. The Cleveland Clinic Institutional Review Board approved this study. Results: There were 497 patients included, and 182 were responders. Most patients had underlying cirrhosis (91.5%). In responders, the INR decreased from 1.89 at baseline (95% CI = [1.74-2.04]) to 1.40 on day 3 (95% CI = [1.30-1.50]). In nonresponders, the INR decreased from 1.97 (95% CI = [1.83-2.13]) to 1.85 ([1.72-1.99]). Factors associated with response included lower body weight, absence of cirrhosis, and lower bilirubin. There was a low incidence of safety events observed. Conclusions: In this study of mainly patients with cirrhosis, the overall adjusted decrease in INR over 3 days was 0.3, which may have minimal clinical impact. Additional studies are needed to identify populations who may benefit from repeated daily doses of high-dose IV vitamin K.

We appreciate the thoughtful discussion surrounding our article of the response to high-dose intravenous (IV) vitamin K. 1 We agree with Dr. Gilbert that the use of vitamin K in nonbleeding cirrhosis patients is likely unnecessary. As a cofactor of γ-glutamyl carboxylase, vitamin K plays a critical role in clotting factor development. 2,3 However, its role in hemostasis may be compromised in cirrhosis where the synthesis of clotting factors is impaired. 4 The evidence to date has not supported the routine use of vitamin K in this population and despite the fact that giving repeated daily doses is not a guideline recommendation, it is commonly seen in clinical practice, which prompted the current evaluation. 5 It should be noted that our objective was not to critique the methods of measuring dysfunctions of hemostasis or to identify who should be the recipient of vitamin K, but rather to evaluate response to repeated supplementation-a common practice we have observed to rule out possible deficiencies in patients with elevated international normalized ratios (INRs).We agree with and acknowledge the limitations noted by Dr. Gilbert of defining coagulopathy using the INR and associating a reduction in INR with a reduction in hemorrhage risk. Since first adopted in the 1980s, the INR has proved to be a simple and valuable laboratory test for monitoring oral anticoagulation therapy and has since been used to provide important clinical information for bleeding and thrombotic disorders. 6 However, like any other clinical tool, its utility is only as good as one's ability to recognize its function and limitations. For better or worse, INR is closely tied to acute and long-term liver disease to inform severity and prognosis. As such, and despite its propensity to mischaracterize patients' risk for bleeding, INR continues to be a regularly monitored laboratory test in those with cirrhosis. As seen in our study, some patients (n=183, 36.8%) even experienced increases in INR following initial vitamin K administration but still may have been nonbleeding. Until an International Sensitivity Index (ISI) is validated for cirrhosis, INR provides little more than a qualitative indication of presence of liver disease. 4 We share similar disdain for the term "auto-anticoagulation" which ignores the deficiencies of the anticoagulation system and increased production of factor VIII seen in cirrhosis, and the risk of thrombotic complications. 7 Instead, we favor employing more functional evaluations of coagulation with viscoelastic testing, as suggested, to direct