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Objectives: To review the current definitions and diagnostic criteria for acute kidney injury (AKI) and type 1 hepatorenal syndrome (HRS) now termed HRS-AKI and discuss the challenges in deciding the most appropriate medication regimens to treat patients with HRS-AKI.Data sources: PubMed (inception to April 2023) with bibliographies of retrieved articles searched for additional articles; organizational websites for clinical practice guidelines (CPGs).Study selection and data extraction: Randomized controlled trials (RCTs) evaluating albumin and vasoconstrictors for HRS-AKI.Data synthesis: A major change in the most recent revision of definitions and diagnostic criteria for HRS-AKI is the elimination of the set cutoff serum creatinine values for AKI. This change should be considered when comparing studies of HRS-AKI over time. Albumin has been administered to both vasoconstrictor treatment and placebo groups in all recent RCTs; however, there has never been a large RCT evaluating a no-albumin group. Most prospective trials comparing a midodrine/octreotide combination or norepinephrine to placebo or terlipressin have enrolled less than 100 patients limiting any conclusions regarding clinically important outcomes. Terlipressin with albumin has shown mixed results for complete HRS-AKI reversal with no reductions in crude mortality but adverse effect concerns involving ischemic and pulmonary events.Relevance to patient care and clinical practice: Type 1 hepatorenal syndrome with acute kidney injury is a potentially life-threatening syndrome with diagnostic and treatment challenges. Albumin plus a vasoconstrictor has become the routine HRS-AKI treatment even though there has not been a large RCT evaluating a no-albumin group. Terlipressin is the vasoconstrictor of choice for HRS-AKI in current CPGs, but it has adverse effect concerns and, until recently, was not available in the United States.Conclusions: In conjunction with changes in the definitions and diagnostic criteria for HRS-AKI, debate continues regarding the optimal therapy for HRS-AKI, particularly considering recent trials demonstrating ischemic and pulmonary adverse events with terlipressin used in combination with albumin.

Monoclonal antibody products are an increasing portion of novel drug approvals. The labeling of initial drug approvals frequently involves body-size-based rather than fixed-dose administration regimens for adults without clear rationale for doing so. This presents challenges when prescribing these products for patients with extremes of body habitus who constitute a small portion of enrollment in pre-approval investigations. Fixed-dose regimens allow for standardized preparation with the potential to reduce the risk of calculation errors, drug waste, and make home administration more practical. Fixed-dose rather than body-size-based monoclonal antibody regimens should serve as the initial approach in early phase 1 clinical trials.

Background: Current critical care pharmacist (CCP) practices and perceptions related to neuromuscular infusion (NMBI) use for acute respiratory distress syndrome (ARDS) maybe different with the COVID-19 pandemic and the publication of 2020 NMBI practice guidelines.Objective: To evaluate CCP practices and perceptions regarding NMBI use for patients with moderate-severe ARDS.Methods: We developed, tested, and electronically administered a questionnaire (7 parent-, 42 sub-questions) to 409 American College of Clinical Pharmacy (ACCP) Critical Care Practice and Research Network members in 12 geographically diverse states. The questionnaire focused on adults with moderate-severe ARDS (PaO2:FiO2<150) whose causes of dyssynchrony were addressed. Two reminders were sent at 10-day intervals.Results: Respondents [131/409 (32%)] primarily worked in a medical intensive care unit (ICU) 102 (78%). Compared to COVID-negative(-) ARDS patients, COVID positive(+) ARDS patients were twice as likely to receive a NMBI (34 ± 18 vs.16 ± 17%; P< 0.01). Respondents somewhat/strongly agreed a NMBI should be reserved until after trials of deep sedation (112, 86%) or proning (92, 81%) and that NMBI reduced barotrauma (88, 67%), dyssynchrony (87, 66%), and plateau pressure (79, 60%). Few respondents somewhat/strongly agreed that a NMBI should be initiated at ARDS onset (23, 18%) or that NMBI reduced 90-day mortality (12, 10%). Only 2/14 potential NMBI risks [paralysis awareness (101, 82%) and prolonged muscle weakness (84, 68%)] were frequently reported to be of high/very high concern. Multiple NMBI titration targets were assessed as very/extremely important including arterial pH (109, 88%), dyssynchrony (107, 86%), and PaO2: FiO2ratio (82, 66%). Train-of-four (55, 44%) and BIS monitoring (36, 29%) were deemed less important. Preferred NMBI discontinuation criteria included absence of dysschrony (84, 69%) and use ≥48 hour (72, 59%).Conclusions and Relevance: Current critical care pharmacists believe NMBI for ARDS patients are best reserved until after trials of deep sedation or proning; unique considerations exist in COVID+ patients. Our results should be considered when ICU NMBI protocols are being developed and bedside decisions regarding NMBI use in ARDS are being formulated.

Albumin has only reduced crude mortality in one randomized controlled trial conducted to date. This raises the question as to why potentially beneficial oncotic and pleiotropic properties of albumin do not consistently translate into clinically important outcomes. Four postulated explanations are provided as to why the theoretical advantages of albumin are not apparent in clinical trials: diminished oncotic action due to leakage of albumin from the intravascular compartment, modification of the pleiotropic properties of albumin both in vitro and in vivo, the ability of other plasma proteins to take over the major functions of albumin, and possible adverse effects.

Objectives The purpose of this article is to summarize the results of major randomized controlled trials (RCTs) comparing clinical outcomes of critically ill patients treated with normal saline (NS) or balanced salt solutions (BSSs), address discordant results of these studies, and provide direction for future investigations.Data Sources PubMed (2011 to January 2022) with bibliographies of retrieved articles searched for additional articles.Study Selection and Data Extraction RCTs comparing NS and BSSs in critically ill adult patients.Data Synthesis Recently published large RCTs comparing NS with BSSs in heterogeneous populations of intensive care unit patients did not find significant differences in mortality, despite positive findings in some end points in prior RCTs. However, there were a number of methodologic issues common to the RCTs including: varying study designs and end points, clinician discretion for the majority or all treatments other than the primary intervention fluid, heterogeneous patients with varying levels of acuity, and lack of power to investigate potential subgroup differences. In addition, there were problematic issues related to blinding and use of nonstudy fluids.Relevance to Patient Care and Clinical Practice Intravenous fluids are a mainstay of supportive care for critically ill patients. Similar to the so-called crystalloid-colloid debate, there has been a long-standing debate among critical care clinicians and researchers concerning the preferred crystalloid solution, NS versus one of the available BSSs.Conclusions Despite the recent publication of large multicenter RCTs, the preferred resuscitation fluid, NS or a BSS, for critically ill patients is still open for debate, although the available investigations do provide some direction for clinicians and for future investigations.

Objectives: To review the clinical usefulness of the biomarker TIMP-2•IGFBP7 in adult, general medical-surgical intensive care unit (ICU) settings.Data Sources: PubMed (1946 to mid-February 2021) and EMBASE (1947 to mid-February 2021) with bibliographies of retrieved articles reviewed for additional articles.Study Selection and Data Extraction: Studies evaluating use of the urinary TIMP-2•IGFBP7 assay in adult patients in ICU settings.Data Synthesis: Studies published after investigations leading to TIMP-2•IGFBP7 assay approval confirm the appropriateness of considerations discussed in product labeling, such as use of the test within 12 hours of assessment, use of a dichotomous 0.3 (ng/mL)2/1000 cutoff, and use only in combination with other assessments of acute kidney injury (AKI). However, as a biomarker routinely used for early identification of patients at risk for AKI in mixed ICU populations, the additional resources required for TIMP-2•IGFBP monitoring are difficult to justify because of limited data demonstrating usefulness in preventing or ameliorating AKI and its attendant complications.Relevance to Patient Care and Clinical Practice: Biomarkers are potentially useful not only for assessment and diagnosis of AKI, but also for practitioners involved in the management of nephrotoxic medications and medications needing adjustment for decreased kidney function.Conclusions: Although there is evidence to suggest that the urinary TIMP-2•IGFBP7 biomarker is helpful in predicting AKI progression in general medical-surgical ICU patients when used within 12 hours of patient assessment in combination with routine testing, including serum creatinine and urine output, there is little evidence that its use leads to improvements in clinically important patient outcomes.

Objectives: To discuss methods for the assessment of creatinine clearance (Clcr) when serum creatinine (SCr) is not at steady state in order to estimate kidney function and apply the estimate to kidney function staging for clinical assessment or drug dosing.Data Sources: A PubMed search was conducted from 1976 to mid-January 2021 with other articles identified through review of bibliographies of retrieved articles and citations in Scopus.Study Selection and Data Extraction: Articles assessing Clcrunder non–steady-state conditions and studies evaluating predictive equations were selected.Data Synthesis: When SCr is systematically changing (ie, trending up or down), kinetic methods to estimate Clcrare appropriate. Estimates from kinetic methods should be individual based and not indexed to body surface area, and careful monitoring is required to confirm predictions as the situation evolves. Standard methods intended for steady-state conditions should not be used to estimate Clcrin patients with unstable SCr.Relevance to Patient Care and Clinical Practice: Creatinine continues to be a monitoring parameter of choice and is an important variable in all the commonly used equations for estimating Clcrand most important for estimating glomerular filtration rate. However, standard methods of estimating Clcrfor medication dosing are not accurate under non–steady-state conditions.Conclusion: The methods for kinetic clearance estimation and standards methods for clearance estimation, such as the Cockcroft-Gault equation, are mutually exclusive. There are no benefits of using the kinetic method in patients with stable SCr concentrations, and standard equations are not appropriate with unstable SCr concentrations.

Objectives The purpose of this critical narrative review is to discuss common indications for ordering serum albumin levels in adult critically ill patients, evaluate the literature supporting these indications, and provide recommendations for the appropriate ordering of serum albumin levels.Data Sources PubMed (1966 to August 2020), Cochrane Library, and current clinical practice guidelines were used, and bibliographies of retrieved articles were searched for additional articles.Study Selection and Data Extraction Current clinical practice guidelines were the preferred source of recommendations regarding serum albumin levels for guiding albumin administration and for nutritional monitoring. When current comprehensive reviews were available, they served as a baseline information with supplementation by subsequent studies.Data Synthesis Serum albumin is a general marker of severity of illness, and hypoalbuminemia is associated with poor patient outcome, but albumin is an acute phase protein, so levels vacillate in critically ill patients in conjunction with illness fluctuations. The most common reasons for ordering serum albumin levels in intensive care unit (ICU) settings are to guide albumin administration, to estimate free phenytoin or calcium levels, for nutritional monitoring, and for severity-of-illness assessment.Relevance to Patient Care and Clinical Practice Because hypoalbuminemia is common in the ICU setting, inappropriate ordering of serum albumin levels may lead to unnecessary albumin administration or excessive macronutrient administration in nutritional regimens, leading to possible adverse effects and added costs.Conclusions With the exception of the need to order serum albumin levels as a component of selected severity-of-illness scoring systems, there is little evidence or justification for routinely ordering levels in critically ill patients.

Background: Inappropriate albumin use in clinical practice remains problematic. Health-systems face continued challenges in promoting cost-appropriate use.Objective: To evaluate the clinical and economic impact of a clinical pharmacist–led intervention strategy targeting inappropriate albumin use in general ward patients.Methods: A retrospective cohort study evaluated all adult (≥18 years) general ward patients administered ≥1 dose of albumin at a university medical center over a 2-year period. The intervention consisted of a clinical pharmacist–led strategy intervening on all albumin orders not in accordance with institutional guidelines. The primary end point was to compare inappropriate albumin utilization before and after implementation. Secondary end points compared the rates of inappropriate albumin use adjusted for hospital admission and patient-days as well as associated costs by appropriateness between study periods.Results: A total of 4420 patients were screened, with 1971 (44.6%) patients meeting inclusion criteria. The clinical pharmacist strategy significantly reduced inappropriate albumin (grams) utilization by 86.0% (P< 0.001). A 7-fold reduction of inappropriate albumin administered adjusted for the number of patient admissions was found from the preimplementation period following clinical pharmacist intervention strategy implementation (415.3 ± 83.2 vs 57.5 ± 34.2 g per 100 general ward hospital admissions, respectively; P< 0.001). Also, the adjusted inappropriate albumin rate was reduced from 62.2 ± 12.3 to 8.6 ± 5.2 g per 100 patient-days in the preimplementation and postimplementation periods, respectively (P< 0.001). Annual cost savings were $421 455 overall, with $341 930 resulting from mitigation of inappropriate use.Conclusion and Relevance: Clinical pharmacist–led interventions significantly reduced inappropriate albumin use and costs in hospitalized patients.

Objectives: To discuss the evidence and caveats associated with estimated and measured creatinine clearance (eClCr and mClCr) and glomerular filtration rate (eGFR and mGFR) assessments of kidney function in patients with more extreme forms of obesity.Data Sources: PubMed (1976 to mid-May 2020) was used, with bibliographies of retrieved articles searched for additional articles.Study Selection and Data Extraction: Articles using gold standard mGFR to evaluate eClCr, mClCr, and eGFR assessments of kidney function in patients with more extreme forms of obesity were included.Data Synthesis: The overestimation of GFR by mClCr is well established, but mClCr is an alternative to mGFR assessments for determining medication dosing in patients with extremes of body size or muscle mass, or in patients receiving narrow therapeutic index medications when eGFR is likely to be inaccurate. The vast majority of studies comparing eGFR assessments with gold standard indicators of kidney function were attempts to validate eGFR equations for diagnosing and staging chronic kidney disease (CKD).Relevance to Patient Care and Clinical Practice: For dosing medications in patients with stable kidney function and extreme obesity, a deindexed 4-variable Modification of Diet in Renal Disease or CKD Epidemiology Collaboration equation is an alternative to Cockcroft-Gault. Consistent use of the same equation by provider and between providers within any given setting is of paramount importance.Conclusions: In patients with extreme obesity and stable kidney function, eClCr or eGFR using deindexed values provides estimates of function for dosing adjustments of medications with elimination by the kidneys, but more research is needed with respect to the best size descriptor to use with estimating equations.

Objectives:The purpose of this critical narrative review is to discuss the revised Starling equation for microvascular fluid exchange and the associated implications for intravenous fluid administration. Data Sources:PubMed (1946 to December 2019) and EMBASE (1947 to December 2019) were used, and bibliographies of retrieved articles were searched for additional articles. Study Selection and Data Extraction:Articles pertaining to the revised Starling equation and microvascular fluid exchange. Additionally, prospective human studies involving the disposition and oncotic action of radiolabeled albumin and large randomized trials comparing fluid requirements associated with isotonic crystalloid and albumin administration were included. Data Synthesis:In the revised Starling equation, oncotic forces act across the endothelial cell layer, more specifically between the fluid in the vessel lumen and the protein-sparse subglycocalyx space. The revised Starling equation and radiolabeled investigations of albumin necessitate a reconsideration of conventional views of the plasma-expanding properties of exogenous albumin. Large clinical trials demonstrate that the administration of iso-oncotic or hyper-oncotic albumin solutions in patients undergoing resuscitation does not have the reductions in fluid requirements anticipated from a traditional understanding of the oncotic actions of albumin. Relevance to Patient Care and Clinical Practice:When used as a resuscitation fluid, albumin does not have the degree of plasma expansion or intravascular retention commonly used to justify its use. Conclusions:The principles underlying the revised Starling equation in conjunction with data from radiolabeled studies of albumin and large clinical trials demonstrate that albumin does not have the perceived degree of plasma expansion or duration of intravascular retention beyond crystalloid solutions predicted by the classic Starling equation.

Background:Optimal albumin use in the intensive care unit (ICU) remains challenging with inappropriate use approaching 50%. No published reports have described clinical pharmacist impact aimed at mitigating inappropriate albumin use in the ICU. Objective:To evaluate the clinical and economic impact of a clinical pharmacist–led intervention strategy targeting inappropriate albumin in the ICU. Methods:A retrospective cohort study evaluated all adult (≥18 years) ICU patients administered albumin at an academic medical center over a 2-year period. Institutional guidelines were developed with clinical pharmacists targeting inappropriate albumin use. The primary end point was to compare inappropriate use of albumin administered before and after pharmacist intervention implementation. Secondary analyses compared the overall albumin use between study periods. In-hospital mortality, length of stay, and albumin-related costs between study periods were also compared. Results:A total of 4419 patients were identified, with 2448 (55.4%) critically ill patients included. The pharmacist-led strategy resulted in a 50.9% reduction of inappropriate albumin use (P< 0.001). The rate of inappropriate albumin use was 44.3 ± 10.5 and 5.5 ± 2.9 g per patient-day in the preimplementation and postimplementation periods, respectively (P< 0.001). Costs associated with overall and inappropriate albumin use in the ICU decreased by 34.8% and 87.1%, respectively. Total annual cost-savings was $355 393 in the ICUs. No differences in clinical outcomes were found. Conclusion and Relevance:Clinical pharmacist–led interventions reduced overall and inappropriate albumin use and costs without negatively affecting clinical outcomes.

The removal of the X-waiver in the Mainstreaming Addiction Treatment (MAT) Act of 2023 has substantial implications for buprenorphine prescribing as one of the options to treat opioid use disorder. The purpose of this commentary is to discuss the unanswered questions regarding buprenorphine in the intensive care unit (ICU) including how the passage of the MAT Act will affect ICU providers, which patients should receive buprenorphine, what is the most appropriate route of administration and dose of buprenorphine, what medications interact with buprenorphine, and how can transitions of care be optimized for these patients.

Since 2020, there have been changes in Food and Drug Administration guidance and in recommendations by national organizations with a focus on kidney diseases pertaining to the choice of equations used to estimate creatinine clearance and glomerular filtration rate in patients with renal impairment. This includes a recommendation by the National Kidney Foundation to avoid the use of the Cockcroft-Gault equation for drug dosing in patients with renal impairment. This commentary provides an overview of recent recommendations concerning kidney function assessment that have important implications for drug dosing in patients with renal impairment and provides suggestions for implementing these recommendations.

Objective:To discuss why opioids have been considered the long-standing first-line therapy for treating acute, severe nociceptive pain in critically ill patients and discuss considerations for limiting opioid overuse in the intensive care unit setting. Data Sources:Articles were identified through searches of PubMed and EMBASE from database inception until December 2018. Additional references were located through a review of the bibliographies of articles and clinical practice guidelines. Study Selection and Data Extraction:Original research articles excluding case reports were included if they concerned nonopioid agents for pain management in critically ill patients. The focus was on studies not included in the most recent pain management guidelines. Data Synthesis:Ten studies were retrieved. Nonopioid therapies or opioid-sparing therapies have been touted as possible alternatives for critically ill patients, but they have particular adverse effects concerns in critically ill patients, often lack parenteral dosage forms, and frequently require dose adjustment or avoidance in patients with renal or hepatic dysfunction. Relevance to Patient Care and Clinical Practice:There is a well-recognized opioid epidemic that has been the subject of much discussion. Attempts to control the epidemic have focused on limiting opioid prescribing and using nonopioid alternatives, but there are special considerations when treating severe pain in critically ill patients that often preclude nonopioid analgesics. Conclusions:There continues to be an unmet need for medications that are as effective as opioids for severe nociceptive pain in critically ill patients but without the adverse effect and abuse concerns. Until such medications are available, clinicians need to optimize prescribing of opioid and nonopioid analgesics.

Background:Acute kidney injury (AKI) commonly occurs in patients with sepsis. Acetaminophen (APAP) has been shown to inhibit lipid peroxidation and, thus, may be renal protective in patients with sepsis. Objective: The objective of this study was to determine the effect of APAP on AKI in patients with sepsis. Methods:This was a retrospective cohort study conducted at 2 affiliated academic medical centers in the United States. Adult patients who were admitted to the intensive care unit with a diagnosis of severe sepsis were included. Patients were categorized based on whether APAP was received within the first 7 days of hospitalization (APAP or no APAP groups). The primary outcome measure was occurrence or increase in AKI stage from admission. Multivariate logistic regression analyses were used to adjust for potential confounders. Results:There were 238 patients who were included in the study cohort. Of these, 122 received APAP and 116 did not receive APAP. AKI or exacerbation occurred in 16.4% (n = 20) of patients in the APAP group and 19.8% (n = 23) of patients in the no APAP group (P= 0.505). After adjusting for the most important confounders, there was no significant association between APAP use and AKI (odds ratio = 1.2; 95% CI = 0.6-2.4; P= 0.639). Conclusion:APAP use in critically ill patients with sepsis may not reduce the occurrence or exacerbation of AKI.

Physicians and nurses have received many accolades in commercial and scientific media for their heroic efforts in caring for patients with COVID-19. These accolades are appropriate and deserved. However, there are a number of clinical pharmacists involved in the daily care of patients who are caring and competent practitioners, and also deserve our thanks and praise. The purpose of this article is to provide the impactful comments of a front-line, critical care pharmacist dedicated to providing the best possible care for patients with COVID-19 in a medical intensive care unit.

BACKGROUND: Three-factor prothrombin complex concentrate (PCC) is commonly used for reversal of international normalized ratio (INR) in patients who are bleeding or require emergency surgery. However, there is little information regarding the optimal dosing strategy for achieving adequate INR reversal.OBJECTIVE: To determine whether patients with higher initial INR levels are less likely to achieve adequate INR reversal after receiving 3-factor PCC.METHODS: A retrospective cohort study was conducted in a tertiary care medical center in the US. Patients who received 3-factor PCC were grouped into 2 categories based on degree of INR reversal after PCC infusion: (1) adequate reversal (final INR ≤1.5) or (2) inadequate reversal (final INR >1.5). Initial INR was compared between the 2 groups using the Wilcoxon rank-sum test. A multivariate logistic regression analysis was used to adjust for confounders and determine predictors of adequate INR reversal.RESULTS: Fifty patients met criteria for inclusion in the final analyses. Of these, 58% achieved adequate reversal after PCC. There were no significant differences in patient demographics or in vitamin K or fresh frozen plasma (FFP) use between the 2 groups. Median PCC dose was also similar between the adequate and inadequate reversal groups (25.2 vs 24.5 units/kg, respectively; p = 0.2). The group that did not achieve adequate reversal had a significantly higher initial INR (3.5 vs 2.5, p = 0.012) prior to PCC administration. In the multivariate logistic regression analysis, initial INR was a significant predictor of adequate INR reversal (ie, reversal less likely as INR increases) after adjusting for PCC dose and concurrent use of vitamin K or FFP (OR = 0.38; 95% CI 0.17 to 0.87; p = 0.02).CONCLUSIONS: Patients with a higher initial INR are less likely to achieve adequate INR reversal after receiving 3-factor PCC and may require higher doses than were used in the study.

Objective: To review the evidence supporting the use of prothrombin complex concentrate (PCC) as a hemostatic agent in individuals without hemophilia.Data Sources: Articles were identified through a search of Ovid/MEDLINE (up to April 2011) and Cochrane Central Register of Controlled Trials (up to April 2011). The search terms used were prothrombin complex concentrate, hemorrhage, and bleeding.Study Selection and Data Extraction: The search was limited to comparative studies. Bibliographies of retrieved articles were reviewed to obtain additional articles. The intent of the search was to identify original research comparing PCC to fresh frozen plasma (FFP) or recombinant factor VIIa for the management of bleeding in patients without hemophilia.Data Synthesis: PCCs are recommended as an alternative to FFP and recombinant factor VIIa for the treatment of serious or life-threatening bleeding related to vitamin K antagonist therapy. Studies in this setting have shown that PCCs are safe and effective and provide prompt reduction of international normalized ratio (INR) compared to FFP. However, most trials are uncontrolled, and the primary outcomes in these studies have been INR reduction rather than hemostatic effect. Other common off-label uses include coagulopathy due to hepatic failure and traumatic hemorrhage; however, there is insufficient evidence to support use of PCC in these settings. Advantages of PCC include the low drug volume required compared to FFP. The use of PCC may be associated with thromboembolic complications.Conclusions: PCC is a safe and effective alternative to FFP and provides rapid reversal of INR in patients on vitamin K antagonist therapy. These agents may be advantageous compared to FFP in patients with volume restrictions. Comparative trials are needed to compare the various PCC products, FPP, and recombinant factor VIIa with regard to clinically significant outcomes such as hemostatic effect.

Objective: To review clinical trials of intravenous opioids for severe acute pain in the emergency department (ED) and to provide an approach for optimization of therapy.Data Sources: Articles were identified through a search of Ovid/MEDLINE (1948-August 2010), PubMed (1950-August 2010), Cochrane Central Register of Controlled Trials (1991-August 2010), and Google Scholar (1900-August 2010). The search terms used were pain, opioid, and emergency department.Study Selection and Data Extraction: The search was limited by age group to adults and by publication type to comparative studies. Studies comparing routes of administration other than intravenous or using non-opioid comparators were not included. Bibliographies of all retrieved articles were reviewed to obtain additional articles. The focus of the search was to identify original research that compared intravenous opioids used for treatment of severe acute pain for adults in the ED.Data Synthesis: At equipotent doses, randomized controlled trials have not shown clinically significant differences in analgesic response or adverse effects between opioids studied. Single opioid doses less than 0.1 mg/kg of intravenous morphine, 0.015 mg/kg of intravenous hydromorphone, or 1 μg/kg of intravenous fentanyl are likely to be inadequate for severe, acute pain and the need for additional doses should be anticipated. In none of the randomized controlled trials did patients develop respiratory depression requiring the use of naloxone. Future trials could investigate the safety and efficacy of higher doses of opioids. Implementation of nurse-initiated and patient-driven pain management protocols for opioids in the ED has shown improvements in timely provision of appropriate analgesics and has resulted in better pain reduction.Conclusions: Currently, intravenous administration of opioids for severe acute pain in the ED appears to be inadequate. Opioid doses in the ED should be high enough to provide adequate analgesia without additional risk to the patient. EDs could implement institution-specific protocols to standardize the management of pain.

Objective: The objective of the study was to discuss the controversies surrounding the use and dosing of direct-acting oral anticoagulants (DOACs) in obese patients recognizing the limitations of the existing evidence base that preclude strong recommendations.Data Sources: A literature search of MEDLINE was performed (2020 to end August 2022) subsequent to recent guidelines using the following search terms: direct acting anticoagulants, obesity, rivaroxaban, apixaban, edoxaban, dabigatran, dabigatran etexilate, and clinical practice guidelines.Study Selection and Data Abstraction: English-language studies and those conducted in adults were selected.Data Synthesis: The available randomized studies evaluating DOACs had relatively small numbers of patients with more extreme forms of obesity (body mass index [BMI] > 40 kg/m2) and none of the larger studies had a specific focus on dosing DOACs in obese patients. Recent guidelines by the International Society on Thrombosis and Haemostasis (ISTH) have specific recommendations for dosing DOACs in obesity. There are pharmacokinetic/pharmacodynamic and observational studies published before and after the ISTH guidelines with a focus on DOAC dosing in obese patients that generally support the recommendations in the guidelines, but most involved small numbers of patients usually with BMIs <45 kg/m2.Relevance to Patient Care and Clinical Practice: This review discusses DOAC dosing in obesity with important considerations for clinicians related to DOAC choice and dosing.Conclusions: Dosing alterations of DOACs do not appear to be necessary when used for either prophylaxis or treatment in patients with BMIs up to approximately 45 to 50 kg/m2, but research is needed for BMIs >50 kg/m2.

At least 30 mL/kg of crystalloid fluid administration within the first 3 hours of resuscitation is suggested by the current Surviving Sepsis Campaign guidelines for management of sepsis and septic shock. This commentary discusses the challenges with using a weight-based approach to bolus fluid dosing during the early phase of resuscitation of adult, obese patients. Based on the available literature, arguments can be made for the use of either ideal or adjusted body weight for weight-based fluid dosing, but there are concerns with fluid overload if using actual body weight to dose patients with more severe forms of obesity.

The intensive care unit (ICU) continues to be a major focus of decentralized pharmacy activities in health systems that care for critically ill patients. This is not surprising, given the need for rapid decision-making involving unstable patients, the large number of powerful medications typically used per patient, the high cost of many drugs used in the ICU and, most importantly, the evidence demonstrating the benefits of having a pharmacist as part of an interdisciplinary team. The purpose of this paper is to highlight important issues to consider when introducing or developing critical care pharmacy services beginning with the establishment of basic services and continuing through practitioner development, guideline/protocol development and implementation, patient safety, residency training, and research.

Objective: To discuss the historical basis and limitations of opioid conversion tables, review the relevant literature, and establish an evidence-based equianalgesic dose ratio (EDR) table for performing conversions in the acute care setting.Data Sources: Articles were identified through searches of MEDLINE (1966–January 2007) using the key words opioid, tolerance, conversion, dose, equianalgesic, equipotent, acute care, morphine, hydromorphone, fentanyl, methadone, and oxycodone. Additional references were located through a review of the bibliographies of articles cited and references cited in conversion tables.Study Selection and Data Extraction: All data sources identified were evaluated, and all information deemed relevant was included, with the exception of case series and case reports when higher level evidence was available.Data Synthesis: Opioid conversion tables are published in major textbooks, medical references, national guidelines, and review articles. Some conversion tables do not accurately reflect the dose ratios for which evidence is available. There is marginal evidence-based clinical data to support the dose ratios cited in these tables, particularly in the acute care setting where the clinical status of patients often changes rapidly. The barriers when performing route and opioid-to-opioid conversions in the acute care setting are formidable, but EDRs are provided, based on the best available evidence.Conclusions: In the acute care setting, calculation of dose ratios for opioids, based solely on opioid conversion tables, is an oversimplification of pain management, with a potential for adverse consequences. The calculation of EDRs is one step in an interdisciplinary process that must take into account patient- and institution-specific factors.

Background: Estimation of renal function in patients with end-stage liver disease (ESLD) is complicated by several factors.Objective: To develop a practical and relatively inexpensive method for estimating creatinine production and clearance in patients with ESLD.Methods: Serum creatinine concentrations and urinary excretion of creatinine were measured in 27 patients with moderate-to-severe liver disease with the goal of developing equations to predict creatinine clearance from serum creatinine. Subjects were studied during an initial evaluation for a liver transplant program. Two 24 hour urine specimens were collected along with 3 serum samples over a 2 day evaluation period. Serum and urine creatinine concentrations were determined using both a modified Jaffé (autoanalyzer) method and an HPLC method. The data were analyzed using nonlinear mixed-effects modeling.Results: Considering both statistical criteria and physiological conventions through allometric scaling theory, creatinine clearance (mL/min) in males can be estimated as (80/serum creatinine) × (actual body weight/70)0.75. For females, the same equation is valid, but the result is multiplied by 0.661. A simplified equation without the exponent is presented, along with equations that are appropriate when an HPLC assay is used for greater specificity.Conclusions: These equations offer potential for improved estimation of creatinine clearance in patients with liver impairment; however, they need further validation using an independent group of subjects.

OBJECTIVE To discuss the controversies regarding the use of epoetin alfa (EPO) for reducing red blood cell (RBC) transfusions in critically ill patients with anemia.DATA SOURCES A MEDLINE search (1966–July 2003) was conducted using the search terms anemia; critical illness; erythropoietin; epoetin alfa; and erythropoietin, recombinant. References of selected articles were reviewed for studies that may have been missed by the computerized search.STUDY SELECTION AND DATA EXTRACTION Studies pertaining to the use of EPO for anemia of critical illness with an emphasis on data obtained from controlled trials.DATA SYNTHESIS Anemia is a common complication in patients admitted to the intensive care unit (ICU). Two prospective, randomized studies have demonstrated decreased transfusion requirements associated with EPO administration in medical/surgical patients who were in the ICU for at least 3 days and had hematocrit concentrations <38%. No differences were found in length of stay or mortality. A multicenter trial found that a restrictive strategy of RBC transfusion (hemoglobin goal 7–9 g/dL) was associated with in-hospital mortality lower than that with a more liberal approach, which calls into question the 38% hematocrit goal in the EPO trials. Furthermore, preliminary results from an economic analysis of EPO use in the ICU setting have demonstrated that EPO is not cost-effective.CONCLUSIONS Given the controversies surrounding EPO administration in critically ill patients, institutions are encouraged to develop EPO guidelines to help ensure the most appropriate use of this expensive product. Additional studies regarding patients most likely to benefit from EPO therapy, the most effective dosing regimen, and use of adjunctive therapies are needed.

OBJECTIVE: To review randomized trials involving the use of systemic hemostatic medications for reducing surgical blood loss.DATA SOURCES: Articles were obtained through searches of MEDLINE (1966–September 2000). The bibliographies of retrieved publications were reviewed for additional references.STUDY SELECTION: All randomized studies and pharmacoeconomic evaluations that involved medications used for systemic hemostasis in the perioperative period were included.DATA EXTRACTION: Randomized studies involving conjugated estrogens, aminocaproic acid, tranexamic acid, desmopressin, and aprotinin for systemic hemostasis were extracted. Studies of proton-pump inhibitors for upper gastrointestinal bleeding and octreotide for variceal bleeding were excluded, as were trials involving the use of any hemostatic agent for cardiovascular surgery. The primary outcome under review was a reduction in bleeding as defined by reduced transfusion requirements.DATA SYNTHESIS: There is limited efficacy and toxicity information concerning the use of conjugated estrogens for reducing surgery-related bleeding. Similarly, there are a limited number of randomized studies involving aminocaproic acid and tranexamic acid, and with the exception of tranexamic acid for reducing transfusion requirements with knee surgery, the study results are either conflicting or negative. For desmopressin, evidence from a substantial number of randomized trials documents its lack of efficacy. Aprotinin has reduced bleeding and transfusion requirements in a number of randomized studies involving patients undergoing orthopedic surgery, but cost-effectiveness studies are needed to better define its therapeutic role. Trials of aprotinin during hepatic surgery have yielded conflicting results.CONCLUSIONS: Most hemostatic medications used for reducing surgery-related bleeding have limited or contradictory evidence of efficacy.

OBJECTIVE: To review the use of proton-pump inhibitors for acute peptic ulcer bleeding.DATA SOURCES: Articles were obtained through computerized searches of MEDLINE (1966–September 2000). Additionally, several textbooks containing information on the diagnosis and management of acute peptic ulcer bleeding were reviewed. The bibliographies of retrieved publications and textbooks were reviewed for additional references.STUDY SELECTION: All randomized studies and pharmacoeconomic evaluations that used proton-pump inhibitor therapy for acute peptic ulcer bleeding were included. Randomized controlled trials and meta-analyses involving other therapies for treating peptic ulcer bleeding were also reviewed for possible inclusion.DATA EXTRACTION: The primary outcomes extracted from the literature were persistent or recurrent bleeding, transfusion requirements, need for endoscopic intervention or surgery, length of stay, and mortality.DATA SYNTHESIS: Data from double-blind, placebo-controlled trials involving more than 1000 patients demonstrate that short-term, high-dose omeprazole therapy is effective for reducing bleeding and transfusion requirements in patients with acute peptic ulcer bleeding. The patients most likely to benefit from this therapy are hospitalized patients at high risk for rebleeding and patients in whom endoscopic evaluation must be delayed or is unavailable.CONCLUSIONS: Omeprazole (and likely other proton-pump inhibitors) is useful in reducing bleeding and transfusion requirements in patients with acute peptic ulcer bleeding, although better delineation of appropriate candidates is needed.

OBJECTIVE: To review the use of octreotide for acute variceal bleeding.DATA SOURCES: Articles were obtained through computerized searches involving MEDLINE (from 1997 to October 2000). Additionally, several textbooks containing information on the diagnosis and management of acute variceal bleeding were reviewed. The bibliographies of retrieved publications and textbooks were reviewed for additional references.STUDY SELECTION: All randomized studies and pharmacoeconomic evaluations that used octreotide therapy for acute variceal bleeding were considered. Randomized controlled trials and meta-analyses involving other therapies for treating variceal bleeding were also reviewed for possible inclusion.DATA EXTRACTION: The primary outcomes extracted from the literature were persistent or recurrent bleeding, need for endoscopic intervention or balloon tamponade, and mortality.DATA SYNTHESIS: Although both endoscopic therapies and medications are used to control bleeding and rebleeding episodes, the endoscopic approach has the additional goal of obliterating the varix. Since rebleeding episodes are common as long as the varix is present, endoscopic and medication therapies cannot be considered interchangeable based on bleeding control alone. However, octreotide by continuous intravenous infusion has demonstrated effectiveness in reducing blood loss and transfusion requirements as both an initial intervention (until definitive sclerotherapy can be performed) or as adjunctive therapy to endoscopic measures. Octreotide can be started quickly, has a relatively rapid onset of action, and does not require someone with endoscopy training to initiate. Additionally, octreotide is relatively free of significant adverse effects.CONCLUSIONS: While additional investigations are needed, particularly in the area of pharmacoeconomics, there is substantial evidence that octreotide is an efficacious therapy with relatively few adverse effects when used in the management of acute variceal bleeding.

OBJECTIVE: To review the controversies surrounding the use of nutritional interventions, particularly enteral support, in patients with acute pancreatitis.DATA SOURCES: Articles were obtained through a MEDLINE search (1966–June 1999). Additionally, several textbooks containing information on the diagnosis and management of acute pancreatitis were reviewed. The bibliographies of retrieved publications and textbooks were reviewed for additional references.STUDY SELECTION: All original investigations in humans pertaining to the use of enteral nutritional support in acute pancreatitis were reviewed for inclusion. Studies that investigated parenteral nutrition in acute pancreatitis were also reviewed, with preference given to controlled comparisons with enteral regimens or no nutritional support.DATA EXTRACTION: The primary outcomes extracted from the literature were time to oral feeding tolerance, complications (e.g., infection) associated with nutritional support, and length of stay.DATA SYNTHESIS: The duration of pancreatitis and time to oral feedings is similar whether patients receive enteral (i.e., jejunal tube feedings) or parenteral nutrition. Additionally, complications, length of stay, and costs are either similar or decreased with enteral versus parenteral nutrition.CONCLUSIONS: Current evidence suggests that the enteral rather than parenteral route should be used to provide nutrition to patients with acute pancreatitis. Parenteral nutrition should be reserved for patients in whom nasojejunal feeding is not possible.

OBJECTIVE: To review studies and drug therapy relating to the treatment of hypertension in perioperative patients.DATA SOURCES: Articles were selected from a MEDLINE search (1966–August 1998), and several textbooks on hypertension and surgery were reviewed. In addition, bibliographies of all articles and textbook chapters were studied for articles not found in the computerized searches.STUDY SELECTION: Clinical studies involving hypertension in the perioperative setting were included. The initial search was limited to studies conducted in humans and published in English.DATAEXTRACTION: Information regarding drug therapy was reviewed and guidelines were constructed for managing surgical patients with acute blood pressure elevations.DATA SYNTHESIS: Although nitroprusside and nitroglycerin, with their short onset of action and duration of effect, are indicated for hypertensive emergencies, a variety of agents are available for hypertensive urgencies. An algorithm that can be used as a template for the development of intrainstitutional guidelines is provided.CONCLUSIONS: Due to the scarcity of comparative trials, decisions involving agents for the treatment of perioperative hypertension must often be made based on combined efficacy, toxicity, cost, and convenience considerations.

OBJECTIVE: To examine and compare the pharmacokinetics and pharmacodynamics of meperidine when administered intramuscularly at gluteal and deltoid sites in elderly postoperative patients.DESIGN: Prospective, randomized investigation.SETTING: Tertiary care university teaching hospital.PATIENTS: Fourteen patients 60 years of age or older who were undergoing general surgery.INTERVENTION: A single dose of meperidine 0.75 mg/kg given intramuscularly at either a deltoid or gluteal site.MAIN OUTCOME MEASURES: Pharmacokinetic (based on concentration—time curves) and pharmacodynamic (i.e., pain scales, need for additional pain medication) comparisons were made, based on site of meperidine injection.RESULTS: No statistically significant differences were found in the maximum plasma concentration, volume of distribution, or clearance of meperidine by site of injection. Substantial interpatient variability in pharmacokinetic parameters was noted for both sites (range of maximum concentrations: 191–500 ng/mL gluteal, 166–374 ng/mL deltoid). Although pain scores were similar for the two groups, four of the patients in the group given gluteal injection required additional breakthrough pain management within 4 hours of meperidine injection compared with one patient in the group given deltoid injection.CONCLUSIONS: There is no obvious relationship between meperidine pharmacokinetic and pharmacodynamic parameters, regardless of intramuscular injection site. Breakthrough pain is common when patients are given intramuscular injections postoperatively, particularly when the gluteal route is used. When meperidine is used for analgesia in elderly postoperative patients, consideration should be given to more rapid and predictable routes (e.g., intravenous injection) of meperidine administration.

OBJECTIVE: To describe the adverse effects associated with human serum albumin (HSA) administration.DATA SOURCES: A MEDLINE search and bibliography scanning were used to identify pertinent review articles, clinical studies, and case reports.STUDY SELECTION: Emphasis was placed on reporting the results of human studies with the primary objective of investigating adverse effects attributable to HSA administration. Clinical trials that reported the occurrence of adverse effects possibly associated with HSA were also reviewed. Animal data were included where pertinent.DATA EXTRACTION: Although isolated case reports were reviewed, data were primarily extracted from human studies involving large series of patients or studies that were randomized and prospective in nature.DATA SYNTHESIS: Alterations in coagulation, renal, cardiovascular, and pulmonary functions were identified as potential adverse effects following the administration of HSA. Occurrences of hypersensitivity reactions, trace metal loading, and serum amino acid alterations associated with these infusions were also noted and are described here. Pulmonary and cardiovascular systems appear to be particularly prone to complications from excessive HSA administration. Adverse effects such as HSA-induced hypersensitivity reactions may be severe, but occur infrequently.CONCLUSIONS: Controlled studies involving large numbers of patients are not currently available for an accurate assessment of the incidence of adverse effects attributable to HSA administration. Many of the reported reactions appear to be extensions of albumin's pharmacologic activities and would be expected to worsen following large doses of HSA.

OBJECTIVE: To examine the multiple factors that influence serum albumin concentrations and to discuss settings in which the monitoring of such concentrations provides clinically useful information.DATA SOURCES: Original investigations, review articles, books, and abstracts published in English.STUDY SELECTION: Studies pertaining to factors affecting serum albumin concentration were chosen based on general applicability. Recommendations related to the appropriate monitoring of albumin concentrations were based on studies performed in the clinical setting with direct applicability to patient care.DATA EXTRACTION: Data on factors affecting serum albumin concentration were extracted from studies that resulted in similar conclusions regardless of assay technique. Appropriate indications for albumin monitoring were derived from studies demonstrating direct clinical relevance.DATA SYNTHESIS: A number of factors may influence serum albumin concentration and ultimately affect interpretation of the concentration. Serum albumin concentrations generally are useful in the institutional setting shortly after admission or preoperatively to determine patient prognosis. Albumin concentrations have limited merit for predicting the free fractions of various hormones, electrolytes, and drugs. When used as an indicator of nutritional support, albumin concentrations are most helpful when measured over longer periods in relatively stable patients.CONCLUSIONS: Serum albumin determinations should be limited to those situations in which the concentrations are likely to provide clinically useful information. Such situations are limited.

OBJECTIVE: To discuss the limitations of conventional monitoring techniques of shock and examine more recent monitoring techniques that are used to titrate therapies to attain supranormal oxygen transport goals.DATA SOURCES: Review articles and investigations published since 1973.STUDY SELECTION: Articles were selected if they examined the monitoring or treatment of shock. Emphasis was placed on finding investigations involving humans that used innovative methods to assess and treat inadequate tissue perfusion.DATA EXTRACTION: Data were extracted primarily from original investigations and review articles published in or translated into English.DATA SYNTHESIS: The conventional monitoring of shock often fails to detect inadequate tissue perfusion, which may lead to inadequate resuscitation of patients, resulting in increased morbidity and mortality. Attainment of supranormal values for oxygen transport variables has been associated with improved outcomes, especially in patients with hypovolemic shock or septic shock. Additionally, interventions used to increase these variables to supranormal values have resulted in improved survival in high-risk preoperative patients with hypovolemic or septic shock, but not in severely ill postoperative patients with multiple complications.CONCLUSIONS: Efforts to increase oxygen transport variables to supranormal values cannot be recommended routinely for all critically ill patients. Preoperative patients in early stages of hypovolemic or septic shock may benefit from therapies titrated to achieve supranormal goals, but patients in later stages of illnesses may be harmed by such attempts. Questions remain regarding how quickly and how long the oxygen transport variables should be elevated. The most effective and least toxic therapeutic interventions for increasing the variables need to be determined.

Severe cardiovascular adverse reactions including death have been associated with high-dose intravenous corticosteroid therapy. Some of the patients appeared to have acute hypersensitivity reactions to the corticosteroid, with rashes and bronchospasm; other problems included arrhythmias and myocardial infarctions. Most of the patients had underlying renal disease and/or were undergoing renal transplantation. All of the patients having the cardiovascular reactions associated with the corticosteroid received individual doses of at least 250 mg of methylprednisolone or its equivalent. The doses were usually administered over a 30-minute period or less. A cause-effect relationship between high-dose corticosteroid therapy and severe cardiovascular reactions has not been scientifically proved by a controlled trial, but caution is advised when high-dose corticosteroid therapy is administered.

Cryptosporidiosis commonly causes severe diarrhea in immunosuppressed patients. There currently are no antiparasitic drugs consistently effective for this infection. This case describes a 26-year-old hemophiliac patient with acquired immunodeficiency syndrome and cryptosporidiosis whose diarrhea improved with continuous intravenous administration of a long-acting somatostatin analog, octreotide. Somatostatin has a variety of inhibitory effects on gastrointestinal hormones as well as a possible nonspecific effect on gastrointestinal mucosal fluid and electrolyte secretion. The somatostatin analog should be considered for patients with secretory diarrhea refractory to other forms of therapy.

OBJECTIVE: To determine the effects of ethanol (EtOH) ingestion by trauma patients on the hematologic system as evidenced by coagulation abnormalities and transfusion requirements.DESIGN: Retrospective chart review. The injury severity score (ISS) was determined for each patient. Patients were grouped according to presence of EtOH (+EtOH) and absence of EtOH (-EtOH) with further subdivision based on an ISS ≤8 or ≥9.SETTING: University medical center.PATIENTS: All adult trauma patients admitted during a one-month period.MAIN OUTCOME MEASURES: The volume of resuscitation fluids (including blood products) administered, laboratory parameters indicative of bleeding, and length of stay.RESULTS: Of 104 evaluable patients, 38 had measurable EtOH concentrations, 46 had undetectable EtOH concentrations, and the remaining 20 patients had not been tested. Although isolated, statistically significant differences were found among groups for some of the outcome measures, there were no clinically important differences.CONCLUSIONS: EtOH ingestion prior to injury did not appear to cause significant alterations in the hematologic system of trauma patients, but a larger study is needed to confirm these findings.