In the 1920s, guanidine, the active component of
Review article
Review of Biguanide (Metformin) Toxicity
George Sam WangORCID
, Christopher Hoyte
Abstract
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In the 1920s, guanidine, the active component of
Venous thromboembolism (VTE) is a major health concern associated with significant morbidity and mortality. Critically ill patients are at an increased risk of VTE compared to general medical patients due to unique risk factors: prolonged immobilization, invasive lines and devices, certain medications, and acquired thrombophilia. Furthermore, VTE in the critically ill is associated with increased duration of mechanical ventilation, increased length of intensive care unit and hospital stay, and a trend toward increased mortality. Clinical practice guidelines therefore recommend VTE prophylaxis with either subcutaneous heparin or low-molecular-weight heparin for all critically ill patients without contraindication. Yet, many patients will develop VTE despite appropriate pharmacologic prophylaxis, which has led to interest in risk-stratifying critically ill patients for more aggressive prophylaxis strategies. Recent research identified patients at highest risk of failure of thromboprophylaxis and provided insight into the pathophysiologic mechanisms. Obesity and the receipt of vasopressors are 2 risk factors consistently identified in observational studies; further clinical data support decreased absorption of anticoagulant administered via the subcutaneous route as the likely mechanism behind thromboprophylaxis failure in these patient populations. Several studies have investigated novel thromboprophylaxis strategies to circumvent pharmacokinetic limitations in patients who are obese or on vasopressors: increased fixed-dose, weight-based subcutaneous, or continuous intravenous infusion of a prophylactic dose of anticoagulant has shown promise in limited studies; however, the results have yet to demonstrate superiority compared to current standard-of-care. This review discusses observational studies identifying patients at risk of thromboprophylaxis failure and critiques clinical studies evaluating novel thromboprophylaxis strategies in high-risk, critically ill patients with a focus on their limitations. Future studies are currently being conducted that will provide further guidance into the appropriate use of individualized thromboprophylaxis.
Stress hyperglycemia is the transient increase in blood glucose as a result of complex hormonal changes that occur during critical illness. It has been described in the critically ill for nearly 200 years; patient harm, including increases in morbidity, mortality, and lengths of stay, has been associated with hyperglycemia, hypoglycemia, and glucose variability. However, there remains a contentious debate regarding the optimal glucose ranges for this population, most notably within the past 15 years. Recent landmark clinical trials have dramatically changed the treatment of stress hyperglycemia in the intensive care unit (ICU). Earlier studies suggested that tight glucose control improved both morbidity and mortality for ICU patients, but later studies have suggested potential harm related to the development of hypoglycemia. Multiple trials have tried to elucidate potential glucose target ranges for special patient populations, including those with diabetes, trauma, sepsis, cardiac surgery, and brain injuries, but there remains conflicting evidence for most of these subpopulations. Currently, most international organizations recommend targeting moderate blood glucose concentration to levels <180 mg/dL for all patients in the intensive care unit. In this review, the history of stress hyperglycemia and its treatment will be discussed including optimal glucose target ranges, devices for monitoring blood glucose, and current professional organizations’ recommendations regarding glucose control in the ICU.
The management of patients with human immunodeficiency virus (HIV) can be a complicated specialty within itself, made even more complex when there are so many unanswered questions regarding the care of critically ill patients with HIV. The lack of consensus on the use of antiretroviral medications in the critically ill patient population has contributed to an ongoing clinical debate among intensivists. This review focuses on the pharmacological complications of antiretroviral therapy (ART) in the intensive care setting, specifically the initiation of ART in patients newly diagnosed with HIV, immune reconstitution inflammatory syndrome (IRIS), continuation of ART in those who were on a complete regimen prior to intensive care unit admission, barriers of drug delivery alternatives, and drug-drug interactions.
Delays in achievement of target mean arterial pressure (MAP) have been associated with increased mortality in patients with septic shock. Vasopressin may be added to norepinephrine to raise MAP or decrease norepinephrine dosage. The purpose of this study was to determine whether early initiation of vasopressin to norepinephrine resulted in a reduced time to target MAP compared to norepinephrine monotherapy.
This retrospective cohort study compared early addition of vasopressin within 4 hours of septic shock onset to norepinephrine versus initial norepinephrine monotherapy in medically, critically ill patients with septic shock admitted from May 2014 to October 2015. Time to goal MAP was compared using Student
Each group contained 48 patients. Mean arterial pressure (61.5 vs 58.6 mm Hg) and intravenous fluid volume received at vasopressor initiation (14.3 vs 25.2 hours,
Early initiation of vasopressin in patients with septic shock may achieve and maintain goal MAP sooner and resolve organ dysfunction at 72 hours more effectively than later or no initiation.
Nitric oxide is utilized after pediatric cardiac surgery as an off-label medication without much evidence, is expensive, and varies among centers of varying surgical volume. The objective of our study was to describe the spectrum of nitric oxide utilization and to evaluate the effect of nitric oxide utilization on outcomes among patients cared for in centers of varying surgical volume using Pediatric Health Information system.
Patients aged ≤18 years undergoing heart surgery were included (2004-2015). Multivariable mixed-effects logistic regression models were fitted to evaluate association of center volume with odds of nitric oxide utilization among patients undergoing heart operations. Centers were classified into 3 volume categories based on tertiles of number of cardiopulmonary bypass cases performed (low volume: 34 792 patients, 21 centers; medium volume: 38 362 patients, 13 centers; high volume: 30 560 patients, 7 centers).
A total of 103 714 patients from 41 hospitals were included. Of these, 15 708 (15.1%) patients received nitric oxide after cardiac surgery. Of the patients receiving nitric oxide, only 3936 (25.1%) patients were associated with a diagnosis of pulmonary hypertension. In adjusted models, low- and medium-volume centers were associated with higher nitric oxide utilization after heart operations as compared to high-volume centers (low vs high, odds ratio [OR]: 1.48, 95% confidence interval [CI]: 1.38-1.60; medium vs high, OR: 1.33, 95% CI: 1.26-1.41). Despite higher nitric oxide utilization, the mortality was worse among patients treated in low- and medium-volume centers, as compared to high-volume centers (low vs high, OR: 1.42, 95% CI: 1.26-1.60; medium vs high, OR: 1.14, 95% CI: 1.04-1.25).
This study demonstrates variation in nitric oxide utilization after heart operations among centers of varying surgical volume. Further, it raises questions on the benefit of nitric oxide administration after pediatric cardiac surgery.
Patients often overstay in intensive care units (ICU) after they are deemed discharge ready. The objective of this study was to examine the impact of such discharge delays (DD) on subsequent in-hospital morbidity and mortality.
Retrospective cohort study.
Single tertiary academic medical center.
Adult patients admitted to the medical ICU between 2005 and 2011.
For all patients, DD (ie, time between request for a ward bed and time of ICU discharge) was calculated. Discharge delays was dichotomized as long (≥24 hours) or short (<24 hours). Multivariable linear and logistic regressions were used to assess the association between dichotomized DD and post-ICU clinical outcomes.
Overall, 9673 discharges were included of which 10.4% patients had long DDs. In the fully adjusted model, a long delay was not associated with increased odds of death (adjusted odds ratio [aOR]: 0.99, 95% confidence interval [CI]: 0.74-1.31,
In this study, long DD was associated with a slight decrease in post-ICU LOS but longer LOS when measured from the point of ward bed request, suggesting a potential role for more aggressive discharge planning in the ICU for patients with long DDs. There was no association between long DD and subsequent mortality or HFD.
Right heart thrombi (RiHT) is characterized by the presence of thrombus within the right atrium or right ventricle (RV). Current literature suggests pulmonary embolism (PE) with RiHT carries a high mortality. Guidelines lack recommendations in managing RiHT. We created a pooled analysis on RiHT and report on our institutional experience in managing RiHT. We aimed to evaluate whether patient characteristics and differing treatment modalities predict mortality.
We created a pooled analysis of case reports and series of patients with RiHT and PE between January 1956 and 2017. We also reviewed a series of consecutive patients with RiHT identified from our institutional PE registry. Age, shock, RV dysfunction, clot mobility, treatment modality, and hospital outcome had to be reported.
We identified 316 patients in our pooled analysis. Patients received the following therapies: no treatment 15 (5%), systemic anticoagulation 73 (23%), systemic thrombolysis 108 (34%), surgical embolectomy 101 (32%), catheter-directed therapy 11 (3%), and systemic thrombolysis with surgery 8 (3%). In-hospital mortality was 18.7%. Univariate analysis showed age and shock reduced odds of survival. Multivariate analysis showed shock reduced odds of survival (odds ratios [OR] 0.36, 95% confidence interval [CI]: 0.19-0.72,
Presence of shock in RiHT is an independent predictor of mortality. Systemic thrombolysis may offer increased odds of survival when compared to systemic anticoagulation. Our findings should be interpreted with caution as they derive from retrospective reports and subject to publication bias.
Sepsis and sepsis-associated encephalopathy (SAE) are common intensive care unit (ICU) diseases; the morbidity and mortality are high. The present study analyzed the sensitivity of different diagnostic criteria of sepsis 1.0 and 3.0, epidemiological characteristics of sepsis and SAE, and explored its risk factors for death, short-term, and long-term prognosis.
The retrospective study included patients in ICU from January 2015 to June 2016. After excluding 58 patients, 175 were assigned to either an SAE or a non-SAE group (patients with sepsis but no encephalopathy). The sensitivity of the diagnostic criteria was compared between sepsis 1.0 and 3.0, respectively. Between-group differences in baseline data, Acute Physiology and Chronic Health Evaluation II score (APACHE II score), Sequential Organ Failure Assessment score (SOFA score), etiological data, biochemical indicators, and 28-day and 180-day mortality rates were analyzed. Survival outcomes and long-term prognosis were observed, and risk factors for death were analyzed through 180-day follow-up.
The sensitivity did not differ significantly between the diagnostic criteria of sepsis 1.0 and 3.0 (
Both diagnostic criteria cause misdiagnosis, and the sensitivity did not differ significantly. The incidence of SAE was high, and 28-day and 180-day mortality rates were significantly higher than those without SAE. Sepsis-associated encephalopathy is a risk factor for poor outcome. The overall long-term prognosis of patients with sepsis was poor, and the quality of life decreased.
Automated electronic sniffers may be useful for early detection of acute respiratory distress syndrome (ARDS) for institution of treatment or clinical trial screening.
In a prospective cohort of 2929 critically ill patients, we retrospectively applied published sniffer algorithms for automated detection of acute lung injury to assess their utility in diagnosis of ARDS in the first 4 ICU days. Radiographic full-text reports were searched for “edema” OR (“bilateral” AND “infiltrate”) and a more detailed algorithm for descriptions consistent with ARDS. Patients were flagged as possible ARDS if a radiograph met search criteria and had a PaO2/FiO2 or SpO2/FiO2 of 300 or 315, respectively. Test characteristics of the electronic sniffers and clinical suspicion of ARDS were compared to a gold standard of 2-physician adjudicated ARDS.
Thirty percent of 2841 patients included in the analysis had gold standard diagnosis of ARDS. The simpler algorithm had sensitivity for ARDS of 78.9%, specificity of 52%, positive predictive value (PPV) of 41%, and negative predictive value (NPV) of 85.3% over the 4-day study period. The more detailed algorithm had sensitivity of 88.2%, specificity of 55.4%, PPV of 45.6%, and NPV of 91.7%. Both algorithms were more sensitive but less specific than clinician suspicion, which had sensitivity of 40.7%, specificity of 94.8%, PPV of 78.2%, and NPV of 77.7%.
Published electronic sniffer algorithms for ARDS may be useful automated screening tools for ARDS and improve on clinical recognition, but they are limited to screening rather than diagnosis because their specificity is poor.
Computed tomography of the head (HCT) is a widely used diagnostic tool, especially for emergency and trauma patients. However, the diagnostic yield and outcomes of HCT for patients on medical intensive care units (MICUs) are largely unknown.
We retrospectively evaluated all head CTs from patients admitted to a single-center MICU during a 5-year period for CT indications, diagnostic yield, and therapeutic consequences. Uni- and multivariate analyses for the evaluation of risk factors for positive head CT were conducted.
Six hundred ninety (18.8%) of all patients during a 5-year period underwent HCT; 78.7% had negative CT results, while 21.3% of all patients had at least 1 new pathological finding. The main indication for acquiring CT scan of the head was an altered mental state (AMS) in 23.5%, followed by a new focal neurology in 20.7% and an inadequate wake up after stopping sedation in 14.9% of all patients. The most common new finding was intracerebral bleeding in 6.4%. In 6.7%, the CT scan itself led to a change of therapy of any kind. Admission after resuscitation or a new focal neurology were independent predictors of a positive CT. Psychic alteration and AMS were both independent predictors of a higher chance of a negative head CT. Positive HCT during MICU is an independent predictor of lower survival.
New onset of focal neurologic deficit seems to be a good predictor for a positive CT, while AMS and psychic alterations seem to be very poor predictors. A positive head CT is an independent predictor of death for MICU patients.
“Rules of thumb” for the replacement of electrolytes, including magnesium, in critical care settings are used, despite minimal empirical validation of their ability to achieve a target serum concentration. This study’s purpose was to evaluate the effectiveness and safety surrounding magnesium replacement in medically, critically ill patients with mild-to-moderate hypomagnesemia.
This was a single-center, retrospective, observational evaluation of episodes of intravenous magnesium replacement ordered for patients with mild-to-moderate hypomagnesemia (1.0-1.9 mEq/L) admitted to a medical intensive care unit from May 2014 to April 2016. The primary effectiveness outcome, achievement of target serum magnesium concentration (≥2 mEq/L) compared to expected achievement using a “rule of thumb” estimation that 1 g intravenous magnesium sulfate raises the magnesium concentration 0.15 mEq/L, was tested using 1-sample
Of 152 days on which magnesium replacements were provided for 72 patients, a follow-up serum magnesium concentration was checked within 24 hours in 89 (58.6%) episodes. Of these 89 episodes, serum magnesium concentration reached target in only 49 (59.8%) episodes compared to an expected 89 (100%;
Medically, critically ill patients who received nonprotocolized magnesium replacement achieved the target serum magnesium concentration less frequently than the “rule of thumb” estimation predicted.
A child’s pediatric intensive care unit (PICU) admission may have wide-ranging family implications. We assessed nonmedical out-of-pocket expenses (NMOOPEs) and disruptions in work and normal life for parents with a child admitted to the PICU for at least 2 days with acute, new onset, or exacerbation of a critical condition.
We conducted a prospective, single-center study; administered a daily verbal response survey on NMOOPEs; stratified families by annual income (<$50 999, $51-99 000, >$100 000); and calculated daily expenditures (DEs), estimated daily budgets (DBs), and percentage of NMOOPEs (%DE/DB). We used a modified caregiver version of the Work Productivity and Activity Impairment Scale to assess the impact of PICU admission on work-related and normal life activities.
The PICU in an academic, tertiary medical center in the United States.
Patients admitted to PICU.
None.
The study included 38 families, with median length of PICU stay of 3 days (range 3-13). The mean total NMOOPE was $127 ± $107 (range $5-$511). Financial impact of DB in the 3 annual income groups ranged from 0% to 136% (median 36%), 5% to 18% (median 10%), and 4% to 39% (median 16%), respectively. Total work absenteeism for cohort was 78 days. High levels of distraction were reported in working families, and normal daily activities were interrupted or suspended.
PICU hospitalization results in a range of direct NMOOPEs of varying burden on families and additional work productivity impact. Further research to understand the array of financial implications on families and additional mitigation strategies are needed.
The REVIVE randomized controlled trial (RCT) investigated the effectiveness of an individually tailored (personalized) exercise program for patients discharged from hospital after critical illness. By including qualitative methods, we aimed to explore patients’ perceptions of engaging in the exercise program.
Patients were recruited from general intensive care units in 6 hospitals in Northern Ireland. Patients allocated to the exercise intervention group were invited to participate in this qualitative study. Independent semistructured interviews were conducted at 6 months after randomization. Interviews were audio-recorded, transcribed, and content analysis used to explore themes arising from the data.
Of 30 patients allocated to the exercise group, 21 completed the interviews. Patients provided insight into the physical and mental sequelae they experienced following critical illness. There was a strong sense of patients’ need for the exercise program and its importance for their recovery following discharge home. Key facilitators of the intervention included supervision, tailoring of the exercises to personal needs, and the exercise manual. Barriers included poor mental health, existing physical limitations, and lack of motivation. Patients’ views of outcome measures in the REVIVE RCT varied. Many patients were unsure about what would be the best way of measuring how the program affected their health.
This qualitative study adds an important perspective on patients’ attitude to an exercise intervention following recovery from critical illness, and provides insight into the potential facilitators and barriers to delivery of the program and how programs should be evolved for future trials.
Continuous renal replacement therapies (CRRTs) either as continuous venovenous hemofiltration (CVVH) or hemodiafiltration (CVVHD) are used frequently in critically ill children. Many clinical variables and technical issues are known to affect the result. The factors that could be modified to increase the survival of renal replacement are sought. As a contribution, we present the data on 104 patients who underwent CRRT within a 7-year period.
A total of 104 patients admitted between 2009 and 2016 were included in the study. The demographic information, admittance pediatric risk of mortality (PRISM) scores, indication for CRRT, presence of fluid overload, CRRT modality, durations of CRRT, and pediatric intensive care unit (PICU) stay were compared between survivors and nonsurvivors.
The overall rate of survival was 51%. Patients with fluid overload had significantly increased rate of death, CRRT duration, and PICU stay. Multiorgan dysfunction syndrome as the indication for CRRT was significantly related to decreased survival when compared to acute renal failure and acute attacks of metabolic diseases. The CRRT modality was not different between survivors and nonsurvivors. Standardized mortality ratio of the group was calculated to be 0.8.
The CRRT in critically ill patients is successful in achieving fluid removal and correction of metabolic imbalances caused by organ failures or attacks of inborn errors of metabolism. It has a positive effect on expected mortality in high-risk PICU patients. To affect the outcome, follow-up should be focused on starting therapy in early stages of fluid overload. Prospective studies defining relative importance of risk factors causing mortality can assist in building up guidelines to affect the outcome.
The aim of this study was to determine whether clevidipine (CLEV) achieved faster blood pressure control compared to nicardipine (NIC) in patients presenting with either an acute ischemic stroke (AIS) or a spontaneous intracerebral hemorrhage (ICH).
This was a retrospective, observational, cohort study conducted in patients with AIS or ICH admitted to the emergency department of a Comprehensive Stroke Center from November 2011 to June 2013 who received CLEV or NIC continuous infusion for acute blood pressure management.
The study included 210 patients: 70 in the CLEV group and 140 in the NIC group. There was no difference in mean time (standard deviation [SD]) from initiation of the infusion to goal systolic blood pressure (SBP), CLEV: 50 (83) minutes versus NIC: 74 (103) minutes,
There was no difference in the mean time from initiation of the infusion to the SBP goal between agents or in the secondary outcomes. Due to the lack of differences observed, each agent should be considered based on the patient care needs of the institution.
We aimed to assess the efficacy and safety of a high loading dose of colistin and no loading dose of colistin to treat multidrug-resistant (MDR)
We conducted a prospective cohort study of patients with MDR
A total of 255 cases were identified. The high loading dose of colistin strategy provided no significant difference in good clinical response when compared to the no loading dose group (65.5% vs 70.4%;
The high loading dose of colistin strategy was effective and safe for treating patients with MDR
In the pediatric population, spontaneous intracerebral hemorrhage (sICH) is as common as ischemic stroke and accounts for significant mortality and morbidity. Differently from the ischemic stroke, there are few guidelines for directing management of sICH. This article aims to analyze both clinical outcomes and prognostic factors in order to produce tools for the design of prospective randomized studies addressed to implement treatment of pediatric sICH.
Twelve-year retrospective review of a single-center consecutivesICH pediatric cases admitted to the pediatric intensive care unit (PICU). Selected end points were survival, PICU stay, and dichotomized Glasgow Outcome Score (GOS), with recovery and moderate disability (GOS 4-5) classified as favorable outcome and vegetative state or severe disability (GOS 2-3) classified as unfavorable.
Data of 107 children younger than 14 years admitted to our PICU due to sICH were analyzed. Overall PICU mortality was 24.2%. On multivariate analysis, the single factor markedly influencing survival was the presence of midline shift (
The severity of presentation of sICH expressed by the midline shift and the GCS at PICU admission are significant prognostic factors for survival and neurological outcome. Some prognostic factors of the adult population have not been confirmed.
Relocation of large numbers of critically ill patients between hospitals is sometimes necessary and the risks associated with relocation may be high. In the setting of adherence to an interhospital intensive care unit (ICU) relocation protocol, we aimed to determine whether the interhospital relocation of all ICU patients in a single day is associated with changes in vital signs, device removal, and worse clinical outcomes. We conducted a prospective, observational, cohort study of all critically ill adults admitted to a tertiary medical center’s ICUs on the day of a planned hospital relocation and exposed to interhospital ICU relocation compared with unexposed critically ill adults. Changes in vital signs were evaluated by the before-and-after interhospital relocation measurement of vital signs, and clinical outcomes were collected for all patients. A total of 699 patients were admitted to the ICU during the observation period, 24 of whom were exposed to interhospital ICU relocation on a single day. The median interhospital transport duration was 28 minutes (interquartile range: 24-35) and 29% of patients were receiving invasive mechanical ventilation. Patients exposed to interhospital ICU relocation had no significant change in any vital sign measurement and no devices were unintentionally removed. Inhospital mortality was similar (8.3%) to patients not exposed to interhospital ICU relocation (9.2%,
Sepsis is a leading cause of hospitalization, and subsequent readmissions are frequent and costly. There is an expanding body of literature describing risk factors for readmissions in patients with sepsis. However, there are little data studying medically underserved patients who typically receive their care at a safety net hospital.
In a retrospective cohort study, we evaluated 1355 sepsis survivors at risk of hospital readmission in fiscal year 2013 at a safety net hospital. We described patient characteristics during their initial and readmission hospitalizations and analyzed risk factors associated with 30-day readmission.
The 30-day readmission rate among sepsis survivors was 22.6%. Comorbid conditions associated with readmissions included end-stage renal disease (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.17-1.36), malignancy (OR, 1.14; 95% CI, 1.08-1.21), and cirrhosis (OR, 1.11; 95% CI, 1.02-1.20). Bacteremia during the initial hospitalization (OR, 1.07; 95% CI, 1.01-1.15) and being discharged with a vascular catheter (OR, 1.10; 95% CI, 1.01-1.20) were associated with readmission. Less severe sepsis during the initial hospitalization was associated with a reduced risk of 30-day readmission (OR, 0.91; 95% CI, 0.87-0.94).
At a safety net hospital, patients who survived their initial sepsis hospitalization had a 30-day readmission rate to our institution of 22.6% that is comparable to rates described in prior studies. Readmission was commonly due to infection. Factors associated with readmission included multiple comorbid medical conditions, bacteremia, and being discharged with a vascular catheter. Further studies in this population are needed to determine potential modifiability of these risk factors in an attempt to reduce sepsis readmissions.