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Podcast Journal Club
25 minutes | Nov 22, 2020
5. Fluid Resuscitation with Emergency Medicine
In this episode we discuss two articles about fluid resuscitation. Recorded on 6/25/20.Presenters: Alex Pizarro, MD and Ivana Margi, MD, Wellspan York Hospital Emergency Medicine DepartmentHosts: Giselle Aerni, MD and Sonya Del Tredici, MDProducer: Robert Stuntz, MD Article 1: Balanced Crystalloids versus Saline in Critically Ill Adults. Semler, Et. Al. N Engl J Med 2018 Mar 1;378(9):829-839. The SMART Investigators and the Pragmatic Critical Care Research Group. Notes By Dr. Pizarro.Question: In critically ill patients does the use of balanced crystalloids compared to normal reduce a 30-day composite outcome of death, new renal replacement therapy, and renal dysfunction?Background: Historically normal saline has been the most commonly administered IV fluid; however, its safety has been questioned. Normal saline is a hypertonic, acidotic fluid so far from “normal”. Balanced crystalloid solutions (such as LR and Plasma-Lyte A) have electrolyte compositions closer to that of plasma which is why they make an excellent alternative! Normal saline causes hyperchloremic metabolic acidosis. Several studies suggest that normal saline is associated with higher rates of acidosis, acute kidney injury, use of renal replacement therapy, and death. Evidence that normal saline is associated with:Hemodynamic instability§ Kellum (2004): Septic rats who received normal saline had more profound hemodynamic dysfunction as compared to LR.§ Orbegozo (2016): Sheep who received normal saline had reduced cardiac index, reduced tissue oxygen levels, impaired microcirculatory perfusion, more coagulopathy, earlier development of oliguria, and earlier death. § Potura (2015): Retrospective control study on patients undergoing renal transplantation randomized to receive normal saline vs. Elomel Isoton solution (an acetate-buffered balanced crystalloid). Patients receiving saline required vasopressors more frequently (30% vs 15%; p=0.03)Increased inflammation§ Kellum (2006): Used hydrochloric acid in septic rats to induce a hyperchloremic acidosis resulting in increased levels of pro-inflammatory cytokines.§ Zhou (2014): In a rat sepsis model, resuscitation with saline produced higher levels of interleukin-6 compared to Plasmalyte.§ Wu (2011): Randomized control trial of patients with pancreatitis comparing LR to normal saline. Normal saline had higher levels of C-reactive protein one day after the initiation of fluid resuscitation. Normal saline also seemed to delay resolution of clinical features of systemic inflammation (SIRS criteria). Based on this study, LR is generally recommended as the fluid of choice for pancreatitis resuscitation by the American College of Gastroenterology guidelines. § de-Madaria (2018): Replicated Wu (2011) results. Patients treated with normal saline had a nonsignificant trend towards more SIRS criteria (p=0.06) and increased level of C-reactive protein. Increased risk of acute kidney injury (Theory: hyperchloremia causes renal vasoconstriction which in turn decreases renal cortical blood flow leading to AKI thus increasing the need for renal replacement therapy and risk of death) § Zhou (2014): In septic rats, saline resuscitation increased the rate of kidney injury compared to Plasmalyte.§ Chawdhury (2012): Patients who received two-liter saline bolus had reduced blood flow to the renal cortex compared to two-liter Plasmalyte. § Yunos (2012): Before-after study which involved avoiding chloride-rich resuscitative fluids in an ICU. Following this intervention, the rate of acute kidney injury decreased. Debunked myths about LR:1. It is cheap – LR is only $0.25 more expensive than normal saline. 2. LR worsens hyperkalemia – Evidence suggests the exact opposite. In fact, normal saline causes hyperchloremic acidosis which may exacerbate a hyperkalemic state due to shift of H+ intracellularly in exchange for K+.§ Martini (2013): Pig model for hemorrhagic shock found that normal saline is more likely to cause hyperkalemia when compared to LR.§ O’Malley (2005), Khajavi (2008), Modi (2012), and Weinberg (2017): Randomized control trials performed during renal transplant surgery showed that normal saline more frequently causes hyperkalemia when compared to LR or Plasmalyte. Design: Pragmatic, unblinded, cluster-randomized, multiple-crossover trialSetting: Location: Conducted in 5 ICUs at a single US academic center (Vanderbilt in Nashville, TN): Medical (34 beds), Neurologic (22 beds), Cardiac (27 beds), Trauma (31 beds), Surgical (22 beds).Dates: From June 1st 2015 to April 30th 2017Population: Inclusion: All adult patients admitted to the ICUExclusion: Age < 18 yrsSample Size: 15,802 adults Median age: 58-years-oldGender: 57.6% maleNo significant differences in baseline characteristics between groupsHow were they assigned?For every month of the trial, each ICUs was randomized to use saline or balanced crystalloids. They then alternated at the beginning of each calendar month. Patients were enrolled at time of ICU admission and assigned to receive either the control (normal saline) or the intervention (balanced crystalloids: LR or plasma-lyte A) according to the unit where they were admitted to. They coordinated with ED and OR so that fluid administered in the ED or OR was the same as that assigned to the ICU they were being admitted to. This was not true for the post cardiac surgery patients. Physicians completed a questionnaire at time of admission to determine if the patient had the relative contraindication of hyperkalemia or traumatic brain injury. If so, then 0.9% sodium chloride could be used in preference to balanced crystalloid at the physician’s discretion. GroupsIntervention-7942 patients were allocated to the balanced crystalloid groupMedian volume of balanced crystalloid administered between ICU admission and hospital discharge or 30 days: 1000ml (IQR 0-3210).Control-7860 patients were allocated to salineMedian volume of normal saline administered between ICU admission and hospital discharge or 30 days: 1020ml (IQR 0-3500)Management of both groupsVolumes and rates were prescribed by the treating physiciansAll other management was at the discretion of the treating physicianOutcomes: Primary outcome: Proportion of patients who met one or more criteria for a Major Adverse Kidney Event at hospital discharge or 30 days whichever came first (MAKE 30) – mortality, new receipt of renal-replacement therapy, or persistent renal dysfunction (defined as final inpatient creatinine of >200% baseline). MAKE 30 was significantly greater in normal saline group (15.4% vs 14.3%; p = 0.04). Number needed to treat was 94.Secondary outcomes: -In hospital death before ICU discharge or within 30 days of ICU admission was greater in normal saline group (11.1% (875) vs 10.3% (818); p = 0.06).-Receipt of new RRT was greater in normal saline group (2.9% (220) vs 2.5% (189); p = 0.08).-Persistent renal dysfunction was greater in normal saline group (6.6% vs 6.4%; p = 0.60).-However, there was no significant difference in ICU free days, ventilator free days, vasopressor free days, and Stage 2 (or higher) AKI developing after enrolment! Sub-group analysis:-In-hospital mortality was significantly greater in normal saline group for sepsis (29.4% vs 25.2%; p = 0.02) and chronic dialysis (18.4% vs 12.2%; p = 0.01)Strengths: -Important question helping guide fluid resuscitation to improve morbidity and mortality in critically-ill patients-Large sample size providing adequate power to detect even slight difference in clinical outcomes.-Balanced population of both medical and surgical critically ill patients thus generalizable.-Median fluid volume was approximately the same between the normal saline and balanced cr.-Separation between groups of fluids received indicating that the allocation was largely successful. Weaknesses: -Single center trial may not be generalizable. Although, population was fairly balanced.-Unblinded-Raises question of Plasmalyte vs LR. Currently no good evidence. -Physicians could exclude patients if they felt that there was a relative contraindication to the assigned fluid.-Used small volumes of fluid.Conclusion: This is a large and strong study that adds further evidence to avoid normal saline in critically ill patients because it is associated with increased mortality, new receipt of renal-replacement therapy, or persistent renal dysfunction. There is a lot of evidence to suggest that normal saline can worsen acidosis, inflammatory markers, and AKI. In addition, a lot of the myths about LR have been debunked. First, LR is not much more expensive than normal saline. Second, LR is less likely to cause hyperkalemia or worsen acidosis.Article 2: Fluid resuscitation in patients with end-stage renal disease on hemodialysis presenting with severe sepsis or septic shock: A case control study. Rajdev, K., Et. Al. J Crit Care. 2020 Feb;55:157-162. Notes By. Dr. Marji.Question: Among patients diagnosed with severe sepsis and septic shock, what percentage of patients with end-stage renal disease (ESRD) on hemodialysis (HD) received an initial fluid resuscitation of ≥30mL/kg compared to non-ESRD patients?Facts: In ESRD patients HD, infection is the second most common cause of mortality after cardiovascular disease (Sarnik 2000). General sepsis guidelines:-Due to systemic inflammation and increased capillary permeability, septic patients have significant risk of fluid imbalances and frequently require large volumes of IV fluids. -The Surviving Sepsis Campaign guidelines provide a strong recommendation for administering a 30mL/kg fluid bolus within 3 hours but have limited evidence (Rhodes 2016).-Fluid administration should be guided by hemodynamic assessment However, treatment of ESRD patients is inconsistent due to…-Lack of studies-ESRD patients appear volume overloaded on physical exam but may be intravascularly deplete-Hesitation to administer a large fluid bolus in ESRD due to risk of cardiogenic shock, pulmonary edema, and respiratory failure Design: Retrospective case-control chart review studyLocation: A single center in Staten Island, New YorkPopulation: Inclusion Criteria:-Adult patients who met criteria for severe sepsis or septic shock based on Surviving Sepsis Campaign definitions admitted from 2015 to 2018-Severe Sepsis: 2 SIRS criteria + sepsis-induced organ dysfunction or tissue hypoperfusion (SBP ≤ 90mmHg or MAP ≤ 70mmHg or fall of > 40mmHg from baseline or lactate ≥ 4mmol/L)-Septic shock = Sepsis-induced hypotension persisting despite a 30mL/kg fluid bolusExclusion Criteria-Patients < 18-years-old-Pregnant patients-Incomplete or illegible documentationDates: 715 patient records were screened from 2015 to 2018Sample Size: 215 met criteria for severe sepsis and septic shock How were they assigned? -Included patients were assigned to one of two groupsCase: ESRD patients (104)Control: Non-ESRD patients (111)Outcomes: Primary outcome: Percentage of patients who received initial fluid resuscitation of ≥30mL/kg presenting to the hospital with severe sepsis or septic shock.Percentage of patients who received ≥ 30mL/kg within the first 6 hours Case (ESRD): 23.08%Control (Non-ESRD): 60.36%P < 0.001Mean fluids received Case (ESRD): 21.38mL/kg (1643.3mL)Control (Non-ESRD): 36.28mL/kg (2669.8mL)P < 0.001Secondary outcomes:ICU admission rate was higher in Control (Non-ESRD) groupCase (ESRD): 66.35%Control (Non-ESRD): 80.18%P = 0.03Need for vasopressors was higher in Control (Non-ESRD) groupCase (ESRD): 53.85%Control (Non-ESRD): 69.37%P = 0.025Rate of intubation for respiratory distress (within 24 hours of presentation), length of mechanical ventilation, mean time to ordering antibiotics, need for urgent dialysis for volume overload, and in-hospital mortality were not significantly different between groups!Source of infectionMost common cause of severe sepsis/septic shock in both groups was pneumoniaCase (ESRD): 45.19%Control (Non-ESRD): 47.75%UTIs were more common in the control (Non-ESRD) groupCase (ESRD): 6.73%Control (Non-ESRD): 27.93%Skin/Soft tissue/IV line infections were more common in the case (ESRD) groupCase (ESRD): 19.23%)Control (Non-ESRD): 3.60%Multivariate logistic regression analysisAge was significantly associated with mortality (p = 0.044); for every year, mortality increased by 2.9%Higher lactic acid levels were associated with higher mortality (p < 0.01)Fluid administration was independently associated with lower mortality in patients with severe sepsis/septic shock (p = 0.035)Subgroup analysis: Compared ESRD patients who received < 30mL/kg (80 patients) to those who received ≥ 30mL/kg (24 patients)No statistically significant difference in need for vasopressor support, number of vasopressors required, rate of ICU admission, ICU LOS, hospital LOS, rate of intubation, rate of urgent dialysis, and mortality. However, there was a trend towards worse outcomes with larger fluid boluses!Vasopressor use< 30mL/kg: 51.25%≥ 30mL/kg: 62.50%Rate of ICU admission< 30mL/kg: 65%≥ 30mL/kg: 70.83%Intubation rate within 24h of presentation for respiratory distress< 30mL/kg: 6.35%≥ 30mL/kg: 16.67%Length of mechanical ventilation (in days)< 30mL/kg: 4≥ 30mL/kg: 6In-hospital mortality<30mL/kg: 38.75%≥30mL/kg: 41.67% Author’s conclusion: “Our study indicates that initial fluid resuscitation of 30mL/kg may be safe, or at least not harmful, in patients with ESRD on HD and can potentially be incorporated in the sepsis triage bundle in the ED.”Strengths: -ESRD group was relatively similar to the control group-Subgroup analysis focused on the outcomes of ESRD patients only Limitations: -Single-center retrospective study design.-Population predominantly Caucasian males in Staten Island, NY limits generalizability.-Small sample size.-Type of crystalloid and use of blood products or albumin was not recorded. Volumes and characteristics of these other products could have affected outcomes.-Primary objective looked at percentage of ESRD patients with severe sepsis and septic shock who received ≥ 30mL/kg fluid bolus compared to non-ESRD patients. This has already been demonstrated by Lowe (2018), Truong (2019), and Dagher (2015).-Secondary outcomes raised more questions. Does ≥ 30mL/kg vs <30mL/kg fluid resuscitation lead to higher rates of intubation, urgent dialysis, hospital LOS, ICU LOS, need for vasopressors, in-hospital mortality, and other outcomes in patients with ESRD?-Only looked at intubation within the first 24 hours -The Non-ESRD group had higher lactic acid, heart rate, ICU admission rate, and need for vasopressors. Was the non-ESRD group sicker at baseline?-Early administration of appropriate antibiotics which has been shown to reduce mortality was not documented.-Subgroup analysis comparing ESRD patients who received < 30 mL/kg vs ≥ 30 mL/kg, intubation rate is more than 2x patients who received ≥ 30mL/kg. Larger sample size may make this statistically significant. Conclusion: This is not a practice changing study. Overall, the sample size was fairly low and homogenous, examined primarily Caucasian males but as we know, significant number of patients with end-stage renal disease are African-American males. In the future, it would be interesting to examine how serial fluid assessments that impact mortality rate inpatient care in patients with severe sepsis or septic shock. For example using things like CVP, ultrasound of the IVC, or passive leg raise to further evaluate fluid status would be more beneficial and could guide fluid resuscitation and hypotensive patient with ESRD more effectively. Overall, this study did not necessarily demonstrate any harm or benefit from a 30 cc/kg bolus.
32 minutes | Aug 29, 2020
4. 5 Notable papers of 2019
Dr. Del Tredici reviews 5 of her favorite papers from 2019. We discuss aortic stenosis, the SGLT2 inhibitors, the safety of PPIs, and whether or not you can treat osteomyelitis with oral antibiotics.Presenter: Sonya Del Tredici, MD Host: Giselle aerni, MDProducer: Robert Stuntz, MDPAPER 1: TAVR and more TAVRTranscatheter Aortic-Valve Replacement with a Balloon-Expandable Valve in Low-Risk Patients MJ Mack, et. al. The PARTNER-3 Investigators. The New England Journal of Medicine, 380 (18): 1695-1705. May 2, 2019.Why is this paper important?More TARVs than SAVRs are performed in the US, but they are traditionally reserved for intermediate and high-risk patients. This trial aimed to evaluate TAVR in low-risk surgical patients with aortic stenosis.What is the clinical question?Population: Patients with severe calcific aortic stenosis and low surgical risk. They excluded patients with low life expectancy, bicuspid aortic valves and disqualifying anatomy. The study included mostly American men, age ~71, 28% with CAD, 30% with DM, 15% with afib.Intervention: Transfemoral TAVR with a balloon-expandable valve, along with ASA+clopidogrel.Comparison: Surgical aortic valve replacement with a bioprosthetic.Outcomes: Patients were followed for 1 year.Primary endpoint: composite of all-cause mortality, stroke, and rehospitalization related to the valve.Secondary endpoints: new-onset afib, length of stay, death (30 d and 1 yr), stroke (30 d and 1 yr), rehospitalization, overall bad outcomes.These outcomes were both clinical and physiological.Is the study valid?I think this was a well-done study, and the conclusions were valid. It was randomized, but non-blinded. They enrolled 1000 patients, which was enough to power the study. The patients were similar at baseline. They had an appropriate intention-to-treat analysis, and pretty complete outcomes data. About 10% of patients in the surgery group withdrew, deciding they didn’t want surgery. The subgroups were pre-specified.Adverse events were reported.Some limitations were that they only collected 1 year of data, and since the patients were relatively young and healthy, they have a lot more than 1 year to go. I would have preferred to see what happened to them over a longer time. It was funded by the manufacturer of the valve, which may have caused some bias as well.What are the results?The results showed that TAVR is safer, has better outcomes at 30 days, and has better outcomes at 1 year. The patients who got a TAVR had shorter length of stay, fewer operative complications, were more likely to be discharged to home. They also had less afib, stroke, major bleeding, rehospitalization, and death. The only thing that was worse for the TAVR group was incidence of new LBBB.How will this study help us in patient care?The patients in this study are similar to my patients. The outcomes were clinically relevant. The benefits were both clinically and statistically significant. And TAVR is both cheaper and easier for patients. Therefore I conclude that this paper establishes TAVR as the treatment of choice for most patients whose anatomy allows it, especially older patients unconcerned about long-term valve durability. From now on surgical risk should no longer determine who should have a TAVR. Instead we can now look at life expectancy, anticoagulation needs, and long-term valve durability.PAPER 2: Doc, I feel fine. Do I have to get my valve replaced?Early Surgery or Conservative Care for Asymptomatic Aortic Stenosis The RECOVERY Trial. D Kang, S Park, S Lee, Et. al. N Eng J Med 382 (2), 111-119, January 9th, 2020Why is this paper important?In asymptomatic patients with aortic stenosis, the ideal time for surgical intervention is not known. Because the surgery is high-risk, previous guidelines recommended only doing valve replacement on symptomatic patients. But asymptomatic patients can die from sudden death, and they can sustain irreversible myocardial damage, causing later morbidity. But now that surgical techniques have improved, perhaps the risk-benefit calculation has changed, and we should be doing valve replacement on patients before they become symptomatic.What is the clinical question?Population: Included: adults with severe AS.The demographics of the participants were Korean adults, enrolled 2010-2015, mean age 64, BMI 24, HTN 40%, high chol 40%, bicuspid aortic valve 60% (which is important because that makes TAVR not an option), degenerative valve 33%.Excluded: symptomatic AS, CHF, other valve problems, and those who were not surgical candidates.Intervention: SAVR (50% mechanical, 50% biological).Comparison: conservative care, but offered surgery if AS became symptomatic. 74% eventually got surgery.Outcomes: primary endpoint: operative mortality (w/in 30 days) or CV death within trial period (4-7 yrs)Secondary endpoint: mortality, stroke, MI, repeat AV surgery, CHF hospitalizationIs the study valid?It is randomized, not blinded, multi-center study. There were 145 patients enrolled, which gave the study sufficient power. The two groups were similar at baseline.There was an intention-to-treat analysis. No patients lost to follow-up. The funding was by the Korean Institute of medicine, and was unlikely to cause bias.What are the results?The results showed that patients who got the early surgery, while they were still asymptomatic, had lower rates of death and CHF. The early surgery group had 7% risk of death. The late surgery group had 21% death. And the early surgery group had no incidence of sudden death, whereas the late surgery group had 14% die of sudden death. The early surgery had somewhat higher rates of stroke: 3% vs. 1 %.How will this study help us in patient care?This high-quality study showed that it is better to operate early on severe aortic stenosis, and not wait for symptoms to develop. As well as surgery being inevitable in these patients, delaying surgery put the patients at risk of sudden death. I will be referring all of my patients with severe aortic stenosis for valve replacement.PAPER 3: Not just for diabetics any more!Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction JJV McMurray, Et. Al. N Eng J Med 381(21), 1995-2008. November 21th, 2019Why is this paper important?The SGLT2 inhibitors are a novel class of agents to treat heart failure. SGLT2 inhibitors had been shown to reduce new-onset CHF as a secondary benefit in DM, but had not been investigated in CHF patients without diabetes..What is the clinical question?Population: Inclusion: adults, EF<40%, NYHA class II, III, or IV, not on an SGLT2-I.Exclusion: DM-I, SBP<95mmHg, eGFR<30, intolerance of SGLT-2-IDemographics: NYHA class II: 67%, class III: 32%, EF ~ 30%, 77% male, age ~66, 70% white and 24% Asian, 42% had DM.Intervention: dapagliflozin 10 mg daily, as well as all standard CHF therapyComparison: PlaceboOutcome: Primary: composite of CHF hospitalization, IV diuretics, and CV death.Secondary: CHF hospitalization, death, decrease in the KCCQ score, worsening renal function, renal death, all-cause mortality.These outcomes were clinical and relevant.Is the study valid?This is a valid study. It was randomized (stratified for diabetes), Placebo-controlled, and blinded. It included enough patients to adequately power the study (4744). The groups were similar at baseline. The duration was a median of 18.2 months, which is long enough to see some outcomes. There was an intention to treat analysis. 11% stopped the medications for a variety of reasons, but it was equal in intervention and control groups. Adverse events were reported, including volume depletion, declining renal function, hypoglycemia, fractures, DKA, and GU infections.The only limitation that concerned me was that it was funded by AstraZenica, which may have caused some bias.What are the results?The study showed that the patients on dapagliflozen had better outcomes than the patients taking placebo. They had fewer CHF exacerbations and death, and as an added bonus their diabetes was better controlled. The adverse events were the same in the two groups as well, except for renal adverse events, which were better on dapagliflozen.How will this study help us in patient care?The benefits of dapagliflozen in CHF were both clinically and statistically significant. These patients were sicker than those in other trials of SGLT-2 inhibitors, and were already receiving maximum CHF therapy, including loop diuretics and mineralocorticoid receptor antagonists. This improved outcomes even beyond that, and no increased adverse effects were noted. The only downside is the cost: about $500 per month retail. So I will be adding an SGLT2-inhib to my patients with CHF, if they are still facing exacerbations on maximal medical therapy.PAPER 4: Cum hoc, ergo propter hoc (with this, therefore because of this. Correlation does not imply causation)Safety of Proton Pump Inhibitors Based on a Large, Multi-Year Randomized Trial of Patients Receiving Rivaroxaban or Aspirin. P. Moayyedi, Et. Al. Gastroenterology 157, 682-691. September 2019Why is this paper important?PPIs are one of the most widely-prescribed classes of prescription drugs in the US, used for treatment of GERD and a variety of other acid-related conditions. Observational studies have associated long-term PPI use with many diverse adverse outcomes: CV events, PNA, fractures, enteric infections, C. diff, CVA, CKD, dementia and death. The mechanisms are biologically plausible but unproven, and the associations have never been satisfactorily evaluated in a randomized trial. This is the first large-scale prospective randomized trial to look at PPI safety in a population with significant underlying comorbidities. This trial was also evaluating rivaroxiban and aspirin for secondary prevention of CVD, which made it a little confusing. I’m just going to discuss the PPI arm here.What is the clinical question?Population: Inclusion: Age≥65 with stable CVD or PAD, or age < 65 with CVD + risk factors.Exclusion: Need for PPI at baseline, high risk of bleeding, severe CHF, significant CKD, need for dual anti-platelet tx,Demographics: age ~67, 79% male, 60% white, from Europe and the Americas, 61% had a previous MI38% had diabetes, 25% had CHF22% had CKDIntervention and Control: Pantoprazole 40 mg daily vs. placebo, followed for ~3.1 yrsOutcomes: Cardiovascular outcomes: MI, stroke, CV death, CHD, acute limb ischemiaPPI safety outcomes: PNA, c. diff, enteric infections, fractures, gastric atrophy, CKD, DM, COPD, dementia, CVD, cancer, hospitalizations, deathIs the study valid?This was a valid study. It was blinded, randomized, placebo-controlled, and multicenter. It included 17598 participants, large enough to adequately power the study. The follow-up was 3.1 years, which I think was long enough to see outcomes in this high-risk population. The two groups were similar at baseline. There was an intention-to-treat analysis.There were some limitations. It excluded those taking PPI at baseline, so may not be a true representative sample of our population of CVD. Also, 22% stopped the medication (placebo and pantoprazole), although it was the same number in both the pantoprazole and control groups. PPI safety data was collected via biannual interviews, rather than review of medical records, and received no independent adjudication. So the data is not as strong as it could have been.What are the results?In the patients randomized to pantoprazole 40 mg daily, there was no increase in MI, stroke, death, enteric infections, gastric atrophy, c. diff, CKD, dementia, pneumonia, or fracture.How will this study help us in patient care?To summarize, in high-risk patients who were not on a PPI, being randomized to get pantoprazole 4 mg daily for about 3 years did not increase the risk of any of the possible adverse events we attribute to PPI use. So PPIs are likely safe, and we can use them in patients for whom they’re indicated.PAPER 5Oral versus Intravenous Antibiotics for Bone and Joint Infection (OVIVA) HK Li, R Romback, Et. Al. N Eng J Med 380(5), 425-436. January 30th, 2019Why is this paper important?Treatment of complex orthopedic infections is difficult, expensive, and risky to the patient. There is a general feeling (unsupported by evidence) that antibiotics by IV are superior to PO. A small meta-analysis in 2012 showed no advantage to IV over PO, but it was not quite big enough to change practice. This paper aimed to determine if oral antibiotics were as good as IV antibiotics.What is the clinical question?Population: Inclusion: age>18, requiring 6 weeks abx for bone or joint infection (osteo, joint infx with arthroplasty, prosthetic joint infx, orthopedic device infx, vertebral osteo)Exclusion: Could not be randomized due to a need for either PO or IV AbxDemographics: UK, av age 60, 64% maleIntervention: 6 weeks of oral antibioticsComparison: 6 weeks of IV antibioticsOutcomes: Primary: definite treatment failure at 1 year (clinical, microbiological, or histological)Secondary: possible treatment failure at 1 yr, discontinuation of antibiotics, catheter complications, c. diff, resource use, health status, and adherence.Is the study valid?This was a valid study. It was randomized, pragmatic, multicenter, but non-blinded. Sample size was large enough, with 1054 participants, to show non-inferiority.There was an intention-to-treat analysis, and endpoint data available for 96% of participants. The one-year follow-up was long enough. The two groups were similar at baseline. The only difference between then was that the IV group may have received more frequent assessments and more overall care than the PO group.What are the results?This study showed that oral antibiotics were as good as IV antibiotics for treating infections, and had the same number of adverse outcomes. Both groups had about 14% treatment failure, and about 27% had some kind of adverse event.How will this study help us in patient care?This study challenges a widely held standard of care, which is that you need 6 weeks of IV antibiotics to treat complex bone and joint infections. But oral therapy was a good as IV along all parameters tested, and so should become the new standard of care.This episode was recorded on 5/7/2020.
18 minutes | May 15, 2020
3: High Cholesterol with Internal Medicine
In this episode we discuss two articles about high cholesterol, one dealing with new targets for treatment, and one about the PCSK9 inhibitors.Presenters: Nam Ha, MD and Britney Plotnick, MD, Wellspan York Hospital Internal Medicine Residency ProgramHosts: Giselle Aerni, MD and Sonya Del Tredici, MDProducer: Robert Stuntz, MDArticle 1: A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke. Amarenco, Pierre MD; Kim, Jong MD et al., N Engl J Med 2020; 382:9-19.BackgroundAfter an ischemic stroke of atherosclerotic origin or TIA, guidelines recommend intensive statin therapy to lower serum lipid levels. The SPARCL trial (2006 by the same author) showed a reduction in recurrent stroke with atorvastatin compared to placebo in patients with stroke, and forms the basis for this recommendation. However, a subsequent analysis of the data from that trial showed patients with LDL < 70 had a 28% lower relative risk reduction of stroke than those with LDL < 100 mg/dL. The current guideline recommends a high intensity statin, but does not specify the LDL target. There are limited data on whether a target LDL of 70 is better than a target LDL of 100. Thus, the Treat Stroke to Target trial (TST) was done.What is the clinical question?Population: 3/2010–12/2018, Adults from France and South Korea, ischemic stroke in prior 3 months or TIA within prior 15 days (modified Rankin 0-3), confirmed with imaging. Some patients were on anticoagulation, but the reason was not given.Intervention: Any type and any dose of statin to reach the target of LDL < 70 mg.dL or LDL 90-110 mg/dL. Ezetimibe was also added throughout the follow-up to maintain target. Other interventions also include blood pressure control (target 130/80 in diabetes; less than 140/90 otherwise), hemoglobin A1c%<7, and encouraging smoking cessation.Comparison: Lower target group versus higher target group.Outcomes: Primary endpoints: Nonfatal cerebral infarction or stroke of undetermined origin, nonfatal myocardial infarction, hospitalization for unstable angina followed by urgent coronary revascularization, TIA with urgent carotid revascularization, cardiovascular death (including unexplained sudden death).Secondary endpoints: MI, urgent coronary revascularization after onset of new symptoms, cerebral infarct or urgent revascularization of carotid or cerebral artery after TIA, cerebral infarction with TIA, urgent or elective revascularization of coronary, cerebral, peripheral artery, CVS death, death from any cause, intracranial hemorrhage, newly diagnosed diabetes.Is the trial valid?Randomized? yesBlinded? Blinded adjudicators of events that are components of end pointsGroups similar at baseline? yes, (although a higher percentage of patients in the lower target group were receiving ezetimibe than the higher target one)Follow-up sufficiently long and complete? Maybe. First follow-up was 3 weeks after randomization to adjust medication dose. Follow-up every 6 months after that with measurement of LDL and readjustment of medication as needed. Median follow-up is 5.3 years for French patients vs 2 years for Korean patients (SK patients recruited much later in the trial). Study stopped short due to sponsors lacking funds. Longer follow-up would help see a better picture (e.g. increased incidence of intracranial hemorrhage with LDL target < 70?).Intention to treat analysis? YesWere there enough patients? There were 3760 patients per protocol, but 2873 patients eventually randomized; this may reduce validity of results.Funding bias? Maybe. Study was funded by Pfizer, AstraZeneca, and Merk. Authors received fees.What are the results?Sample size: 2873 patients; 2860 included.Treatment effects: primary endpoint 8.5% in the lower-target (2.27 per 100 person-years) vs 10.9% in the higher-target (2.98 per 100 person-years). Adjusted hazard ratio, 0.78; 95% CI; 0.61-0.98; P=0.04.NNT = 42 for the follow-up intervalAdverse events: Intracranial hemorrhage 18 patients (1.3%) in lower-target vs 13 patients (0.9%) in higher-target. Hazard ratio 1.38, 95% CI, 0.68-2.82. New diabetes in 103 patients (7.2%) in lower-target vs 82 (5.7%) in higher-target. Hazard ratio 1.27; 95% CI, 0.95-1.70.Will the results help me in patient care?Perhaps…in the future. It is good to keep in mind that keeping a lower target LDL is shown here to prevent more cardiovascular events, although the confidence intervals have not been adjusted for multiple comparisons in the trial. Patients, recruited in the FOURIER trial where there was addition of PCSK9 inhibitor for patients with persistent LDL > 70 despite of being on high-dose statin, have LDL level around 30 mg/dL in the intervention group, and these patients have a reduction in major cardiovascular events (including stroke and cardiovascular death).Secondary endpoints such as intracranial hemorrhage could not be statistically analyzed due to hierarchical testing. Perhaps we need more studies to see whether stricter control of LDL can be associated with increased risk of intracranial bleed before making a final determination.Patients included have Rankin score from 0-3; what about 4-5?(Rankin Score: 0 = no symptoms, 1 = no disability, 2-3 = need help with daily activities, 4-5 = dependent or bedridden, and 6 = death)ReferencesAmarenco, Pierre MD; Kim, Jong MD et al., A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke. N Engl J Med 2020; 382:9-19JAMA Users Guide article for reference: II How to Use An Article About Therapy or PreventionAmarenco et al. High Dose Atorvastatin after Stroke or Transient Ischemic Attack. N Engl J Med 2006; 355:549-559Sabatine, Marc MD et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med 2017; 376:1713-1722SPARCL Investigators. High-Dose Atorvastatin after Stroke or Transient Ischemic Attack. N Engl J Med 2006; 355:549-559Article 2: Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. By GG Schwartz, et. al. N Eng J Med 2018; 379: 2097-2107. (Odyssey Trial)Why is this study important?Patients who have had ACS are at a high risk for recurrent ischemic cardiovascular events. Patients who receive statins to lower LDL have a lower risk. PCSK9 helps to degrade LDL receptors, decreasing the clearance of LDL from the circulation. Hence, monoclonal antibodies to PCSK9 were developed to reduce LDL cholesterol. Prior to this study, it was unknown if PCSK9 decreases cardiovascular risk after ACS. ACS is fairly common in my outpatient practice, so I was interested in learning further medical treatment to reduce cardiovascular events.What is the clinical question?Does alirocumab, a PCSK9 monoclonal antibody, reduce the risk of recurrent ischemic cardiovascular events among patients who had an ACS within the prior 1-12 months and in whom lipid levels exceed specified thresholds despite high intensity or maximum dose tolerated statin therapy? To put it simply, does alirocumab improve cardiovascular outcomes after an ACS in patients receiving high intensity statin?Population: ≥ 40 yo, hospitalized for ACS (MI or UA) 1-12 months prior, with LDL ≥ 70 mg/dL, non-HLD ≥ 100 mg/dL, or an apolipoprotein B level of ≥ 80. Lipid levels needed to be stable for a minimum of 2 weeks with atorvastatin (40-80mg), rosuvastatin (20-40mg), or the maximum tolerated dose.Demographics: ACS: MI (83%), UA (16.8%). Most patients were receiving guideline-recommended medications & had a coronary revascularization. Mean LDL: baseline was 92 +/- 31 mg/dL. At the time of randomization, 88.8% of patients were receiving atorvastatin 40-80mg or rosuvastatin 20-40mg daily.Intervention: Alirocumab 75mg subQ every 2 weeks. Target LDL 25-50mg/dL (avoided LDL < 15mg/dL)-> Alirocumab was adjusted every 2 weeksControl: PlaceboOutcomes: Primary endpoints: Death from CHD, Nonfatal MI, fatal or nonfatal ischemic stroke, or UA requiring hospitalization.Secondary endpoints: CHD event (Primary endpoint), ischemia driven coronary revascularization procedure, & hospitalization for CHFIs the study valid?Randomized? YesMulti-center? 57 countries, 1315 sitesBlinded? Yes, double-blindWere the groups similar at the start of the trial? YesWas the sample size large enough? Yes, with 18924 participantsWere all the participants accounted for at the end of the study? Yes.Premature discontinuation for reasons other than death: Alirocumab discontinued: 1343 (14.2%) Placebo discontinued: 1496 (15.8%)Was the follow up long enough? Yes, patients were followed for 2.3-3.4 years (median 2.8 years).Was the statistical analysis appropriate? yesIs the hypothesis biologically plausible? yesWhat are the results?Alirocumab + statins lowered LDL more than statins alone. At month 48, mean LDL = 66 mg/dL in the alirocumab group, and 103 mg/dL in the placebo group. Note that the alirocumab group includes values measured after discontinuation of alirocumab & after blinded substitution of placebo for alirocumab.The composite primary endpoint was lower in the alirocuman group thatn th eplacebo group (9.5% vs. 11.1%).The secondary endpoints were lower in the alirocumab group than the placebo group.Number needed to treat? 62.5 needed to treat to prevent the occurrence in the primary endpoint in 2.8 years, or 49 patients would need to be treated for 4 years to prevent the occurrence of 1 primary endpoint.Are the results precise? Yes, except for death from CHDAre the results statistically significant? Yes, except for death from CHDAre the results clinically significant? YesWere there adverse events reported? Similar except local injection site reactions were more common in alirocumab (3.8%) than placebo (2.1%).Summary of results: In patients who had ACS and with lipid levels exceeding threshold while on high intensity or maximum tolerated statin dose, the risk of death from CHD, non-fatal MI, fatal or non-fatal ischemic stroke, or UA requiring hospitalization, was lower among those who were treate
25 minutes | May 15, 2020
2: Sports Medicine
This episode features the sports medicine department. We discuss a systematic review of the treatment of musculoskeletal pain, and a meta-analysis of the timing of splenic rupture.Presenters: Rebecca King, MD and Laura Shaffer, MD, Wellspan Health Sports Medicine Fellows. Hosts: Giselle Aerni, MD and Sonya Del Tredici, MDProducer: Robert Stuntz, MDDr. King presented the article What does best practice care for musculoskeletal pain look like? Eleven consistent recommendations from high-quality clinical practice guidelines: systematic review. Lin I, Wiles L, Waller R, et al. Br J Sports Med 2020;54:79–86.This article collects several Clinical Practice Guidelines from around the world addressing different MSK complaints to create a set of common recommendations that can be applied broadly to all MSK conditions. The authors find 11 consistent recommendations, based off of high-quality evidence, to aid in the treatment of MSK conditions in general. Essentially, the recommendations emphasize the importance of a thorough history and physical exam, discourages the use of unnecessary imaging studies, and highlights the importance of excellent patient education and communication with an early return to activity and exercise.AGREE II tool link: https://www.agreetrust.org/agree-ii/Dr. Shaffer presented the article Association of Splenic Rupture and Infectious Mononucleosis: A Retrospective Analysis and Review of Return-to-Play Recommendations Sylvester JE, Buchanan, BK, Paradise SL, Yauger JJ, Beutler AI. Sports Health, Nov-Dec 2019. v. 11 no. 6, pp 543-549.Why is this study important?Something that can be managed across medical disciplines. Splenic rupture (although rare) is a very serious medical emergency. Current guidelines for RTP are 21 days from symptom onset. Based off case reports.What are the results?Of the 42 cases meeting inclusion criteria, the overall mean to splenic rupture was 15.4 days with SD of 13.5 days. 73.8% of splenic ruptures occurred by 21 days (current standard), leaving over 25% of cases yet to occur. 90.5% occurred by 31 days. 80.5 cases were reported as atraumatic.When assessing just the traumatic rupture cases, the mean time to rupture was 22.9 days and included things like running, fall, or abdominal blow. Most cases of IM were laboratory confirmed after their traumatic splenic rupture.35 of the 42 cases also had documented information regarding their return to sport/activity post-illness. 71.4% returned to pre-activity/sport level. Of those, nearly half did so within 90 days and nearly 3/4ths did so within 180 days.How will this study help us in patient care?This study shows that 1 in 4 splenic ruptures are occurring after the current return to play recommendation of 21 days after symptom onset. This challenges the current guidelines.
20 minutes | Apr 19, 2020
This is our Podcast Journal Club Pilot Episode. We will be discussing two articles chosen by Dr. Del Tredici on opiate use and misuse, and a related current events topic—safe injection sites.Presenter: Sonya Del Tredici, MDHost: Giselle Aerni, MDProducer: Robert Stuntz, MD“Harm reduction” is treatment that focuses on reducing harm from opiate use, rather than on eliminating opiate use.Article 1: Mortality risk during and after opioid substitution treatment: systematic review and meta-analysis of cohort studies. Luis Sordo, Gregorio Barrio, Maria J Bravo, B Iciar Indave, Louisa Degenhardt, Lucas Wiessing. Marica Ferri, Roberto Pastor-Barriuso. BMJ 2017;357:j1550.This article discusses mortality before, during, and after treatment of opioid use disorder with buprenorphine and methadone. It tackles one type of “harm reduction” which is substituting the risky opiate (heroin) for a less risky opiate (buprenorphine and methadone). The article shows that there are substantial reductions in mortality while using methadone and buprenorphine.Article 2: No evidence of compensatory drug use risk behavior among heroin users after receiving take-home naloxone. Jones JD, Campbell A, Metz VE, Comer SD.Addict Behav. 2017 Aug;71:104-106.Another type of harm reduction is providing opiate users and their friends and family with naloxone to use in the event of an overdose. Some people feel that this will reduce the fear of overdose, and thus encourage more drug use. This article discusses whether or not patients who are given naloxone (to treat overdose) use opiates more risky ways. It showed that when given naloxone and trained how to use it, their risky drug-using behavior did not increase.Current Events Topic: We discussed that opening of a “safe injection site” in Philadelphia, where opiate users could go to use their opiates in a safe, clean site where clean needles would be provided, medically-trained staff would be there in the case of overdose, and to offer entrance into treatment and other social services if the patient were interested. You can read more about it in this article from the Pew Trust. For background, you could also look at this article from the NY Times about Kensington (where the proposed safe injection site will be) that has been called “The Wal-Mart of heroin.” The United States Attorney opposes the safe injection site.
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