Good morning.
Several interesting studies have been presented at the ESICM meeting in Paris. Some of these have simultaneously been published online.
One such study, attempted to evaluate the risk benefit aspects of stress ulcer prophylaxis (SUP) among critically ill patients. Although SUP is extensively prescribed and is considered as a quality marker for ICU care, concerns have been raised of late about the increased incidence of nosocomial pneumonia and diarrhea attributable to SUP. This study aimed to answer some of those concerns
Krag et al: Pantoprazole in Patients at Risk for Gastrointestinal Bleeding in the ICU. NEJM Oct 24 2018
This was a multi center, blinded RCT carried out in Europe. The authors hypothesized that SUP with Pantoprazole would decrease the incidence of Gastro Intestinal Bleeding while increasing the incidence of nosocomial infections and Myocardial Ischemia.
The patients included in this study had to have atleast one risk factor for clinically important GI bleeding among shock, oral anticoagulant usage, renal replacement therapy, need for mechanical ventilation > 24 hours, history of liver disease or ongoing coagulopathy. Pantoprazole was used as SUP as an intravenous injection of 40 mg diluted in 10ml of 0.9% saline. A matching placebo was used.
The primary end point of interest was 90 day mortality. Secondary end points included clinically important gastrointestinal bleeding, new-onset pneumonia, C. difficile infection, or acute myocardial ischemia. Need for RRT and Mechanical ventilation were also included as end points.
This study was carried out between January 2016 and October 2017, enrolling 3298 patients ( 1645 - pantoprazole 1653 placebo). More than 3/4ths of the patients needed mechanical ventilation and more than 2/3rds required vasopressor support. Median SOFA scores of the cohort was 9. More than half the patients received enteral nutrition on the first day of the trial. Average LOS was 6 days and duration of therapy was 4 days.
At the end of 90 days, approximately 30% of patients in both arms had died. There was no difference between the Pantoprazole and the placebo groups. Clinically important events like gi bleed, infection or myocardial ischemia happened in 21-22% of the patients in both the groups. Specifically, GI bleed occurred in 2.8% of patients receiving pantoprazole and 4.2% patients receiving placebo. This difference was statistically insignificant. There were no serious adverse incidents in either group.
The authors concluded that " 90-day mortality, percentages of days alive without the use of life support, and numbers of patients with clinically important events, infectious adverse events, or serious adverse reactions were similar between those treated with pantoprazole and those who received placebo". At the same time incidence of myocardial ischemia and nosocomial infections were not higher in the pantoprazole group.
My opinion: A serious rethinking has to happen regarding the " routine" use of SUP with Pantoprazole. Although the concerns of harm have been partially allayed, the basis for blanket use for all comers is also under question. If enteral feed can be started on the first day, addition of pantoprazole may not confer any additional benefit.
Wednesday, October 24, 2018
Sunday, October 14, 2018
Early versus Late RRT - Should the paradigm change?
Good morning
This week we discuss the results of the IDEAL - ICU ( The Initiation of Dialysis Early Versus Delayed in the Intensive Care Unit ) study which appears to challenge the benefits of early RRT in the ICU.
Barbar et al Timing of Renal-Replacement Therapy in Patients with Acute Kidney Injury and Sepsis.
N Engl J Med 2018; 379: 1431-42
Acute Kidney Injury is very frequent amongst critically ill septic patients. Attributable mortality is also high. The popular belief is that early aggressive RRT is beneficial in terms of ICU survival and long term recovery of renal function.
The IDEAL ICU multicenter study attempted to evaluate whether initiating RRT as soon as a diagnosis of "Failure" as per RIFLE criteria is made, confers survival advantage to the critically ill patient.
They identified patients who satisfied the criteria to define Failure as per the RIFLE criteria. They then randomized this cohort into those who received RRT as soon as failure was diagnosed and into those in whom RRT was initiated only when metabolic problems or hyperkalemia or fluid overload mandated such therapy.
Originally this study was designed to recruit 800+ patients to show a 10% difference in outcomes with 80% power. The primary end point was 90 day mortality. Secondary outcomes were death at 28 days and at 180 days, RRT free days, ventilator and vasopressor free days at 28 days, ICU and hospital LOS, adverse events during the entire ICU stay, fluid balance in the first 7 days after enrollment; the need for emergency renal-replacement therapy in the delayed strategy group; death of patients in the delayed strategy group in whom at least one criterion for emergency renal-replacement therapy was met; and dependence on renal-replacement therapy at hospital discharge.
The study was stopped midway due to apparent futility of the early RRT strategy. Fluid balance also did not show any beneficial pattern with early RRT. The incidence of metabolic complications was higher in the delayed RRT group. Emergency RRT was needed in 17% of patients in the delayed group ( 41 patients). Twenty eight of the 41 died. The dependence on the RRT at hospital discharge was also not significantly different between the two groups.
The authors concluded that " Among patients with septic shock who had severe acute kidney injury, there was no significant difference in overall mortality at 90 days between patients who were assigned to an early strategy for the initiation of renal-replacement therapy and those who were assigned to a delayed strategy."
My view:
1. We need to think twice before initiating RRT just on the basis of creatinine.
2. Failure may not be the ideal comparator. Injury stage may need to be focused on
3. In the delayed strategy emergency need for RRT could be associated with higher mortality
This week we discuss the results of the IDEAL - ICU ( The Initiation of Dialysis Early Versus Delayed in the Intensive Care Unit ) study which appears to challenge the benefits of early RRT in the ICU.
Barbar et al Timing of Renal-Replacement Therapy in Patients with Acute Kidney Injury and Sepsis.
N Engl J Med 2018; 379: 1431-42
Acute Kidney Injury is very frequent amongst critically ill septic patients. Attributable mortality is also high. The popular belief is that early aggressive RRT is beneficial in terms of ICU survival and long term recovery of renal function.
The IDEAL ICU multicenter study attempted to evaluate whether initiating RRT as soon as a diagnosis of "Failure" as per RIFLE criteria is made, confers survival advantage to the critically ill patient.
They identified patients who satisfied the criteria to define Failure as per the RIFLE criteria. They then randomized this cohort into those who received RRT as soon as failure was diagnosed and into those in whom RRT was initiated only when metabolic problems or hyperkalemia or fluid overload mandated such therapy.
Originally this study was designed to recruit 800+ patients to show a 10% difference in outcomes with 80% power. The primary end point was 90 day mortality. Secondary outcomes were death at 28 days and at 180 days, RRT free days, ventilator and vasopressor free days at 28 days, ICU and hospital LOS, adverse events during the entire ICU stay, fluid balance in the first 7 days after enrollment; the need for emergency renal-replacement therapy in the delayed strategy group; death of patients in the delayed strategy group in whom at least one criterion for emergency renal-replacement therapy was met; and dependence on renal-replacement therapy at hospital discharge.
The study was stopped midway due to apparent futility of the early RRT strategy. Fluid balance also did not show any beneficial pattern with early RRT. The incidence of metabolic complications was higher in the delayed RRT group. Emergency RRT was needed in 17% of patients in the delayed group ( 41 patients). Twenty eight of the 41 died. The dependence on the RRT at hospital discharge was also not significantly different between the two groups.
The authors concluded that " Among patients with septic shock who had severe acute kidney injury, there was no significant difference in overall mortality at 90 days between patients who were assigned to an early strategy for the initiation of renal-replacement therapy and those who were assigned to a delayed strategy."
My view:
1. We need to think twice before initiating RRT just on the basis of creatinine.
2. Failure may not be the ideal comparator. Injury stage may need to be focused on
3. In the delayed strategy emergency need for RRT could be associated with higher mortality
Tuesday, October 9, 2018
Have we found an answer to DVT prophylaxis in Neurosurgical patients
Deep Vein Thrombosis is a well recognized complication amongst hospitalized patients. Providing prophylaxis against DVT is acknowledged as a high impact intervention. Neurosurgical patients ( cranial and spinal) constitute a special cohort. On the one hand the incidence of DVT amongst this population is as high as 40%. On the other hand, use of chemical prophylaxis is viewed with caution and with the fear of producing a major hemorrhage. Mechanical prophylaxis has been used as an alternative. But the relative risk reduction with mechanical prophylaxis is not very high. Several attempts have been made in the past to review literature related to this aspect. But the results have been ambiguous.
Khan et al have carried out the latest meta analysis to answer the question of safety of chemical prophylaxis in relation to neurosurgical patients.
Chemical venous thromboembolism prophylaxis in neurosurgical patients: an updated systematic review and meta-analysis
Nickalus R Khan et al J Neurosurg 129:906–915, 2018
The authors carried out a search of literature to identify studies which evaluated the efficacy and safety of chemical prophylaxis among patients undergoing cranial and spinal surgery. Studies which didn't have a control or placebo arm were not included. The funnel plot of the overall study list appears symmetrical excluding publication bias. A total of 9 studies withstood the methodological scrutiny and were eligible for the meta analysis.
The chemical prophylaxis used in six of the studies included was enoxaparin.
The total patient base for this study was 1232. Chemical prophylaxis showed a significant benefit in preventing DVT when compared to placebo with an OR of 0.51. The absolute risk reduction was 42%. The number needed to treat (NNT) for prevention of DVT was 11. The heterogeneity I2 statistic was 0%.
The incidence of major Intra Cranial Hemorrhage in the treatment group was 2.7% compared to 1.6% in the control group. The OR was 1.42, 95% CI 0.61–3.30 which was not statistically significant. The Forrest plots of both these data is shown below.
The rates of major extra cranial bleeds and overall minor bleeds were also not significantly different.
This study seems to conclude that there is a significant benefit in using chemical prophylaxis in prevention of DVT amongst neurosurgical patients with no significant increase in the incidence of major intra cranial hemorrhage.
My opinion: DVTpharmaco prophylaxis amongst Neurosurgical patients may now be approached with a little more confidence. However, close monitoring is needed.
Khan et al have carried out the latest meta analysis to answer the question of safety of chemical prophylaxis in relation to neurosurgical patients.
Chemical venous thromboembolism prophylaxis in neurosurgical patients: an updated systematic review and meta-analysis
Nickalus R Khan et al J Neurosurg 129:906–915, 2018
The authors carried out a search of literature to identify studies which evaluated the efficacy and safety of chemical prophylaxis among patients undergoing cranial and spinal surgery. Studies which didn't have a control or placebo arm were not included. The funnel plot of the overall study list appears symmetrical excluding publication bias. A total of 9 studies withstood the methodological scrutiny and were eligible for the meta analysis.
The chemical prophylaxis used in six of the studies included was enoxaparin.
The total patient base for this study was 1232. Chemical prophylaxis showed a significant benefit in preventing DVT when compared to placebo with an OR of 0.51. The absolute risk reduction was 42%. The number needed to treat (NNT) for prevention of DVT was 11. The heterogeneity I2 statistic was 0%.
The incidence of major Intra Cranial Hemorrhage in the treatment group was 2.7% compared to 1.6% in the control group. The OR was 1.42, 95% CI 0.61–3.30 which was not statistically significant. The Forrest plots of both these data is shown below.
The rates of major extra cranial bleeds and overall minor bleeds were also not significantly different.
This study seems to conclude that there is a significant benefit in using chemical prophylaxis in prevention of DVT amongst neurosurgical patients with no significant increase in the incidence of major intra cranial hemorrhage.
My opinion: DVTpharmaco prophylaxis amongst Neurosurgical patients may now be approached with a little more confidence. However, close monitoring is needed.
Monday, October 1, 2018
Can Response to Iron therapy in ICU be predicted
Anemia in the Intensive Care Unit is a common problem. Transfusion triggers are getting lower across specialties as discussed last week. Iron infusion therapy is sometimes used to augment the marrow response to the stress of critical illness. But, the effect of iron therapy on reducing the transfusion requirement has not been reported. Litton et al attempted to evaluate the efficacy of Hepcidin in predicting the response to iron therapy and thereby reduce transfusion requirements. This was a nested cohort as a part of the IRONMAN study.
Hepcidin predicts response to IV iron therapy in patients admitted to the intensive care unit: a nested cohort study.
Litton et al. Journal of Intensive Care (2018) 6:60
This was a prospective observational study across four tertiary care Australian ICUs which participated in the IRONMAN study.
The response to Iron therapy among critically ill patients is variable. Hepcidin is an integral part of the iron metabolism and serum levels fall in iron deficiency states.
The primary aim of this study was to determine whether low serum hepcidin concentration could identify a subset of critically ill patients with anaemia in whom IV iron therapy was effective in reducing RBC transfusion requirement.
Septic patients and those with well established Iron deficiency were excluded.
The treatment arm received 500 mg IV ferric carboxy maltose. Hepcidin 25 levels were measured prior to administration of parenteral Iron
A total of 133 patients were included in this study
Majority of the patients were post operative patients predominantly from trauma and cardiothoracic ORs. APACHE II score was 12 and mean SOFA score was 6. Eighty eight patients fell in the lower two tertiles of hepcidin concentration. Half of them received parenteral iron and the other half received placebo. Patients who had lower hepcidin concentration responded to Iron and required lesser packed cell transfusions. Patients who had Hepcidin concentration in the highest tertile did not show any decreased requirement for blood transfusion despite iron therapy. Hepcidin levels did not correlate with standard determinants of iron deficiency like transferrin saturation index.
The authors surmised that serum hepcidin concentration identified a subset of anaemic, critically ill patients in whom IV iron therapy was effective in reducing RBC transfusion requirement.
What I understood?
Predicting response to iron therapy is always difficult and unpredictable. Using the Hepcidin level, if response to therapy can be predicted, lot of blood transfusions can be safely avoided
Where this study fails?
No septic patients included
No correlation with perfusion markers.
Hepcidin predicts response to IV iron therapy in patients admitted to the intensive care unit: a nested cohort study.
Litton et al. Journal of Intensive Care (2018) 6:60
This was a prospective observational study across four tertiary care Australian ICUs which participated in the IRONMAN study.
The response to Iron therapy among critically ill patients is variable. Hepcidin is an integral part of the iron metabolism and serum levels fall in iron deficiency states.
The primary aim of this study was to determine whether low serum hepcidin concentration could identify a subset of critically ill patients with anaemia in whom IV iron therapy was effective in reducing RBC transfusion requirement.
Septic patients and those with well established Iron deficiency were excluded.
The treatment arm received 500 mg IV ferric carboxy maltose. Hepcidin 25 levels were measured prior to administration of parenteral Iron
A total of 133 patients were included in this study
Majority of the patients were post operative patients predominantly from trauma and cardiothoracic ORs. APACHE II score was 12 and mean SOFA score was 6. Eighty eight patients fell in the lower two tertiles of hepcidin concentration. Half of them received parenteral iron and the other half received placebo. Patients who had lower hepcidin concentration responded to Iron and required lesser packed cell transfusions. Patients who had Hepcidin concentration in the highest tertile did not show any decreased requirement for blood transfusion despite iron therapy. Hepcidin levels did not correlate with standard determinants of iron deficiency like transferrin saturation index.
The authors surmised that serum hepcidin concentration identified a subset of anaemic, critically ill patients in whom IV iron therapy was effective in reducing RBC transfusion requirement.
What I understood?
Predicting response to iron therapy is always difficult and unpredictable. Using the Hepcidin level, if response to therapy can be predicted, lot of blood transfusions can be safely avoided
Where this study fails?
No septic patients included
No correlation with perfusion markers.
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