Dissertation: Nursing Literature Search

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Aim

This study aims to discover the optimal dose of the activated protein C (APC) in order to achieve a proper amount of anticoagulant for hemodialysis for patients in end-stage renal disease. This can be used to create a standard safe drug.

Methods

12 patients were involved in the study with a stable condition during hemodialysis therapy. This study was designed as a dose-finding study, where different dosages of APC were employed instead of heparin. This helped discover a range of APC for extracorporeal circuit anticoagulation. The level of partial thromboplastin time was observed at fixed intervals during hemodalysis therapy.

Results

On average, the dosage that was required to induce adequate anticoagulation was 24-30 μg/kg/h. The average age of the patients were 49 ± 12 years. 66.7% were male and 75% of these patients were African-American. No hazardous events occurred as a result of the experiment, although one patient had an early cancellation of their infusion due to refractory intradialytic hypertension.

Conclusions

The initial starting dosage of 24-30 μg/kg/h aided in obtaining the target partial thromboplastin time for end-stage renal disease patients that were undergoing hemodialysis. This was enough for circuit anticoagulation and was safe for all patients.

PMID: 24969781 DOI: 10.1159/000362154

2. Ann Intensive Care. 2018 Jan 31;8(1):16. doi: 10.1186/s13613-018-0353-2.

Pharmacogenomic biomarkers do not predict response to drotrecogin alfa in patients with severe sepsis.

Annane D, Mira JP, Ware LB, Gordon AC, Hinds CJ, Christiani DC, Sevransky J, Barnes K, Buchman TG, Heagerty PJ, Balshaw R, Lesnikova N, de Nobrega K, Wellman HF, Neira M, Mancini ADJ, Walley KR, Russell JA.

Abstract

This study investigated the best possible design for pharmacogenomic trials in sepsis patients, where the interaction between activated drotrecogin alfa proteins (DrotAA) and pharmacogenomic biomarkers is observed. This trial study helps to ascertain whether or not the known improved response polymorphisms (IRPS A and B) are correlated or interact with improving the outcome of DrotAA in patients with severe sepsis.

Aim

This study will determine whether IRPS A and B positively influence DrotAA in patients with severe patients, as well as underlying the activate between pharmacogenomic biomarkers and DrotAA. This study design can provide a template for future studies.

Methods

Two groups of patients that had severe sepsis were already at high risk of death and may or may not have received DrotAA. Their DNA were matched to controls and also adjusted for age. Some factors that were observed included ventilation, organ dysfunction, SAPS II or APACHE II, medical/surgical status, propensity score, and infection site. The propensity score was based upon the chance that a patient received DrotAA due to baseline factors. A two-phase data transfer and also an independent genotyping helped to lessen any bias. Primary analysis consisted of a comparison between IRP- and IRP+ groups and the effects of DrotAA within in-hospital 28-day mortality patients. The secondary endpoints included the time to death within the hospital, the intensive care unit, the overall DrotAA treatment influence on mortality rate, and the ventilator free days.

Results

Ultimately, 1935 patients that were not treated with DrotAA were successfully matched to 692 patients that were treated with DrotAA. It was found that genotyping was successful for both the non-DrotAA patients and DrotAA patients. The first hypothesis was not significant for the genotype-by-treatment interaction, which was analyzed through a conditional logistic regression analysis and revealed. Additionally, there was no significant genotype by treatment interaction for the secondary endpoint as well.

Conclusion

At the end of the trial, it was found that none of the groups, IRPA and IRPB, had a unique response to DrotAA within the in-hospital 28-day mortality period.

PMID: 29388048 PMCID: PMC5792380 DOI: 10.1186/s13613-018-0353-2

3. BMJ Open. 2014 Jul 31;4(7):e005622. doi: 10.1136/bmjopen-2014-005622.

Recombinant human activated protein C for the treatment of severe sepsis and septic shock: a study protocol for incorporating observational evidence using a Bayesian approach.

Zhang Z.

Abstract

Studies show that activated proteins, such as activated protein C (aPC), play a strong role in managing severe inflammatory reactions for patients with severe sepsis. Although, some research has revealed in randomised controlled trials that aPC isn’t essentially beneficial when it concerns the heightened level of survival rates in critically ill patients that suffer from sepsis. The researchers of this study believe that the observational evidence is ignored, which is why no significant interactions were identified. This study aims to understand how observational data can influence the findings of these trials utilizing a Bayesian approach.

Aims

The purpose to reveal that activated proteins have a major effect on inflammation responses with patients with severe sepsis and show that previous research data was largely misinterpreted or ignored.

Methods

Studies and research clinical trials were analyzed to better understand the influence of aPC on the level of mortality in critically ill patients who are suffering from sepsis. A Delphi list is being utilized to assess the quality of these studies, where publication bias will be prevented through the Egger regression test and Begg rank correlation test in a quantitative analysis. All observational evidence will be down-weighted with the power of α with values 0 to 1. All trial sequential analysis will be executed in order to calculate how reliable the data is within the meta-analysis with some adjustments for significance levels for multiple testing and the lack of data through the combination of several research studies.

Conclusion

Overall, it was found that the only approved drug for the treatment of sepsis was aPC. Unfortunately, this drug was removed from the market after the clinical trial PROWESS-SHOCK had failed to exhibit any positive outcomes in patients with sepsis. APC was approved for use because it had originally proved to have a strong beneficial result in patients, where studies were halted early because of how high the results were.

PMID: 25082420 PMCID: PMC4120342 DOI: 10.1136/bmjopen-2014-005622

4. Crit Care Med. 2004 Nov; 32(11): 2199–2206. doi: PMC4714718

The Effect of Drotrecogin Alfa (activated) on Long-Term Survival after Severe Sepsis

Derek C. Angus, MB, CB, MPH, Pierre-Francois Laterre, MD, Jeff Helterbrand, PhD, E. Wesley El, MD, MPH, Daniel E. Ball, BS, MBA, Rekha Garg, MD, Lisa A. Weissfeld, PhD, and Gordon Bernard, MD

Abstract

In order to analyze if drotrecogin alfa (DrotAA) is beneficial in the long-term mortality rate of patients with severe sepsis, 164 tertiary care institutions within 11 countries were included in an intervention study. The number of patients that received DrotAA were 850 at a dosage of 24 μg/kg/h for 96 hours. 840 patients received a placebo. The total of 1690 subjects who had severe sepsis were treated with the PROWESS’s drug from their study. 1220 were alive at the end of the 28 days of the original PROWESS follow-up.

Aims

The aim of this study is to identify the long-term survival rate for patients who have severe sepsis that were in a previous multi-cententer PROWESS trial who are being treated with activated drotrecogin alfa (DrotAA) or a placebo.

Methods

The researchers collected long-term survival data, and also had additional follow-up data for 100% of test patients within 28 days. Also, data was recorded for 98% after hospital discharge, 94% at 3 months and 93% within 1 year. The longest of these follow-ups was a check-in at 3.6 years. Data shows that the hospital survival was higher with the DrotAA treatment as opposed to placebo, which was 70.3% versus 65.1%. However, there was no significant difference between the survival time duration or the survival rates in patients who had received a placebo and who had been treated with DrotAA. This was 846 days for placebo, and 1113 days for Drot AA for survival time duration. Landmark survival rates were 66.1% for DrotAA and 62.4% for placebo at 3 months, 62.2% for DrotAA and 60.3% for placebo at 6 months, 58.9% for DrotAA and 57.2% for placebo at 1 year. A strong interaction occurred between the baseline APACHE II scores and treatment assignment, which shows that there was an effect from the treatment on patients with the severe illness. Patients who had an APACHE II score that was equal to or greater than 25 had a higher survival time with DrotAA, which was 450 days as opposed to 71 at 3 months. At 6 months, this rate was 55.2% for DrotAA as opposed to 45.3%, and 52.1% for DrotAA as opposed to 41.3% for one year.

Conclusions

The survival of patients with severe sepsis had greatly improved in groups that had received DrotAA. However, after hospital discharge the survival benefit severely declined with time. The effect of DrotAA changes due to the APACHE II score, where the long-term survival rate in patients had been enhanced with the growth of APACHE II scores that were equal to or above 25. However, no benefit was found in lower scores.

doi/PMCID: PMC4714718 NIHMSID: NIHMS202592 PMID: 15640631

5. Int J Infect Dis. 2015 Apr;33:90-6. doi: 10.1016/j.ijid.2014.12.032. Epub 2014 Dec 19.

Thymosin alpha1 based immunomodulatory therapy for sepsis: a systematic review and meta-analysis.

Li C, Bo L, Liu Q, Jin F.

Abstract

In a study on the effects of an immunomodulatory drug Thymosin alpha (Tα1), it is unknown whether or not this drug is beneficial for sepsis. A meta-analysis was performed in this study to understand how effective Tα1 is on immunomodulatory therapy in septic patients.

Aims

The aim is to identify whether Tα1 is a beneficial drug for sepsis, and whether it can improve immunomodulatory therapy for patients with sepsis and their mortality level.

Methods

Any clinical trials before Dec. 12, 2014 were analyzed and sourced from electronic databases. All of these trials were based upon Tα1 which involved immunomodulatory therapy for sepsis. Authors were hired to select these studies, analyze the quality, and also compile data. The information was related to the mortality of the patient.

Results

The Tα1 immunomodulatory therapy was found to be involved with the creation of lower mortality in patients with sepsis.

Conclusion

While research study revealed the effectiveness of this therapy, researchers feel that data should be reviewed carefully because there is a lot of poor quality research studies, or studies had too few participants within each trial. It is thought that there needs to be additional trials worldwide for more conclusive results.

PMID: 25532482 DOI: 10.1016/j.ijid.2014.12.032

6. Ann Intensive Care. 2013; 3: 30. doi: 10.1186/2110-5820-3-30

Near-infrared spectroscopy StO2 monitoring to assess the therapeutic effect of drotrecogin alfa (activated) on microcirculation in patients with severe sepsis or septic shock

Jordi Masip, Jaume Mesquida, Cecilia Luengo, Gisela Gili, Gemma Gomà, Ricard Ferrer, Jean Louis Teboul, Didier Payen, and Antonio Artigas

Abstract

Studies show that an increase in microcirculatory alterations may occur due to improvements in macrohemodynamic from advanced in clinical efforts. Microperfusion treatment and monitoring show some promise. These researchers observed the usefulness of thenar muscle oxygen saturation (StO2). In addition, the researchers are concerned with its changes when put through a transient vascular occlusion test (VOT). This was in order to measure the microcirculatory reaction to drotrecogin alfa (activated) (DrotAA) in patients with sepsis.

Aims

In septic patients, it is being observed whether drotrecogin alfa (activated) (DrotAA) has an effect on microcirculatory processes.

Methods

In this study, 58 patients were observed in three general intensive care units within their respective hospitals. Each of these patients had at least two organ dysfunctions and had a resent occurrence of severe sepsis or septic shock. 32 of these patients received DrotAA, while 26 did not due to a formal contraindication. VOT was executed in order to obtain the deoxygenation and reoxygenation slopes, and StO2 was monitored with near-infrared spectroscopy. These calculations were collected before DrotAA began and were consistently repeated daily for a period of 96 hours.

Results

Each of the patients’ outcomes, in terms of severity, baseline values for DeOx/ReOx and StO2, did not significantly differ between the test groups. Patients that were treated had drastically improved with in the DeOx and ReOx values as time passed, where control patients did not reveal a difference. Researchers believe that norepinephrine dose reductions were correlated to improvements in ReOx values.

Conclusions

The treated patients had a noticeable improvement of DeOx values within the 48-hour time period and had the ability to predict mortality.

PMCID: PMC3847092 PMID: 24007807 doi: 10.1186/2110-5820-3-30

7. PLoS One. 2014; 9(3): e90983. doi: 10.1371/journal.pone.0090983

Recombinant Human Activated Protein C in the Treatment of Acute Respiratory Distress Syndrome: A Randomized Clinical Trial

Alexander D. Cornet, A. B. Johan Groeneveld, Jorrit J. Hofstra, Alexander P. Vlaar, Pieter R. Tuinman, Arthur van Lingen, Marcel Levi, Armand R. J. Girbes, Marcus J. Schultz, and Albertus Beishuizen

Abstract

In acute respiratory distress syndrome (ARDS), it is believed that pulmonary coagulopathy plays a pathogenetic role by improving permeability and benefiting alveolocapillary inflammation. The recombinant human activated protein C (rh-APC) can potentially inhibit inflammatory responses and benefit patient health.

Aims

The aim is to understand how well the pulmonary coagulopathy influences ARDS through the use of rh-APC.

Methods

In a saline-controlled trial with randomized single-blinded design, patients with ARDS were tested within the intensive care units of two university hospitals. These patients were pre-screened for inclusion criteria and began a 4-day intervention course which involved 33 patients treated with intravenous rh-APC (24 mcg/kg/h) and 38 patients treated with saline. The primary outcome parameter measured the pulmonary leak index (PLI) of the enzyme 67Gallium-transferrin, which was utilized as a measure of alveolocapillary permeability. The secondary parameter was the disease severity score, ventilator free days, and other contributory factors.

Results

In 87% of the patients, the PLI was found to be above baseline while in 90% there was a mechanical or non-invasive ventilation, which was found at a median lung injury score of 2.5. However, the Rh-APC treatment didn’t appear to influence the lung injury or PLI, and sequential organ failure assessment scores didn’t seem to budge. The mean average score of ventilator-free days had risen to 14 for rh-APC, and 12 days for saline. It was found that the 28-day mortality rate for the rh-APC was 6%, while for saline patients it was 6%, where no difference in bleeding events occurred. The study had been terminated early on because rh-APC was taken off of the market.

Conclusion

With the use of intravenous rh-APC during 4 days for inflammatory or infectious ARDS, no evidence was apparent for whether it helped increase alveolocapillary permeability. Additionally, it did not seem to change the outcome of ARDS patients. However, the mortality rate did improve.

PMCID: PMC3954619 PMID: 24632673 doi: 10.1371/journal.pone.0090983

8. N Engl J Med. 2018 Mar 1;378(9):809-818. doi: 10.1056/NEJMoa1705716.

Hydrocortisone plus Fludrocortisone for Adults with Septic Shock.

Annane D, Renault A, Brun-Buisson C, Megarbane B, Quenot JP, Siami S, Cariou A, Forceville X, Schwebel C, Martin C, Timsit JF, Misset B, Ali Benali M, Colin G, Souweine B, Asehnoune K, Mercier E, Chimot L, Charpentier C, François B, Boulain T, Petitpas F, Constantin JM, Dhonneur G, Baudin F, Combes A, Bohé J, Loriferne JF, Amathieu R, Cook F, Slama M, Leroy O, Capellier G, Dargent A, Hissem T, Maxime V, Bellissant E.

Abstract

This study attempted to determine the ratio of benefit to risk when utilizing activated protein C (drotrecogin-alfaactivated, DAA) and corticosteroids. This is to see if it benefits patients whether combined or given individually. It is hypothesized in this study that hydrocortisone therapy with fludrocortisone and activated drotrecogin alfa can help patients undergoing septic shock. The outcomes of this study are to show that there is an improvement in clinical trials.

Aims

This study reveals whether hydrocortisone and fludrocortisone in treatment with drotrecogin alfa (activated) has a beneficial outcome on patient recovery from septic shock. It discovers whether patients with septic shock benefited from the treatment of corticosteroids, DAA, or both combined.

Methods

This study utilized a 2 by 2 factorial design in a publicly funded, multi-center, randomized trial led by investigators. This double-blind trial was placebo-controlled and performed in four parallel groups where adults who had suffered from persistent septic shock, with no formal contraindications to DAA, were treated with either hydrocortisone at 50 mg intravenous bolus q6 for 7 days and fludrocortisone 50 µg once daily alone through a nasogastric tube for 7 days, with DAA alone at 24 mg/kg/h for 96 h, a combination of both treatments, or with placebos. The primary endpoint observed was the 90-day mortality rate, where follow-up duration went on to 6 months. A statistical analysis was done in order to analyze participants after a 180-day follow-up within the two by two factorial design.

Results

The first patient was recruited in 2008, and the trial was suspended in 2011, because of the removal of DAA from the market. 411 patients had been enrolled. The trial continued in 2012, where two parallel groups were tested after approval by legal authorities, where the investigation of benefit to risk ratio of the use of corticosteroids were observed. In 2014, the trial was suspended again. The trial was successfully completed in 2015 after 1241 patients had been recruited. Within the 1241 patients, it was found that the patients had a 43% 90-day mortality rate, where 254 of the 614 patients had died. In the hydrocortisone-plus-fludrocortisone group, the mortality rate was at 49.1%, which was 308 of the 627 patients within the placebo group. The risk of death was 0.88 in the hydrocortisone-plus-fludrocortisone group. Additionally, it was found that mortality was far lower in the hydrocortisone-plus-fludrocortisone group as opposed to the placebo group within the ICU discharge. This was a rate of 35.4%, while the placebo mortality rate was at 41.0%. The mortality rate for those post-hospital discharge was at 39.0%, as opposed to 45.3% for the placebo. At day 180, this rate was at 46.6%, as opposed to the mortality rate of 52.5% for the placebo. At day 28, the rate was 33.7% and 38.9% respectively. For the number of vasopressor-free days, on day 28 the rate was significantly higher for the hydrocortisone-plus-fludrocortisone group as opposed to the placebo group, where the days numbered 17 and not 15 days. The number of organ failure free days were 14 versus 12 days.

Conclusion

The level of hazardous events didn’t change between groups, however those in the hydrocortisone-plus-fludrocortisone group tended to have more hypoglycemia. The 90-day all-cause mortality was lower in septic patients for those who had hydrocortisone and fludrocortisone as opposed to those that only received placebo.

PMID: 29490185 DOI: 10.1056/NEJMoa1705716

9. Pancreatology. 2015 Nov-Dec;15(6):635-41. doi: 10.1016/j.pan.2015.10.001. Epub 2015 Oct 20.

Twenty-four-hour infusion of human recombinant activated protein C (Xigris) early in severe acute pancreatitis: The XIG-AP 1 trial.

Miranda CJ, Mason JM, Babu BI, Sheen AJ, Eddleston JM, Parker MJ, Pemberton P, Siriwardena AK.

Abstract

Patients with intense systemic inflammatory response in their pancreas can greatly benefit from the human recombinant activated protein C (Xigris). This study shows whether an inflammatory response can be improved through clinical treatment.

Aim

This study aims to create initial safety data from the use of Xigris in trials with patients suffering from acute pancreatitis.

Methods

Patients within the trial were treated with human recombinant activated protein C (Xigris) for 24 hours with an intravenous dosage of 24 μg/kg/h. The group was matched with a historical control group that were treated the same way. 43 of the patients were screened for severe pancreatitis out of the 166 admitted patients, but only 19 were recruited for testing and analysis.

Results

In the group treated with Xigris, there was less bleeding, although there was not much of a significance between groups. Intervention was less frequent in the treatment group. The length of stay for patients in the Xigris group was 19 days versus 41 days for the control group. The mortality rate and level of infection were similar in both groups. It was found that the biomarker protein C had increased, and IL-6 decreased post-infusion.

Conclusion

The use of Xigris in a 24-hour infusion was safe when utilized on patients with severe acute pancreatitis.

PMID: 26547592 DOI: 10.1016/j.pan.2015.10.001

10. Crit Care. 2015 Apr 28;19:193. doi: 10.1186/s13054-015-0921-x.

Clinical impact of stress dose steroids in patients with septic shock: insights from the PROWESS-Shock trial.

Póvoa P, Salluh JI, Martinez ML, Guillamat-Prats R, Gallup D, Al-Khalidi HR, Thompson BT, Ranieri VM, Artigas A.

Abstract

This study investigates the influence of intravenous steroids with or without activated drotrecogin-alfa (DrotAA) in clinical studies. The outcomes in septic shock patients are observed.

Methods

A PROWESS-Shock trial was performed, where the propensity score for the intravenous steroids for septic shock was observed against a baseline created from a multivariable logistic regression. The effect of intravenous steroids with or without DrotAA was observed within a 28 day and 90-day all-cause mortality rate. Of the 1695 patients, 49.5% received intravenous steroids for septic shock at baseline. A group of 436 patients received DrotAA and steroids, 414 received DrotAA and no steroids, 403 received placebo and steroids, and 442 received placebo and no steroids.

Results

The weighted risk of the 28-day and 90-day mortality rate in those who were treated and those not treated with steroids didn’t differ from those randomly placed in trials treated with DrotAA or with no treatment (placebo). No difference was found in the randomized treatment. Patients with lungs with lung infection, gram-positive sepsis, abdominal infection, gram-negative sepsis, and those with the weighted risk of 28-day and 90-day mortality who were treated as opposed to those not treated with any steroids did not differ from randomized trials with DrotAA treatments versus a placebo treatment.

Conclusion

The researchers did not find any beneficial influences stemming from the treatment of intravenous steroids as opposed to DrotAA and placebo for the treatment of septic shock.

PMID: 25928214 PMCID: PMC4456711 DOI: 10.1186/s13054-015-0921-x