Fluid volume, fluid balance and patient outcome in severe sepsis and septic shock: A systematic review

Accepted Manuscript Fluid volume, fluid balance and patient outcome in severe sepsis and septic shock: A systematic review

Bereket Molla Tigabu, Majid Davari, Abbas Kebriaeezadeh, Mojtaba Mojtahedzadeh PII: DOI: Reference:

S0883-9441(18)30676-2 doi:10.1016/j.jcrc.2018.08.018 YJCRC 53010

To appear in:

Journal of Critical Care

Please cite this article as: Bereket Molla Tigabu, Majid Davari, Abbas Kebriaeezadeh, Mojtaba Mojtahedzadeh , Fluid volume, fluid balance and patient outcome in severe sepsis and septic shock: A systematic review. Yjcrc (2018), doi:10.1016/j.jcrc.2018.08.018

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ACCEPTED MANUSCRIPT Fluid volume, fluid balance and patient outcome in severe sepsis and septic shock: a systematic review Bereket Molla Tigabu1,2,3 , Majid Davari1,2 , Abbas Kebriaeezadeh1,2 , Mojtaba Mojtahedzadeh4,5

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1 Department of Pharmacoeconomics and Pharmaceutical Administration, Faculty of Pharmacy,

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International Campus, TUMS, Tehran, Iran

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2 Pharmaceutical research center, Faculty of Pharmacy, TUMS, Tehran, Iran

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3 School of Pharmacy, Haramaya University, Ethiopia

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4 Department of Clinical Pharmacy, Faculty of Pharmacy, TUMS, Tehran, Iran

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5 Sina Hospital, Division of Critical Care Medicine, Tehran, Iran

author: and

Majid

Pharmaceutical

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Pharmacoeconomics

Dr.

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*Corresponding

Davari,

administration,

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University of medical sciences, Tehran, Iran. Email:

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[email protected]; Faculty

of

Department

Pharmacy,

of

Tehran

ACCEPTED MANUSCRIPT Abstract Purpose: This systematic review and meta-analysis was conducted to evaluate the mortality risk in severe sepsis and septic shock with a low and high fluid volume/balance.

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Methods: Cohort studies that compared the mortality of patients with low or high fluid

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volume/balance were included. Electronic databases: PubMed/Medline PLUS, Embase, Scopus,

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and Web of Science were searched. Patient mortality at the longest follow-up was the primary outcome measure. The data were analyzed using STATA 14 statistical software.

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Results: The current study included fifteen studies with 31,443 severe sepsis and/or septic shock

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patients. Patients with a high fluid balance have a 70% increased risk of mortality (pooled RR: 1.70; CI: 1.20, 2.41; P=0.003). Survivors of severe sepsis and/or septic shock received higher

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fluid volume in the first three hours. However, fluid volume administered in the first 24 hours

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mortality reduction (P=0.02).

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was higher for non-survivors. Low volume resuscitation in the first 24 hours had a significant

Conclusion: High fluid balance from the first 24 hours to ICU discharge increases the risk of

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mortality in severe sepsis and/or septic shock. However, randomized clinical trials should be

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conducted to resolve the dilemma of fluid resuscitation. Keywords: Fluid volume, fluid balance, mortality, severe sepsis, septic shock, systematic review

ACCEPTED MANUSCRIPT Introduction Severe sepsis and septic shock are characterized by a deficit in effective vascular volume as a result of vasodilation, vascular leakage and third space loss (1, 2). Therefore, fluid replacement is a core of management. Large fluid resuscitation (30ml/Kg) in the first 6 hours was recommended

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in Early Goal-Directed Therapy (1, 3). However, too much fluid has its own negative consequences. Although positive fluid balance was found to increase mortality and time spent on

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mechanical ventilation (4-6), too little fluid may also lead to hypoperfusion and aggravate organ

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dysfunction (7). The primary goal of resuscitation is to optimize the central venous pressure to 812mmHg for non-ventilated patients and to 12-15mmHg during mechanical ventilation (1).

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Nevertheless, the optimal volume for fluid resuscitation has been debatable.

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In spite of progresses made in the development of protocols, severe sepsis and septic shock

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causes significant morbidity and mortality in the intensive care units (8, 9). Previously, two reviews tried to address the risk of mortality with resuscitation strategy and fluid balance in

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critically ill patients (10, 11). However, both of these reviews were not specifically designed to

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deal with severe sepsis and septic shock (10, 11).

Therefore, we conducted this systematic

review and meta-analysis to evaluate the mortality risk in severe sepsis and septic shock with a

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low versus high fluid volume/balance.

ACCEPTED MANUSCRIPT Methods This systematic review was done based on PRISMA recommendations (12) and the details of the protocol are registered at PROSPERO (Registration number: CRD42017079560).

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Search strategy

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Bibliographic electronic databases (PubMed/Medline PLUS, Scopus, Embase, and Web of

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Science) were searched for cohort studies from January 2000 to September 2017 with the following keywords: fluid, colloids, crystalloids, albumin, “normal saline”, saline, “ringer’s

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lactate”, “lactated ringer”, volume, balance, outcome, mortality, sepsis, “severe sepsis”, “septic

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shock”, “critical illness”, “critical care”, “intensive care” and ICU.

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Eligibility criteria

Cohort studies on adult patients with severe sepsis and/or septic shock published in the English

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language were included. High fluid volume/balance or positive fluid balance was taken as an

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intervention whereas low fluid volume/balance or negative fluid balance was the comparator.

Study selection

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Patient mortality at the longest follow-up was the primary outcome measure.

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Screening of the records based on the title and abstracts, and the selection of full text articles based on the eligibility criteria was done by two reviewers independently. Differences between the reviewers were settled by discussion and consensus including a third reviewer. Data extraction Study characteristics, patient characteristics, fluid volume, fluid balance, and outcome were extracted by two reviewers independently, and the extracted data were cross-checked by a third

ACCEPTED MANUSCRIPT reviewer. Mortality at different fluid volume and fluid balances were recorded at the longest follow-up. The mean/median fluid volume was recorded for the comparator groups as reported in the reviewed articles. However, when fluid volume/balance was reported only for quartiles, the lowest quartile fluid volume/balance was taken as a low fluid volume/balance and the highest

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quartile fluid volume/balance was taken as a high fluid volume/balance. If the quartile volume

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was reported in a range the average of the two extremes was used during the analysis.

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Quality assessment

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Two reviewers had assessed the quality of selected studies using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement-checklist (13) and the checklist

The overall validity of the studies was rated as complete and incomplete for

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Black (14).

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for the quality assessment of randomized and non-randomized studies developed by Downs and

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STROBE statement-checklist fulfillment. The overall quality index was calculated considering the reporting, internal validity, bias, confounding and power of the study for the Downs and

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Statistical analysis

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Black checklist.

The pooled relative risk (RR) with 95% confidence intervals (CIs) was calculated. Statistical

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heterogeneity of the data was assessed by the Mantel-Haenszel chi-square test with a P<0.01. I2 test value > 50% was taken to indicate significant heterogeneity. The random-effects model was used if heterogeneity was observed; otherwise, the fixed effect model was used. P <0.05 was considered statistically significant. STATA 14 statistical software was used to analyze the result.

ACCEPTED MANUSCRIPT Results The database search revealed of 5191 records of which fifteen articles that fulfilled the inclusion criteria were selected for the current review. A total of 31,443 severe sepsis and/or septic shock

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patients were analyzed. The characteristics of the included studies were shown in Table 1.

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The quality of the included studies was summarized in Table 2.

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Quality assessment

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Fluid volume and mortality

Survivors of severe sepsis and septic shock received a higher volume of fluid than non-survivors

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in the first 3 hours (2085ml vs 1600ml, P=0.007). The higher fluid volume received within the

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first 3 hours had a statistically significant association with in-hospital mortality (OR, 0.34; 95% CI, 0.15-0.75; P= .008) (15). Survivors of septic shock received a significantly lower volume

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fluid in the first 24 hours (<5Li) (16, 17). A study on patients with negative fluid balance showed

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survivors of septic shock received a higher volume of fluid in the first 48 hours (53.7ml/Kg, P<0.001) (18). However, this volume is less than 4 liters when a standard adult weight is

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considered. On the other hand, three studies revealed no significant relationship between the

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volume of fluid administered in the first 24 hours and patient mortality in the first 3 days, 30 days, 90 days or 365 days (19-21). Nevertheless, the cumulative number of study participants in these three studies (n=332) (19-21) is smaller than the number of patients (n=24,561) in the studies that showed the association (16, 17).

ACCEPTED MANUSCRIPT Fluid balance and mortality Eight studies reported the mortality risk of fluid balance. The average fluid balance after 24 hours was 2334.7 ml ±882.9 ml for survivors and 3763.8 ml±863.0 ml for non-survivors. Micek, et al.(22) and Sakr, et al.(23) revealed a notably low fluid balance among survivors of severe

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sepsis and/or septic shock than non-survivors at the first 24 hours and cumulative balance in intensive care unit (ICU), respectively (P=0.003 and P<0,001, respectively) . Although Sirvent,

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et al.(24) also found remarkably high fluid balance among non-survivors at 48, 72, and 96 hours.

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The difference was not statistically significant for the first 24 hours.

Five of the reviewed studies identified fluid balance as an independent predictor of mortality.

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The study by Boyd, et al.(25) revealed that patients with a low positive fluid balance at 12 hours

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and 4th day had a lower 28-day mortality compared to those with a higher fluid balance. Four of

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these studies were included in the meta-analysis (21, 26-28). A fixed effect model was used to calculate the pooled relative risk as there was no significant heterogeneity (P=0.389, I 2 =0.5%).

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The analysis revealed a 70% increased risk of mortality for patients with a higher positive fluid

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balance (pooled RR: 1.70; CI: 1.20, 2.41; P=0.003) (Fig 2). The Egger’s test (P=0.082) and the shape of the funnel plot suggest no small study effect nor publication bias (Fig 3). However,

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Brotfain, E. et al.(28) presented the result by grouping the fluid balance into four groups. Therefore, the analysis was repeated by using the group with a highest fluid balance to check the sensitivity of the result. Similarly, the heterogeneity (P=0.382, I2 =2.2%) and the pooled relative risk (pooled RR: 1.51; CI: 1.20, 1.90; P<0.001) were significant (Fig 4).

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Discussion The current review revealed a positive fluid balance recognized at different times from the first

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24 hours in ICU to cumulative balance at discharge predicts mortality. Patients with a higher

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fluid balance are 1.70 times as likely to die compared to patients with a lower fluid balance. This

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result is theoretically appealing when the hemodynamics of septic patients and the associated organ failures are considered. The inflammation-mediated injury on the glycocalyx is responsible

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for clinical effects of sepsis including edema, acute kidney injury and respiratory failure (30). Excessive infusion of fluid aggravates glycocalyx damage, thereby further increasing tissue

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permeability and leading to poor prognosis (31). Moreover, fluid overloading can lead to atrial

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and ventricular stretching of the heart that stimulates the release of atrial and brain natriuretic

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peptides. These peptides have been found to aggravate the endothelial glycocalyx injury (32). The treatment of sepsis attenuates the inflammatory cascade and returns fluid from the interstitia

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and third space to the central circulation. However, sepsis-related organ dysfunctions complicate

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the excretion process and associated with an increased risk of death (33-35). Therefore, the organs involved in intravascular fluid balance (i.e. the kidneys and heart) should be optimized to

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excrete excess fluid.

The current review demonstrates that for patients with severe sepsis and septic shock, the higher volume of fluid in the first 3 hours improves patient survival.

However, this finding was

reported in a single study. The low volume resuscitation in the first 24 hours had mortality reduction benefit. However, Carlsen, et al.(20) and Smith, et al.(19) reported no association between the fluid volume received in the first 24 hours and 90 days mortality of patients. However, these studies evaluated a significantly lower number of patients as compared to the

ACCEPTED MANUSCRIPT studies by Koonrangsesomboon, et al.(17) and Marik, et al.(16) which demonstrated the association. Although the study by Shen, et al.(18) revealed survivors received a higher volume of fluid than non-survivors, the study included only patients with negative fluid balance. Therefore, it would be difficult to generalize this outcome to all septic shock patients most of Furthermore,

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whom expected to have organ failure that leads to excessive fluid accumulation.

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the mortality reduction benefit of higher fluid volume for patients who remained in shock for

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three or more days reported by Smith, et al.(19) has a flaw. The cut-off point reported by the

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study was lower than the volume considered to be high in clinical trials (3, 36, 37). The strength of this review includes the precision of the clinical question restricted to severe

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sepsis and septic shock, the inclusion of both fluid volume and fluid balance, and the inclusion of

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cohort studies. This better studies the effectiveness than the efficacy of fluid therapy. This review has several limitations. First, most of the included articles were done retrospectively. Second, the

Third, the cut-off point for the fluid volume and fluid balance used varied

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included studies.

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time points at which the fluid balance was measured and the follow-up periods vary among the

among studies. Fourth, only articles published in the English language are include. Finally, all of

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Conclusion

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the included articles are of low quality.

We cautiously conclude that high fluid balance from the first 24 hours to ICU discharge increases the risk of mortality in severe sepsis and septic shock. Moreover, high fluid volume resuscitation in the first 3 hours and low fluid volume therapy in the first 24 hours have survival benefits. We, therefore, strongly recommend that randomized clinical trials should be conducted to determine the cut-off points for fluid volume and fluid balance during fluid therapy in severe sepsis and septic shock management.

ACCEPTED MANUSCRIPT Authors’ contributions BMT and MD conceptualize the study, conducted the article review, do the analysis, interpreted the results, and drafted and finalized the manuscript. AK and MM participated in the study designed, conducted the article review and revised the manuscript. BMT, MD, AK and MM

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revised the manuscript and approved the final manuscript.

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The authors declared that they have no conflict of interest.

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Competing interests

Funding

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Not applicable

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References

Alsous F. et al., 2000(21) Boyd, J. H. et al., 2011(25)

Patient population

Sample size Septic shock patients with 36 no history of dialysis

Age* 67.4

Fluid Mortality measured measured 24 hrsb 3 days

Septic shock patients receiving a minimum of 5µg norepinephrine per minute

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12hrs b

28 days

day 4b

28 days

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Authors

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Table1. Characteristics of included studies

H >(-500ml) Q1-710ml Q2-2880ml Q3-4900ml Q4-8150ml Q1-1560ml Q2-8120ml Q3-13000ml Q4-20500ml L< 4.0L H ≥ 4.0L

Remark

RR, 5.0; 95% 10.9;P=0.000

Septic shock

132

60

24hrsa

30-days 90-days 365-days

Smith, S. H. et al., 2012(19)

Septic shock

164

66

Day 1a

90-days

L< 4.0L

Days 1-3a

90-days

H > 4.0L L<7.5L H> 7.5L

In patients w days or more

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Carlsen, S.et al., 2011(20)

Adjusted HR 0.569 (0.405 0.581 (0.414 0.762 (0.562 Adjusted HR 0.466 (0.299 0.512 (0.339 0.739 (0.503 No differenc between the (P=0.36), 90 365 days (P= P=0.27

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778

Fluid volume/ balance L ≤(-500ml)

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Septic shock

325

S- 54.8 NS-63.0

24hrsb

Hospital mortality

S-2959ml NS-4374ml

Septic shock

350

65.4

24hrsb

Hospital mortality

Q1=0-6L Q2=6-12L Q3=12-18L Q4=18-24L

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Micek, S. T. et al., 2013(22) Sadaka, F. et al., 2014(26)

were associa mortality (P= P=0.003 (tot survivors= 1 163 Adjusted haz 1.519 (95% 1.740 (95% 1.620 (95% respectively

Sample size 594

Age* S-69 NS-74

Fluid measured 0-3 hrsa

Mortality measured Hospital mortality

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Lee, S. J. et al., 2014(15)

Patient population Severe sepsis and septic shock

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Authors

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Table 1. Characteristics of included studies (continued)

de Oliveira, F. S. et al., 2015(29)

Severe sepsis and septic shock

Septic shock

6 hrsa Day 4,5,6b

Hospital mortality

116

S-57 NS-63

24-48 hrsb

Hospital mortality

Fluid balance > 3000ml

1048

S-62 NS-56

24 hrsa

Hospital mortality

S-3.92L NS-4.64L S-7.08L NS-8.23L S-9.88L NS-11.43L

173

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Koonrangs esomboon, W. et al., 2015(17)

S-660ml NS-880ml

S-60 NS-63

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Sepsis patients in ICU

3.1-6 hrsa

S-3150ml NS-2875ml Negative fluid balance Positive fluid balance

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Acheampo ng, A. et al., 2015(27)

Fluid volume/ balance S-2085ml NS-1600ml

48 hrsa 72 hrs a

Remark

The higher propor received within th associated with de mortality (OR, 0.3 0.75; P= .008) P=0.09

P=0.10

A positive fluid b independently ass mortality (adjuste [1.007–1.022] per <0.001). fluid balance mor the 24th and the 4 diagnosis were in associated with hi 3.14; 95% CI, 1.1 Non-survivors ha higher median cu at 24, 48, and 72 h

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Table 1. Characteristics of included studies (continued) Authors Sirvent, J.M. et al., 2015(24)

Patient population Severe sepsis and septic shock

Sample size 42

Age* S-58.9 NS-66.9

Fluid measured 24 hrsb

Mortality measured 28-days mortality

48 hrsb

Sepsis patients in ICU

296

G1-61.08 G2-63.79 G3-63.23 G4-61.51

At ICU discharge b

Marik, P. et al., 2017(16)

Severe sepsis and septic shock

23,513

NMV,NS Day 1a h-67.5

Hospital mortality

Hospital mortality

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Brotfain, E. et al., 2016(28)

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96 hrsb

Shen, Y. F. et al., 2017(18)

Sepsis (critically ill)

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Sepsis patients in ICU

1,808

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Sakr, Y. et al., 2017(23)

4440ml

S-59.3 NS-69.3

5459ml Cumulative balance in ICUb 48 hrs a

Non-survivors had h positive fluid balanc hours (P=0.02,P=0.0 respectively)

ICU mortality

S-354ml NS-3680ml

hospital mortality

S-53.7ml/Kg NS-48.3ml/Kg

The positive cumulat found to be an indepe ICU mortality (OR, 1 1.06; P < .001; and in (OR, 1.06; 95% CI, 1 Low volume resuscit associated with a sm reduction in mortality (95% CI −1.0%, −0.4 However, in patients volume resuscitation mortality increased b 2.5%; p = 0.0003) fo above 5 L. P<0.001

Fluid intake was stat (P<0.001)

mean/median a fluid volume, b fluid balance, G-group, H-higher fluid balance/volume, L-lower fluid balance/volume, MV- mechanical ventilation, NMV-no mechanical ventilation, NSh- no shock, NS-non-survivors, Q-quartile, Sh- shock, S-survivors

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*

2,068

3618ml

3889ml

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MV,NSh -65.3 NMV,Sh -68.5 MV,Sh66.3 62

Remark

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72 hrsb

Fluid volume/ balance S-1710.4ml NS-3153.5ml S-1791.6ml NS-4394.3ml S-1128.1ml NS-5401.6ml S-4612.6ml NS-6678.6ml < 10 L 10-20 L 20-30 L >30L

ACCEPTED MANUSCRIPT Table2. Quality assessment

2 3 3 3 3

0 0 0 0 0 0 0 0 0 0

2 3 3 3 3

0 0 0 0 0

0.52 0.59 0.70 0.70 0.67

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1 1 3 3 3

3 3 2 2 3 3 3 3 3 3

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9 9 10 10 9

3 3 2 2 3 3 3 3 3 3

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9 7 10 9 9 8 9 8 8 9

Quality index, total/27 0.59 0.59 0.59 0.59 0.63 0.56 0.59 0.56 0.56 0.63

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Alsous F. et al., 2000(21) Boyd, J. H. et al., 2011(25) Carlsen, S.et al., 2011(20) Smith, S. H. et al., 2012(19) Micek, S. T. et al., 2013(22) Sadaka, F. et al., 2014(26) Lee, S. J. et al., 2014(15) Acheampong, A. et al., 2015(27) de Oliveira, F. S. et al., 2015(29) Koonrangsesomboon., W. et al , 2015(17) Sirvent, J.M. et al., 2015(24) Brotfain, E. et al., 2016(28) Marik, P. et al., 2017(16) Sakr, Y. et al., 2017(23) Shen, Y. F. et al., 2017(18)

External validity, 3 points 1 3 2 2 2 1 1 1 1 2

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Reporting, 10 points

Downs and Black checklist Bias, 7 Confounding, Power, points 6 points 1 point

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Included studies

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8. Fleischmann C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, Schlattmann P, et al. Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations. American journal of respiratory and critical care medicine. 2016;193(3):259-72. 9. Vincent J-L, Marshall JC, Ñamendys-Silva SA, François B, Martin-Loeches I, Lipman J, et al. Assessment of the worldwide burden of critical illness: the intensive care over nati ons (ICON) audit. The Lancet Respiratory Medicine. 2014;2(5):380-6. 10. Silversides JA, Major E, Ferguson AJ, Mann EE, McAuley DF, Marshall JC, et al. Conservative fluid management or deresuscitation for patients with sepsis or acute respiratory distress s yndrome following the resuscitation phase of critical illness: a systematic review and meta-analysis. Intensive care medicine. 2017;43(2):155-70. 11. Malbrain ML, Marik PE, Witters I, Cordemans C, Kirkpatrick AW, Roberts DJ, et al. Fluid overload, de-resuscitation, and outcomes in critically ill or injured patients: a systematic review with suggestions for clinical practice. Anaesthesiology intensive therapy. 2014;46(5):361-80. 12. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting ite ms for systematic reviews and meta-analyses: the PRISMA statement. PLoS medicine. 2009;6(7):e1000097. 13. Vandenbroucke JP, Von Elm E, Altman DG, Gøtzsche PC, Mulrow CD, Pocock SJ, et al. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration. PLoS medicine. 2007;4(10):e297. 14. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. Journal of Epidemiology & Community Health. 1998;52(6):377-84. 15. Lee SJ, Ramar K, Park JG, Gajic O, Li GX, Kashyap R. Increased Fluid Administration in the First Three Hours of Sepsis Resuscitation Is Associated With Reduced Mortality A Retrospective Cohort Study. Chest. 2014;146(4):908-15. 16. Marik PE, Linde-Zwirble WT, Bittner EA, Sahatjian J, Hansell D. Fluid administration in severe sepsis and septic shock, patterns and outcomes: an analysis of a large national database. Intensive Care Medicine. 2017;43(5):625-32. 17. Koonrangsesomboon W, Khwannimit B. Impact of positive fluid balance on mortality and length of stay in septic shock patients. Indian Journal of Critical Care Medicine. 2015;19(12):708-13. 18. Shen YF, Huang XM, Zhang WM. Association between fluid intake and mortality in critically ill patients with negative fluid balance: a retrospective cohort study. Critical Care. 2017;21. 19. Smith SH, Perner A. Higher vs. lower fluid volume for septic shock: Clinical characteristics and outcome in unselected patients in a prospective, multicenter cohort. Critical Care. 2012;16(3). 20. Carlsen S, Perner A, East Danish Septic Shock Cohort I. Initial fluid resuscitation of patients with septic shock in the intensive care unit. Acta Anaesthesiologica Scandinavica. 2011;55(4):394-400. 21. Alsous F, Khamiees M, DeGirolamo A, Amoateng-Adjepong Y, Manthous CA. Negative fluid balance predicts survival in patients with septic shock: a retrospective pilot study. Chest. 2000;117(6):1749-54. 22. Micek ST, McEvoy C, McKenzie M, Hampton N, Doherty JA, Kollef MH. Fluid balance and cardiac function in septic shock as predictors of hospital mortality. Critical Care. 2013;17(5). 23. Sakr Y, Rubatto Birri PN, Kotfis K, Nanchal R, Shah B, Kluge S, et al. Higher Fluid Bal ance Increases the Risk of Death From Sepsis: Results From a Large International Audit. Crit Care Med. 2017;45(3):386-94. 24. Sirvent J-M, Ferri C, Baró A, Murcia C, Lorencio C. Fluid balance in sepsis and septic shock as a determining factor of mortality. The American journal of emergency medicine. 2015;33(2):186-9. 25. Boyd JH, Forbes J, Nakada TA, Walley KR, Russell JA. Fluid resuscitation in septic shock: A positive fluid balance and elevated central venous pressure are associated with increased mortali ty. Critical Care Medicine. 2011;39(2):259-65.

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Patients with a high fluid balance have a 70% increased risk of mortality. Survivors of severe sepsis and/or septic shock received higher fluid volume in the first three hours. Non-survivors received higher volume of fluid in the first 24 hours Low volume resuscitation in the first 24 hours had a significant mortality reduction

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