Supplemental Digital Content




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Supplemental Digital Content


Supplemental Methods


Inclusion/exclusion criteria: Patients were included who presented with severe sepsis and/or septic shock on the day of admission to the ICU, i.e. on day 0. Day 0 had a variable amount of hours up to a maximum of 24 hours, depending on the time of admission. Day 1 started on midnight following admission. Patients were excluded from analysis if they were < 18 years, had received solid organ transplantation, had renal failure requiring hemodialysis before ICU, received extracorporeal membrane oxygenation, if serum creatinine values were missing at admission, or if they were admitted during the 1 month wash-out period between changes in resuscitative fluid regimens.

Sepsis was defined according to consensus conference definitions, and severe sepsis was defined by sepsis plus at least one organ failure (27). Screening for the presence of severe sepsis or septic shock was performed routinely by the senior ICU physicians and documented by trained research nurses.

Severe sepsis was defined as the presence of microbiologically proven, clinically proven, or suspected infection; presence of Systemic Inflammatory Response Syndrome (SIRS); and development of at least one organ dysfunction within the last 24 hours. Diagnosis of SIRS required the fulfillment of at least two of the following criteria: hypo- (≤36°C) or hyperthermia (≥38°C), tachycardia (≥90 bpm); tachypnea (≥20 breaths/min) and/or an arterial pCO2 ≤4.3 kPa (32 mmHg) and/or mechanical ventilation; leukocytosis ≥12,000/μl or leukopenia ≤4,000/μl and/or a left shift in the differential white blood cell count ≥10%. For the diagnosis of organ dysfunction one of the following criteria had to be fulfilled: presence of acute encephalopathy with reduced vigilance, agitation, disorientation, delirium not explained by psychotropic medication; thrombocytopenia ≤100.000/μl or a drop in the thrombocyte count >30% within 24 hours not explained by hemorrhage; arterial hypoxemia with an arterial pO2 <10 kPa (75 mmHg) when breathing room air or an oxygenation index (paO2/FiO2 ≤33kPa (250 mmHg) not explained by presence of a pulmonary or cardiac disease; arterial hypotension with a systolic blood pressure ≤90 mmHg or mean arterial blood pressure ≤70 mmHg for at least one hour despite adequate fluid loading not explained by other causes of shock; renal dysfunction with an urine output ≤0.5 ml/kg/h for at least one hour despite adequate fluid loading and/or increase of serum creatinine more than twofold above the reference range of the local laboratory; metabolic acidosis with a base deficit ≥5.0 mmol/l or a serum lactate ≥ 1.5fold above the reference range of the local laboratory.

Septic shock was defined as the presence of infection and SIRS as defined in severe sepsis as well as presence of arterial hypotension with a systolic blood pressure ≤90 mmHg or a mean arterial blood pressure ≤70 mmHg for at least 2 hours or administration of a vasopressor (dopamine ≥5 μg kg-1 min-1; noradrenaline, epinephrine, phenylephrine, or vasopressin in any dosage) to maintain systolic blood pressure ≥90 mmHg or mean arterial blood pressure ≥70 mmHg despite adequate fluid loading.

Study groups:

HES period: From 1st January 2004 until 31st January 2006, patients were treated with predominantly 6% HES (6% HES 130/0.4; Voluven; Fresenius-Kabi, Bad Homburg, Germany) and crystalloids. 88 % of the administered HES was 6% HES 130/0.4, the rest 10% HES 200/0.5. Gelatin period: Standard colloid therapy was switched from 6 % HES 130/0.4 to 4% gelatin as a result of increased renal failure in association with starch use (13). From 1st March 2006 until 31st of March 2008, patients were volume resuscitated with 4% modified gelatin (Gelafusal; Serumwerk Bernburg AG, Bernburg, Germany) and crystalloids. Crystalloid period: Because a prospectively planned analysis showed that the change of standard colloid from HES to gelatin had not decreased the incidence of acute kidney injury (26), we abandoned the use of synthetic colloids altogether. Patients received only balanced crystalloid solutions (Jonosteril; Fresenius Kabi, Bad Homburg, Germany) except for patients with hyperkalemia who received normal saline (NaCl 0.9%; Fresenius Kabi, Bad Homburg, Germany). All consecutive patients with severe sepsis from 1st May 2008 until 8th April 2010 were included in this group.


Management of sepsis patients

Therapy for sepsis followed institutional standard operating procedures (SOPs) based on the guidelines of the Surviving Sepsis Campaign (16) and the German Sepsis Society (19). During all three study periods, hemodynamic resuscitation was guided by Early Goal Directed Therapy (EGDT) as has been described by Rivers et al. (2) with the modification that a preset goal of MAP of ≥ 70 mm Hg was used instead of ≥ 70 mm Hg. Briefly, hemodynamic resuscitation had to achieve the following primary endpoints: a central venous pressure (CVP) of at least 8 mmHg, an arterial mean blood pressure (MAP) of at least 70 mmHg, and a central venous oxygen saturation (ScvO2) of at least 70%. Standard hemodynamic management included vasopressors with noradrenaline to achieve preset hemodynamic goals in addition to repeated fluid challenges with crystalloids and/or synthetic colloids (gelatin or hydroxyethyl starch) to allow the lowest possible dose of vasopressors. Human albumin 20% was not used for volume replacement. Its use was restricted to the treatment of severe hypoalbuminemia < 15 g/L (Albunorm 20%, Octapharma, Langenfeld, Germany).

ScvO2 and serum lactate levels were measured by blood gas measurement (Radiometer Copenhagen, Radiometer GmbH, Willich-Schifbahn, Germany). Extended hemodynamic monitoring with pulmonary artery catheter (Swan-Ganz CCOmbo; Edwards Life Sciences, Unterschleissheim, Germany) or PiCCO (Pulsiocath 5-Fr Thermodilution Catheter; Pulsion Medical Systems Munich, Germany) was considered if the required vasopressor dose increased > 0.3 µg/kg/min of noradrenaline.


Acute kidney injury (AKI)

RIFLE “risk” was fulfilled by a 1.5-fold increase in serum creatinine levels or urine output < 0.5 mL/kg/hr (or both) for > 24 hrs, RIFLE “injury” by a two-fold increase in serum creatinine levels or urine output < 0.3 mL/kg/hr (or both) for >24 hrs, and RIFLE “failure” was defined by a three-fold increase in serum creatinine levels and new RRT or serum creatinine > 354 µmol/L with an acute rise of at least 44 µmol/L or urine output < 0.3 mL/kg/hr > 24 hrs (or both) or anuria 12 hrs for 24 hrs (41). Urine output was measured over 24 hrs and calculated back to 6- or 12- hourly values.

Continuous veno-venous hemodialysis was the single modality for RRT in our ICU during all study periods. Indications for RRT included diuretic-resistant oliguria (urine output < 0.5 mL/kg body weight) persistent for 6 hrs or anuria persistent for 3 hrs despite adequate volume therapy or associated with volume overload with threatened or established pulmonary edema, the presence of hyperkalemia, or severe metabolic acidosis (pH < 7.1).

Electronic patient data management system (PDMS)

The PDMS (Copra System GmbH, Sasbachwalden, Germany) automatically records data from vital sign monitors, ventilators, and infusion pumps. The system also records order entries (e.g., medication, fluid dose and duration), laboratory and microbiology results.


Supplemental Table 1: Nephrotoxic drugs and adjunctive sepsis therapy





HES group

(n = 360)

p value

Gelatin group

(n = 352)

p value

Crystalloid group (n = 334)

NSAID, n (%)a

324 (90.0)

0.899

315 (89.5)

0.705

302 (90.4)

Diuretics, n (%)b

328 (91.1)

< 0.001

304 (86.4)

0.004

260 (77.8)

ACE inhibitors, n (%)c

135 (37.5)

0.266

147 (41.8)

0.022

111 (33.2)

Vancomycin, n (%)

115 (31.9)

0.262

98 (27.8)

0.022

121 (36.2)

Aminoglycosides, n (%) d

43 (11.9)

0.635

32 (9.1)

0.523

36 (10.8)

Antimycotics, n (%) e

62 (17.2)

0.537

35 (9.9)

0.038

51 (15.3)

Iodinated contrast media, n (%)

80 (22.2)

0.401

70 (19.9)

0.924

65 (19.5)

Insulin, n (%)a

331 (91.9)

0.046

321 (91.2)

0.109

291 (87.1)

Hydrocortisone, n (%)

169 (46.9)

<0.001

208 (59.1)

<0.001

79 (23.7)

HES hydroxyethyl starch. P values were calculated with Fisher’s exact test. For p value adjustment the Bonferroni-Holm method was used.

a Nonsteroidal anti-inflammatory drugs, including ibuprofen and diclofenac

b including mannitol and furosemide

c angiotensin-converting enzyme (ACE) inhibitors, including ramipril, perindopril, lisinopril and enalapril

d including tobramycin and gentamicin

e including amphotericin B and fluconazole


Supplemental Table 2: Parameters at onset of renal replacement therapy





HES group

(n = 120)

p value

Gelatin group

(n = 111)

p value

Crystalloid group

(n = 74)

Serum creatinine (µmol/l) at onset renal replacement therapy, median [IQR]

277

[213-363]

< 0.001

162

[121-244]

0.209

191

[137-248]

Mean urine output at onset renal replacement therapy, (ml/kgBW/h), median [IQR]

0.19

[0.06-0.49]

0.602

0.25

[0.12-0.58]

0.237

0.22

[0.06-0.53]

Serum potassium levels at onset renal replacement therapy, (mmol/L), median [IQR]

5.0

[4.6-5.4]

0.591

4.9

[4.6-5.4]

0.648

4.8

[4.6-5.3]

Serum bicarbonate levels at onset renal replacement therapy, (mmol/L), median [IQR]

20.1

[17.6-22.2]

0.911

20.8

[17.2-23.2]

0.331

20.1

[17.7-22.2]

paO2/FiO2-ratios at onset renal replacement therapy, (%), median [IQR]

218

[170-283]

0.789

203

[157-270]

0.344

218

[153-289]

HES hydroxyethyl starch, IQR interquartile range. P values were calculated with the Mann–Whitney test.


Supplemental Table 3: Multiple logistic regression analysis with RRT as dependent binary variable.





n

Adjusted OR (95%CI)

p value

Baseline creatinine: (per µmol/l)

1024

1.006 (1.004,1.008)

< 0.001

Baseline SAPS-II: (per point)

1024

1.02 (1.01,1.03)

< 0.001

Cardiac / thoracic surgery: yes vs. no

1024

2.96 (2.14,4.11)

< 0.001

Liver cirrhosis: yes vs. no

1024

2.30 (1.31,4.03)

0.004

Antimycotics: yes vs. no

1024

1.50 (0.99,2.29)

0.057

Vancomycin: yes vs. no

1024

2.58 (1.86,3.58)

< 0.001

Ionidated contrast media: yes vs. no

1024

2.32 (1.61,3.35)

< 0.001

Human albumin 20%: yes vs. no

1024

2.06 (1.51,2.83)

< 0.001













Added after model selection:






















Period effects:










Period: ref.=Crystalloids










Gelatin 4%

1024

1.92 (1.32,2.82)

< 0.001

HES 6% (130/0.4)

1024

2.01 (1.34,3.02)

< 0.001

HES hydroxyethyl starch

Variables considered in the analysis: age, liver cirrhosis, diabetes, baseline creatinine, baseline SAPS-II, cardiac / thoracic surgery, non-steroidal anti-inflammatory drugs, ACE inhibitors, aminoglycosides, antimycotics, vancomycin, ionidated contrast media, diuretics, human albumin 20%, study period using dummy coding. Forward and backward stepwise multiple logistic regression analysis based on AIC (Akaike Information Criterion) was used to derive a multivariable model where the Hosmer-Lemeshow goodness of fit test (C-test: p = 0.108, H-test: p = 0.281) and ROC curve analysis (AUC = 0.67) indicate an acceptable fit and discrimination, respectively. P values were obtained by Wald's test. After model selection the period effect was studied.


Supplemental Figure 1: Patient flow





1 Mainly patients receiving heart, lung or liver transplants. Patients undergoing renal transplantation were treated by urologists at a different location and are therefore not included.


Supplemental Figure 2: Heart rate, MAP, CVP, ScvO2, hemoglobin and noradrenaline dose during the ICU stay. Daily means of heart rate, mean arterial pressure (MAP), central venous pressure (CVP), central venous saturation concentrations (ScvO2), hemoglobin values, and cumulative daily dose of noradrenaline, presented as median and interquartile ranges. ***/+++ p < .001, **/++p < .01, */+p < .05 (*comparisons between HES and crystalloid groups; +comparisons between gelatin and crystalloid groups); n denotes patients with available data.



Supplemental Figure 3: Daily procalcitonin serum levels. Presented as median and interquartile ranges, +p < .05 (+comparisons between gelatin and HES groups); n denotes patients with available data.


Procalcitonin


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