Impact of Shenfu injection on a composite of organ dysfunction development in critically ill patients with coronavirus disease 2019 (COVID-19): A structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: This study aims to determine the protection provided by Shenfu injection (a traditional Chinese medicine) against development of organ dysfunction in critically ill patients with coronavirus disease 2019 (COVID-19). TRIAL DESIGN: This study is a multicenter, randomized, controlled, open-label, two-arm ratio 1:1, parallel group clinical trial. PARTICIPANTS: The patients, who are aged from 18 to 75 years old, with a confirmed or suspected diagnosis of severe or critical COVID-19, will be consecutively recruited in the study, according to the guideline on diagnosis and treatment of COVID-19 (the 7th version) issued by National Health Commission of the People's Republic of China. Exclusion criteria include pregnant and breastfeeding women, atopy or allergies to Shenfu Injection (SFI), severe underlying disease (malignant tumor with multiple metastases, uncontrolled hemopathy, cachexia, severe malnutrition, HIV), active bleeding, obstructive pneumonia caused by lung tumor, severe pulmonary interstitial fibrosis, alveolar proteinosis and allergic alveolitis, continuous use of immunosuppressive drugs in last 6 months, organ transplantation, expected death within 48 hours, the patients considered unsuitable for this study by researchers. The study is conducted in 11 ICUs of designated hospitals for COVID-19, located in 5 cities of China. INTERVENTION AND COMPARATOR: The enrolled patients will randomly receive 100 ml SFI (study group) or identical volume of saline (control group) twice a day for seven consecutive days. Patients in the both groups will be given usual care and the necessary supportive therapies as recommended by the latest edition of the management guidelines for COVID-19 (the 7th version so far). MAIN OUTCOMES: The primary endpoint is a composite of newly developed or exacerbated organ dysfunction. This is defined as an increase in the sequential organ failure assessment (SOFA) score of two or more, indicating sepsis and involvement of at least one organ. The SOFA score will be measured for the 14 days after enrolment from the baseline (the score at randomization). The secondary endpoints are shown below: • SOFA score in total • Pneumonia severity index score • Dosage of vasoactive drugs • Ventilation free days within 28 days • Length of stay in intensive care unit • Total hospital costs to treat the patient • 28-day mortality • The incidence of adverse drug events related to SFI RANDOMISATION: The block randomization codes were generated by SAS V.9.1 for allocation of participants in this study. The ratio of random distribution is 1:1. The sealed envelope method is used for allocation concealment. BLINDING (MASKING): The patients and statistical personnel analyzing study data are both blinded. The blinding of group assignment is not adopted for the medical staff. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): This study is expected to recruit 300 patients with COVID-19, (150 in each group). TRIAL STATUS: Protocol version 2.0, February 15, 2020. Patient recruitment started on February 25, and will end on August 31, 2020. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR2000030043. Registered February 21, 2020, http://www.chictr.org.cn/showprojen.aspx?proj=49866 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.

Normal saline for intravenous fluid therapy in critically ill patients.

The efficacy and safety of normal saline (NS) for fluid therapy in critically ill patients remain controversy. In this review, we summarized the evidence of randomized controlled trials (RCTs) which compared NS with other solutions in critically ill patients. The results showed that when compared with 6% hydroxyethyl starch (HES), NS may reduce the onset of acute kidney injury (AKI). However, there is no significant different in mortality and incidence of AKI when compared with 10% HES, albumin and buffered crystalloid solution. Therefore, it is important to prescribe intravenous fluid for patients according to their individual condition.

Early fluid loading for septic patients: Any safety limit needed?

Early adequate fluid loading was the corner stone of hemodynamic optimization for sepsis and septic shock. Meanwhile, recent recommended protocol for fluid resuscitation was increasingly debated on hemodynamic stability vs risk of overloading. In recent publications, it was found that a priority was often given to hemodynamic stability rather than organ function alternation in the early fluid resuscitation of sepsis. However, no safety limits were used at all in most of these reports. In this article, the rationality and safety of early aggressive fluid loading for septic patients were discussed. It was concluded that early aggressive fluid loading improved hemodynamics transitorily, but was probably traded off with a follow-up organ function impairment, such as worsening oxygenation by reduction of lung aeration, in a part of septic patients at least. Thus, a safeguard is needed against unnecessary excessive fluids in early aggressive fluid loading for septic patients.

Sources of Heterogeneity in Trials Reporting Hydroxyethyl Starch 130/0.4 or 0.42 Associated Excess Mortality in Septic Patients: A Systematic Review and Meta-regression.

BACKGROUND: This meta-analysis was to determine the association of the cumulative dose of 130/0.4 or 0.42 (hydroxyethyl starch [HES] 130/0.4*) or delta daily fluid balance (i.e., daily fluid balance in HES group over or below control group) with the heterogeneity of risk ratio (RR) for mortality in randomized control trials (RCTs). METHODS: Three databases (PubMed, EMBASE, Cochrane) were searched to identify prospective RCTs reporting mortality in adult patients with sepsis to compare HES130/0.4* with crystalloids or albumin. Meta-analysis was performed using random effects. Sensitivity and meta-regression analyses were used to examine the heterogeneity sources of RR for mortality. RESULTS: A total number of 4408 patients from 11 RCTs were included. The pooled RR showed no significant difference for overall mortality in patients with administration of HES130/0.4* compared with treatment of control fluids (RR: 1.02, 95% confidence interval: 0.90-1.17; P = 0.73). Heterogeneity was moderate across recruited trials (I2 = 34%, P = 0.13). But, a significant variation was demonstrated in subgroup with crystalloids as control fluids (I2 = 42%, P < 0.1). Sensitivity analysis revealed that trials with high risk of bias did not significantly impact the pooled estimates for mortality. Meta-regression analysis also did not determine a dose-effect relationship of HES130/0.4* with mortality (P = 0.298), but suggested daily delta fluid balance being likely associated with mortality in septic patients receiving HES130/130/0.4* (P = 0.079). CONCLUSIONS: Inappropriate daily positive fluid balance was likely an important source of heterogeneity in these trials reporting HES130/0.4* associated with excess mortality in septic patients.

Extensive variability in vasoactive agent therapy: a nationwide survey in Chinese intensive care units.

BACKGROUND: Inconsistencies in the use of the vasoactive agent therapy to treat shock are found in previous studies. A descriptive study was proposed to investigate current use of vasoactive agents for patients with shock in Chinese intensive care settings. METHODS: A nationwide survey of physicians was conducted from August 17 to December 30, 2012. Physicians were asked to complete a questionnaire which focused on the selection of vasoactive agents, management in the use of vasopressor/inotropic therapy, monitoring protocols when using these agents, and demographic characteristics. RESULTS: The response rate was 65.1% with physicians returning 586 valid questionnaires. Norepinephrine was the first choice of a vasopressor used to treat septic shock by 70.8% of respondents; 73.4% of respondents favored dopamine for hypovolemic shock; and 68.3% of respondents preferred dopamine for cardiogenic shock. Dobutamine was selected by 84.1%, 64.5%, and 60.6% of respondents for septic, hypovolemic, and cardiogenic shock, respectively. Vasodilator agents were prescribed by physicians in the management of cardiogenic shock (67.1%) rather than for septic (32.3%) and hypovolemic shock (6.5%). A significant number of physicians working in teaching hospitals were using vasoactive agents in an appropriate manner when compared to physicians in nonteaching hospitals. CONCLUSIONS: Vasoactive agent use for treatment of shock is inconsistent according to self-report by Chinese intensive care physicians; however, the variation in use depends upon the form of shock being treated and the type of hospital; thus, corresponding educational programs about vasoactive agent use for shock management should be considered.

Factors associated with low adherence to head-of-bed elevation during mechanical ventilation in Chinese intensive care units.

BACKGROUND: Elevating the head of bed (HOB) 30° - 45° has been widely supported as a means of ventilator associated pneumonia (VAP) prevention. However, it was poorly adhered in clinical practice. This observational study aimed to investigate the factors impeding this simple practice at the bedside. METHODS: This prospective study was conducted in 33 Chinese academic hospital intensive care units (ICUs). HOB angle was measured four times daily at 5 - 7 hour intervals. The predefined HOB elevation goal was an angle ≥ 30°. RESULTS: The overall rate of achieving the HOB goal was 27.8% of the 8647 measurements in 314 patients during 2842 ventilation days. The HOB goal of ≥ 3 times/d was consistently achieved only in 15.9% of the cases. Almost 60% of patients had at least one 24 hours period during which the HOB goal was never documented. This low rate of protocol compliance was not associated with acute physiology and chronic health evaluation (APACHE) II score or dependence on vasopressors. In a survey, "nurse workload" was identified as the most important factor for non-compliance with the HOB goal. In addition, the rates of compliance were significantly different (P < 0.001) between physicians self-reporting that they either did or did not know the Institutes of Healthcare Improvement (IHI) ventilator bundle. CONCLUSIONS: Low adherence to a HOB angle of ≥ 30° was found in this nationwide survey. Nursing workload and lack of knowledge on VAP prevention were important barriers to changing this practice.

[The relationship of ultrastructure and function of hypothalamus-pituitary-adrenal axis in early stage of sepsis in rats].

OBJECTIVE: To observe the changes in ultrastructure and function of hypothalamic-pituitary-adrenal axis (HPAA), and to approach the relationship between them in early stage of sepsis in rats. METHODS: Thirty male Sprague-Dawley (SD) rats were randomly divided into normal control group, sham group, sepsis group. The sepsis model was reproduced by cecal ligation and puncture (CLP). The rats were sacrificed after collection of blood at 6 hours after CLP, and the levels of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) in the plasma, and the corticotropin release hormone (CRH) in the tissue of hypothalamus were detected. The histopathological changes in HPAA were observed with transmission electron microscopy. RESULTS: The levels of ACTH and CORT in plasma, and the CRH in hypothalamus tissue of sepsis group were increased in the early stage of sepsis compared with the normal control group or sham group [ACTH (pmol/L): 5.78±0.36 vs. 1.94±0.31, 2.51±0.10; CORT (nmol/L): 88.48±4.47 vs. 22.02±1.62, 34.20±2.51; CRH (µg/L): 101.92±6.61 vs. 61.65±6.05, 66.65±4.03, P<0.05 or P<0.01]. The changes in ultrastructure of the hypothalamus, pituitary and adrenal were also found. In sepsis group, the ultrastructure of hypothalamus was as follows. Rough endoplasmic reticulum expansion and degranulation of rough endoplasmic reticulum, and swelling of Golgi complex were found. A large number of endocrine granules could be seen in ATCH cells in the pituitary with depletion of adrenal lipid droplets. CONCLUSION: In septic rats, the HPAA was excessively activated, and ACTH and CORT in plasma, and CRH in hypothalamus were significantly increased in early stage of sepsis. The changes in ultrastructure of HPAA were obvious, and the change in function was closely related to the ultrastructural changes.

[Effect of endothelial nitric oxide synthase gene polymorphisms upon disease severity and outcome in septic patients].

OBJECTIVE: To investigate the association of eNOS 894G-->T, -786T-->C gene polymorphisms with disease severity and outcome in septic patients. METHODS: A total of 117 patients with severe sepsis were randomly selected from ICUs at 9 academic hospitals in Beijing during April 2007 to May 2009. PCR-RFLP and PCR-SSCP were used to analyze the alleles and genotypes in eNOS 894G-->T and -786T--> C gene polymorphisms. Recorded clinical data included demographics, pathogens, APACHE II score within 24 hours and SOFA score within 7 days after ICU admission, percentage of shock patients, days to shock onset (from infection to shock onset), duration of shock and the mortality at Days 7 and 28. RESULTS: In comparison with genotype GT carriers, the patients with genotype GT in eNOS 894G-->T polymorphism had a incremental trend in frequency of shock (87% vs 68.1%, P = 0.071) and a significantly shortened days to shock onset [1.0 (0.1 - 6.5) vs 2.0 (0.10 - 27.0) days, median (range), P < 0.05]. Those patients had been shown to have a significantly high APACHE II score (23.61 +/- 7.00 vs 19.50 +/- 6.99, P < 0.05), SOFA score (9.43 +/- 3.42 vs 5.26 +/- 2.94, P < 0.001) and mortality at Day 7 (34.8% vs 0%, P < 0.001) and Day 28 (78.3% vs 23.4%, P < 0.001). Multivariate analyses revealed that age in years, SOFA score and genotype GT in eNOS 894G-->T polymorphism were independent high-risk factors for the outcome in septic patients. However, eNOS -786T-->C gene polymorphism was not associated with disease severity and outcome in septic patients. CONCLUSION: Carriage of genotype GT in eNOS 894G-->T polymorphism is associated with the occurrence of shock and impaired organ function.

[Clinical investigation on the compliance and the validity of ventilator bundle].

OBJECTIVE: To investigate the compliance of ventilator bundle implementation and its preventive effect on ventilator associated pneumonia (VAP). METHODS: A before and after design was used in this single center study. Patients aged from 18 to 80 years, with mechanical ventilation (MV) duration over 48 hours were recruited during 1 year before (control group) and 2 years after bundle implementation (intervention group). Measurements included the rate of successful ventilator bundle implementation in intervention group, incidence of VAP, duration of MV and mortality within 28 days in both groups. RESULTS: A total number of 237 patients, including 71 patients in control arm and 166 patients in intervention arm, were recruited in this study. There was no statistical significance in ratio of sex, mean age, category of diseases or mean acute physiology and chronic health evaluation II (APACHE II) score between two groups (all P>0.05). Significant changes were not found in MV duration [(5.9+/-5.6) days vs. (5.2+/-6.1) days], incidence of VAP (21.1% vs. 20.5%) and mortality within 28 days (16.9% vs. 19.8%) between control and intervention group as well. In intervention group, 57 of 166 (34.3%) patients were successfully implemented all of four ventilator bundle items. The successful rate of ventilator bundle implementation were 62.5% (35/56), 22.1% (21/95) and 6.7% (1/15) in patients received MV duration < or =3 days, 4-7 days and >7 days respectively. Among the four items of the bundle, head of bed elevation > or =30 degree angle had the lowest successful rate [43.4% (72/166)]. But it was much better in the implementation of daily wake-up plus weaning, prevention of peptic ulcer and prevention of deep vein thrombosis formation [92.2% (153/166), 88.0% (146/166) and 83.1% (138/166) respectively]. CONCLUSION: The poor compliance of ventilator bundle is an important factor in impacting the efficacy of ventilator bundle.

[Relationship between severity of illness and mental status in ICU conscious patients: a nationwide multi-center clinical study].

OBJECTIVE: To survey the incidence of psychological adverse events in critical conscious patients during their ICU stay and analyze the relationship between the incidence and the severity of illness. METHODS: 234 conscious patients, 133 males and 101 females, aged (55.4 +/- 19.6), 80 with internal medicine diseases and 154 with surgical diseases, were treated in the ICUs of 31 grade 3 A hospitals over the country consecutively during the period of 2 months and then successfully transferred to other departments. The patients were interviewed with specific questionnaire within the 2 days after transfer to investigate the incidence of anxiety and depression and the tolerance of invasive medical and nursing procedures of the patients. RESULTS: The overall incidence of psychological adverse events (PAE) was 69.6%. Multi-variate Logistic analysis showed that acute physiology and chronic health evaluation (APACHE) II score was an independent high risk factor of PAE (OR = 1.07, 95% CI: 1.02-1.13, P < 0.05). The relative risk (RR) values of the patients with APACHE II scores 1-10, 11-20, and >20 were 1.29, 2.53, and 4. 85 respectively. The higher the APACHE II score, the more invasive interventions received (P < 0.01) , and the lower the mental stress threshold (P < 0.01) the higher the incidence of PAE (P < 0.01). The APACHE II scores of those who failed to tolerate noise and medical and nursing procedures were 15.8 +/- 5.7 and 16.5 +/- 6.1 respectively, both significantly higher than those of the patients who tolerated (12.1 +/- 4.4, P < 0.05; and 10.6 +/- 2.9, P < 0.01). CONCLUSION: APACHE II score is an independent high risk factor of PAE. The conscious ICU patients with higher APACHE II scores receive more invasive medical and nursing procedures. Low mental stress threshold greatly contributed to the incidence of PAE in ICU conscious critical patients with high APACHE II score.

[Epidemiology of unpleasant experiences in conscious critically ill patients during intensive care unit stay].

OBJECTIVE: To survey the incidences of psychological and physiological unpleasant experiences in conscious critically ill patients during their intensive care unit (ICU) stay, and investigate the inducing factors. METHODS: A two-month consecutive nationwide investigation was prospectively performed in 31 academic hospital ICUs. An in-person questionnaire interview to each conscious patient was performed by specific trained staff from RMC-ROMIT Healthcare Consulting Company within 2 days after the patient was transferred from ICU. RESULTS: Two hundred and thirty-four cases were interviewed in this survey. One hundred and sixty-three of the 234 patients (69.6%) appeared psychological unpleasant experience. The ratio of patients with physiological unpleasant experience was as high as 97.0%, and 74.8% of whom were with serious physiological unpleasant experiences. The incidence of serious physiological unpleasant experiences was markedly higher in patients with than without psychological unpleasant experience (46.5% vs. 86.5%). The difference was shown to be statistical significant (P < 0.01). The percentage of patients complained of ICU noise and medical or nursing manipulations not tolerable was 65.8% and 74.8%, respectively. Compared with the tolerable cases, the incidences of psychological and physiological unpleasant experiences were significantly increased in those patients (P < 0.05 or P < 0.01). Acute physiology and chronic health evaluation II (APACHE II) score was the independent high risk factor inducing psychological unpleasant experience through multiple factor analysis [odds ratio (OR) = 1.070, 95% confidence interval (CI) = 1.020-1.130, P < 0.05]. Age was the high risk factor inducing physiological unpleasant experience (OR = 0.936, 95% CI = 0.879-0.998, P < 0.05). In addition, adequate sedation significantly reduced the incidence of the psychological and physiological unpleasant experiences. CONCLUSION: A high incidence of unpleasant experience is found in conscious critically ill patients during their ICU stay. Patients with psychological unpleasant experiences are with higher possibility of occurring physiological unpleasant experiences. The data show that APACHE II score is the independent high risk factor inducing psychological unpleasant experiences. ICU environment, noise for instance, and medical or nursing manipulations are closely related with the incidence of psychological and physiological unpleasant experiences. Meanwhile, adequate sedation is one of the effective methods to reduce the incidences of them.

[Midazolam attenuates mental stress in conscious patients during cardiopulmonary resuscitation performed next bed in intensive care unit].

OBJECTIVE: To evaluate the mental stress level and alterations in circulatory physiology in conscious patients during cardiopulmonary resuscitation (CPR) performed next bed in intensive care unit (ICU), and to investigate the possible effective interventions. METHODS: Eighty-seven conscious patients, selected consecutively from June 2003 to September 2006, were randomly allocated into control group (received normal saline), psychological nursing group (received psychological nursing intervention) or sedation group (received midazolam 0.1 mg/kg intravenous injection based on psychological nursing intervention) when CPR was performed in our ICU. Plasma concentrations of norepinephrine, epinephrine, cortisone and glucose were analyzed at the time points of beginning of CPR, 10 minutes, 4 and 24 hours after CPR in the first 40 patients. Heart rate (HR), systolic blood pressure (SBP), mean arterial pressure (MAP) and arrhythmia within 24 hours after CPR were recorded in all patients. RESULTS: Plasma levels of norepinephrine, epinephrine and cortisone were significantly increased at 10 minutes after CPR and persisted for 4 hours in 13 patients of the control group (P<0.05 or P<0.01). Though with the similar tendency, significant increase of cortisone level was observed in 13 patients who had received psychological nursing intervention (P<0.05 or P<0.01). The analyzed stress hormones showed little variation in 14 patients who were given midazolam at 10 minutes and 4 hours after CPR. Notably, 24 hours after CPR, they were decreased below the levels which were observed at the beginning of CPR (all P<0.01). Blood glucose levels were markedly higher in both control and psychological nursing groups than the level in sedation group within 24 hours. HR was accelerated 10 minutes after CPR, SBP was significantly increased, the incidence rate of arrhythmia was high (84.6%, 22/26; 54.5%, 18/33) in the non-sedation groups. Circulatory physiological alterations were least marked in sedation group (21.4%, 6/28, both P<0.01). CONCLUSION: Mental stress is significantly heightened in conscious patients during CPR performed next bed in ICU, and it induces severe circulatory physiological alterations. Psychological nursing alone is not affective in alleviating this acute mental stress. However, low dose of midazolam is found to be an effective intervention.

[Prospective, multi-center investigation on safety of critical patients in intensive care units].

OBJECTIVE: To perform a prospective, multi-center investigation of the incidence and causes of medical errors happened in intensive care unit (ICU). METHODS: This investigation was performed in eight ICUs in level A, grade 3 teaching hospitals from October 23 to December 23, 2006. One attending physician and the head nurse in each center were entrusted with the responsibility for this project. Medical errors were identified as (1) type of errors (happened in diagnosis, medication, caring procedures or monitoring etc.); (2)characteristics of errors (related to complications, emergency intervention, low ability or carelessness of care givers and others); (3) consequence of errors (resulted in non-serious influence, vital signs fluctuation, alternation of respiratory or circulatory function, organ injury or death). Besides the medical errors, data included ICU beds, numbers of doctors or nurses, numbers of critical patients receiving intensive care during the investigation period and their acute physiology and chronic health evaluation II (APACHE II) scores, the academic degree and title and years of ICU working experience of doctors or nurses who made medical errors. RESULTS: Data from three of eight centers were excluded due to lack of objectivity. A total number of 232 critical patients were surveyed in 1 319 ICU patient x days. Two hundred and ninety-six ICU errors were found. One error occurred in average of 4.46 patient x days. Medical errors happened in 157 patients (67.6%). The percentage of error related to nursing (74.3%) was significantly higher than that made by doctor's caring (25.7%). Two hundred and twelve errors (71.6%) were devoid of serious effects to patients. However, Eighty-two errors were followed by vital signs instability. Medical errors occurred more frequently in patients with the higher (greater than 20) than the lower (less than 20) APACHE II score. The frequency of nursing oriented errors was closely positively correlated with the rates of shortage of working force, low educational level and working years less than 3 years respectively. CONCLUSION: Our survey indicates that critical patients are facing high medical error risk in the higher level Chinese teaching hospitals. There is a close relationship between ICU errors and severity of patient's disease, inadequate training and less working experience.