|Year : 2020 | Volume
| Issue : 1 | Page : 10-17
Clinical Features and Predictors for Outcome in Critically Ill Patients with COVID-19 Infection from Wuhan, China
Bo Hu1, Dawei Wang1, Chang Hu1, Ming Hu2, Fangfang Zhu1, Hui Xiang1, Beilei Zhao3, Kianoush B Kashani4, Zhiyong Peng1
1 Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
2 Department of Critical Care Medicine, Wuhan Pulmonary Hospital, Wuhan, Hubei, China
3 Department of Pulmonary and Critical Care Medicine, Nanjing Jinling Hospital, Nanjing, China
4 Division of Nephrology and Hypertension, Mayo Clinics, Rochester, MN, USA
|Date of Submission||14-Sep-2020|
|Date of Acceptance||23-Nov-2020|
|Date of Web Publication||31-Dec-2020|
Dr. Zhiyong Peng
Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei
Objective: The information about the critically ill coronavirus disease 2019 (COVID-19) was limited and controversy. This study was to analyze the clinical feature and predictors for outcome in critically ill COVID-19. Design: This was a descriptive study from two hospitals. Setting: This study was conducted in intensive care units (ICUs) from university hospitals. Methods: Critically ill COVID-19 patients admitted in ICU from Zhongnan Hospital of Wuhan University and Wuhan Pulmonary Hospital from January 8 to February 20, 2020, were screened. Interventions: None. Measurements and Main Results: Clinical, laboratory data were collected with management strategies and outcomes. Sixty-eight critically ill patients were enrolled. Their median age was 64 (interquartile range, 54–72) years, and 67.65% were male. In this cohort, 44 (65%) patients survived for 28 days. The invasive mechanical ventilator was used in 51 (75%) patients, with 20 of them requiring prone positioning, and 17 switched to extracorporeal membrane oxygenation. The compliance scores of lungs on the day of intubation among survivors were higher than those in nonsurvivors (25.00 [13.50–39.00] vs. 17.00 [12.00–22.00], P = 0.01). The blood interlukin-6 (IL-6) levels at the ICU admission were significantly higher in nonsurvivors compared to survivors (71.27 [51.48–144.15] vs. 18.15 [7.55–68.02] ng/ml, P = 0.025). The heart rates, lung injury scale, and positive end-expiratory pressure were constantly higher for 10 days in nonsurvivors. The frequency of vasopressor uses and neuromuscular blockers was higher in nonsurvivors from day 5 to day 10 (P < 0.05). In the whole cohort, the most common complications were acute respiratory distress syndrome (95.59%), shock (48.53%), arrhythmia (33.82%), acute cardiac injury (33.82%), and acute kidney injury (27.94%). Multivariate analysis indicated that lower lung compliance at the day of intubation and higher Acute Physiology and Chronic Health Evaluation II (APACHE II) at ICU admission were related to higher mortality (P = 0.02 and 0.05, respectively). Conclusion: COVID-19-related critical illness predominantly affected old individuals and was characterized by severe hypoxemic respiratory failure, often requiring prolonged mechanical ventilation and rescue therapies. High APACHE II scores and low lung compliance indicated poor outcomes.
Keywords: Acute respiratoryw distress syndrome, coronary virus, infection, pneumonia
|How to cite this article:|
Hu B, Wang D, Hu C, Hu M, Zhu F, Xiang H, Zhao B, Kashani KB, Peng Z. Clinical Features and Predictors for Outcome in Critically Ill Patients with COVID-19 Infection from Wuhan, China. J Transl Crit Care Med 2020;2:10-7
|How to cite this URL:|
Hu B, Wang D, Hu C, Hu M, Zhu F, Xiang H, Zhao B, Kashani KB, Peng Z. Clinical Features and Predictors for Outcome in Critically Ill Patients with COVID-19 Infection from Wuhan, China. J Transl Crit Care Med [serial online] 2020 [cited 2021 Apr 18];2:10-7. Available from: http://www.tccmjournal.com/text.asp?2020/2/1/10/305786
| Introduction|| |
In December of 2019, a new coronavirus was isolated for the first time from a patient in Wuhan, China, which presented with acute pneumonia, acute respiratory distress syndrome (ARDS), and multi-organ dysfunction syndrome (MODS).,, The virus was identified as a coronavirus and was designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The clinical disease caused by SARS-CoV-2 was named coronavirus disease 2019 (COVID-19). As of April 11, 2020, statistical data showed that the outbreak constituted an epidemic threat in China, where the exponential increase in the number of individuals who acquired COVID-19 has reached 83,485 confirmed cases, and 3,349 (4%) died. The critically ill COVID-19 has a high fatality rate and several clinical features that resemble the infection caused by SARS-CoV and Middle East respiratory syndrome CoV (MERS-CoV).,,,, This viral infection has resulted in a significant concern regarding the global pandemic. While the knowledge about this virus is accumulating, the information regarding critical illness among infected individuals with COVID-19 remains limited. The report by Yang et al. on critically ill COVID-19 demonstrated considerably high mortality, with 61.50% of 28-day mortality. However, the major limitation from Yang's study was that all these patients were from Jinyintan Hospital, which is a hospital specifically for infectious diseases and was the first hospital open to the COVID-19. Limited medical resources contributed to the high mortality. Therefore, the results from Yang's study cannot reflect the real picture of critically ill COVID-19. The recent study about the critically ill COVID-19 in the Lombardy region of Italy showed a 26% mortality in ICU. However, in this study, 58% of patients were still in the treatment and the final outcome was unknown. In order to provide more information regarding the severe COVID-19, we described the clinical course and outcomes of 68 critically ill patients with COVID-19 admitted to 2 intensive care units (ICUs) in tertiary hospitals in Wuhan, China, and analyzed the factors to predict the outcome.
| Methods|| |
Study design and participants
This case series was approved by the Institutional Ethics Board of Zhongnan Hospital of Wuhan University (No. 2020020) and Wuhan Pulmonary Hospital (No. 2020020). Oral consent was obtained from patients or patients' relatives. All consecutive patients with COVID-19 admitted to ICUs of the two hospitals from January 8 to February 20, 2020, were screened. Included patients with COVID-19 had virology confirmation with RT-PCR methods and required organ supports due to multiple organ failure. Zhongnan Hospital and Wuhan Pulmonary Hospital located in Wuhan, Hubei Province, the endemic areas of COVID-19, are responsible for the treatments for COVID-19 assigned by the government. All patients with COVID-19 enrolled in this study were diagnosed according to the World Health Organization interim guidance.
The medical records of patients were analyzed by the research team of the Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University. The electronic medical records were used to abstract the information regarding demographics, medical history, exposure history, underlying comorbidities, symptoms, signs, laboratory findings, chest computed tomography (CT) scans, and management or treatment strategies (i.e., antiviral therapy, antibiotics, vasopressor, sedative-analgesic agents, corticosteroid therapy, respiratory support, extracorporeal membrane oxygenation (ECMO), and renal replacement therapy) and patient outcomes. The data were reviewed by a trained team of physicians. Heart rate, mean arterial pressure, arterial blood gas, and ventilation parameters were obtained at 8 a.m. of every day during ICU stay. All patients were followed for the assessment of complications and outcomes for 28 days. ARDS was defined according to the Berlin definition. Acute kidney injury was identified according to the Kidney Disease: Improving Global Outcomes criteria. The cardiac injury was defined when the serum levels of cardiac biomarkers (e.g., troponin I) were above the 99th percentile upper reference limit or new abnormalities were shown in electrocardiography (ECG) and transthoracic echocardiography (TTE). The Acute Physiology and Chronic Health Evaluation (APACHE II), Glasgow Coma Score, Sequential Organ Failure Assessment (SOFA), and Murray scores were followed every 2 days during ICU stay. Furthermore, the information regarding dyspnea, ARDS, use of high-flow nasal cannula (HFNC) oxygen therapy, invasive or noninvasive mechanical ventilator, intubation, and ECMO were abstracted.
Categorical variables were described as frequencies and percentages, and continuous variables were summarized using mean and standard deviations or median and interquartile range (IQR) values, as appropriate based on the variable normal distribution. Means for continuous variables were compared using independent group t-tests when the data were normally distributed; otherwise, the Mann–Whitney test was used. Data (nonnormal distribution) from repeated measures were compared using the generalized linear mixed model. Proportions for categorical variables were compared using the Chi-square test, although the Fisher's exact test was used when the data were limited. For unadjusted comparisons, a two-sided α of <0.05 was considered statistically significant. Factors associated with 28-day mortality in bivariate logistic regression with P < 0.1 were included in a multivariate analysis. Results are reported as odds ratios (ORs) and 95% confidence intervals (CIs). P < 0.05 represented statistical significance, and all reported P values were two-sided. All statistical analyses were performed using Statistical Package for the Social Sciences version 13.0 software (SPSS Inc., IBM, Armonk, NY, USA).
| Results|| |
Characteristics of study patients
[Table 1] shows the basic characteristics of the 68 enrolled patients (54 from Zhongnan Hospital and 14 from Wuhan pulmonary Hospital). Forty-four (65%) patients survived for 28 days, and 24 (35%) patients died. The median age of the enrolled patients was 64.50 (IQR, 54–72) years, and 46 (67.65%) of them were male. The median of APACHE II score, SOFA, and LIS scores at the ICU admission was 12, 5, and 3.33, respectively. The APACHE II and SOFA in survivors were lower than those in nonsurvivors (12 vs. 16 and 4 vs. 6, P = 0.01 and 0.02, respectively). Meanwhile, arterial oxygen partial pressure-to-fractional inspired oxygen ratio (PaO2/FiO2) and partial pressure of carbon dioxide (PaCO2) were 104.20 mmHg (IQR, 79.70–159.00) and 35.35 mmHg (IQR, 31.30–41.08), respectively. The median of ICU length of stay was 12.5 days (IQR, 8.0–19.0). [Table 1] demonstrates the variables related to pulmonary function detected in the invasive mechanical ventilation (IMV) patients (N = 51) at the 1st h of intubation. The median of static lung compliance (Cstat), positive end-expiratory pressure (PEEP), and driving pressure was 20.00 ml/cm H2O (IQR, 13.00–27.00), 10.00 cmH2O (IQR, 8.00–11.00), and 18.00 mm H2O (IQR, 14.00–23.00).
|Table 1: Baseline characteristics of clinically ill patients infected with corona virus disease-19 on the day admitted in intensive care unit|
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As shown in [Table 2], there were abnormal laboratory values in the 68 enrolled patients, which included elevated level of neutrophil counts (7.69 × 109/L [5.12–10.87]), IL-6 (62.2 pg/ml [IQR, 18.2–67.2]), lactate dehydrogenase (527.90 U/L [IQR, 353.00–638.00]), aspartate aminotransferase (50.50 U/L [IQR, 31.25–70.50]), prothrombin time (13.45 s [IQR, 12.50–15.60]), and lymphopenia (0.54 × 109/L [IQR, 0.32–0.80]).
|Table 2: Parameters of mechanic ventilation at the first hour of intubation in critically ill corona virus disease-19|
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Comparisons of survivors and nonsurvivors
The nonsurvivors were older than survivors (68.00 years [IQR, 61.00–71.50] vs. 61.00 years [IQR, 48.00–69.00], P = 0.03) [Table 1]. The Cstat on the 1st day of tracheal intubation was lower in nonsurvivors than that in survivors (17.00 [12.00–22.00] ml/cm H2O vs. 25.00 [13.50–39.00] ml/cm H2O, P = 0.01) [Table 1]. Meanwhile, the IL-6 concentration in nonsurvivors was also higher than that in survivors (71.27 pg/ml [IQR, 51.48–144.15] vs. 18.15 pg/ml [7.55–68.02], P = 0.02) [Table 2]. There were continuously elevated heart rates, LIS, and PEEP since day 5 in nonsurvivors compared to survivors [P < 0.05, respectively, [Figure 1]. Nonsurvivors received significantly more vasopressors and muscular relaxants than survivors [P < 0.05; [Figure 1].
|Figure 1: Timeline charts illustrate several parameters in 68 discharged patients with COVID-19 (24 nonsurvivors and 44 survivors) every other day. Data expressed as median (interquartile range). P values indicate differences between survivors and nonsurvivors. P < 0.05 was considered statistically significant. COVID-19: Corona virus disease 2019, FiO2: Fraction of inspiration O2, LIS: Lung injury score, PaCO2: Partial pressure of carbon dioxide, PaO2: Partial pressure of oxygen, PEEP: Positive end-expiratory pressure, SOFA: Sequential organ failure assessment. * means P < 0.05, and was considered statistically significant.|
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Dynamic clinical course of illness
[Figure 1] shows the dynamic changes of vital signs, mechanical ventilation parameters, treatment measures, and scores from day 1 to day 10. During this period, the vital signs were roughly kept within normal range using various organ support therapy modalities, although nonsurvivors had higher heart rates. From day 5, the LIS, SOFA, and PEEP were higher in nonsurvivors than those in the survivors. Vasopressors and neuromuscular blockers were used more frequently in nonsurvivors from day 5 than those in survivors (P < 0.05).
Treatments, complications, and outcomes
As shown in [Table 3], among the enrolled 68 patients, all of them received HFNC + NIV initially, but only 17 (25%) patients liberated from HFNC + NIV, and the other 51 patients (75%) switched to IMV. In the 51 intubated patients, 14 patients (21%) were on IMV in supine position, 20 patients (29%) were on IMV in prone position, and 17 patients (25%) escalated to ECMO (all of these ECMO patients were proned before or during ECMO). The antiviral therapy, glucocorticoid therapy, and antibiotic use were used in 94%, 69%, and 90% of patients, respectively. The most common complications were ARDS (96%), shock (49%), arrhythmia (34%), acute cardiac injury (34%), and acute kidney injury (28%). Less common complications included cerebral infarction, cerebral hemorrhage, and hypoxic-ischemic encephalopathy. Among those with AKI, 50% required continuous renal replacement therapy. Twenty-six (38%) patients suffered a secondary bacterial infection. These infections included nosocomial pneumonia and bacteremia. The nosocomial pneumonia cases were associated with included Klebsiella pneumoniae, Escherichia More Details coli, Elizabethkingia meningosepticum, and Aspergillus fumigatus. The bacteremia pathogen included K. pneumoniae and Enterococcus faecium. Among the causes of death, majority of patients died from multi-organ failure associated with ARDS.
|Table 3: Laboratory findings of critically ill corona virus disease-19 on the day of intensive care unit admission|
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28-Day mortality and analysis for mortality-related risk factors
Supplemental Figure 1[Additional file 1] shows the 28-day survival curve of critically ill patients with COVID-19. The median duration from ICU admission to death was 14.00 days (8.00–20.00). The overall 28-day mortality was 35%. [Table 4] shows the risk factors associated with death for severe COVID-19 patients who needed IMV (N = 51). On univariate analysis, the risk factors associated with death were low Cstat (OR: 0.93 [0.87–0.99], P = 0.02) and elder age (OR: 1.04 [1.00–1.09], P = 0.05). However, the multivariate analysis demonstrated the high APACHE II (OR: 1.12 [1.00–1.26], P = 0.05) and low Cstat (OR: 0.92 [0.86–0.98], P = 0.02) to be significantly associated with death [Table 5].
|Table 4: Treatments and outcomes of patients infected with corona virus disease-19 in intensive care unit|
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|Table 5: Univariate and multivariate analysis of risk factors associated with death in severe corona virus disease-19 in intensive care unit|
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| Discussion|| |
Our analysis of critically ill patients with COVID-19 revealed that this disease affected older patients with comorbidities. These patients had severe hypoxia/ARDS, and the majority of them required mechanical ventilation. Some of these patients needed prone ventilation and ECMO to maintain their gas exchange. The survivors had lower IL-6 on the 1st day of ICU admission and higher Cstat at the 1st h after intubation than nonsurvivors. The dynamic assessment of variables indicated that the persistent elevation in LIS, HR, and SOFA occurred more often in nonsurvivors. Furthermore, nonsurvivors persistently required higher PEEP, more neuromuscular blockers, and vasopressor support. Lower Cstat and higher APACHE II were risk factors for mortality.
To our knowledge, this is the first report to summarize the clinical features and dynamic pulmonary parameters among critically ill patients with COVID-19.
The high median age in this cohort of critically ill patients was similar to SARS and MERS., The timeline between the illness onset and ICU admission was about 10 days, which was similar to previous reports., This time point may represent the peak viral shedding period. The 28-day mortality was 35%, which was similar to the mortality from severe community-acquired pneumonia (about 25%–50%), but much higher than the standardized mortality (18%–20%) in 2019 calculated with the similar APACHE II in these two ICUs. The main reason was related to the increased capacity in the early stage. There are 66 ICU beds in three ICUs, engaging 30 physicians and 130 nurses within our department. In the early stage of the outbreak, we were asked to open a 16-bed ICU for COVID patients in 2 days except the routine care. The ICU beds in Wuhan Pulmonary Hospital were increased from 10 to 15 in 5 days. All these beds were opened for COVID with 10 physicians and 32 nurses. Another reason was that most of the patients admitted to ICU due to severe hypoxemia, while the initial APACHE II was not high. The initial APACHE II was not high. Nevertheless, this mortality was still lower than that from Yang's reports (62%). The median ICU LOS for nonsurvivors was 12 days, but the median time to death from ICU admission was 14 days. This suggests that a substantial number of patients died after ICU discharge. Some of the reported mortality after ICU discharge was their destination care as comfort measures.
The general feature of these critically ill COVID-19 patients was characterized with severe ARDS only in the early stage and subsequently complicated with multiple organ failure if not treated well. Cardiac complications, including new-onset arrhythmia and acute cardiomyopathy, were the major organ injury (68%) secondary to ARDS (96%) and were likely to induce sudden cardiac arrest. The arrhythmia we observed included atrial fibrillation, ventricular fibrillation, ventricular tachycardia, and atrioventricular block. We routinely used ECG and bedside TTE to monitor the cardiac functions. In EKG, the new-onset changes of ST segment and Q wave were considered as abnormal findings. In TTE, the enlargement of the right ventricle (RV) without increased thickness in the ventricular wall, ventricular septal paradox, and “D” shape of the left ventricle (LV) indicated RV injury. This was also called acute cor pulmonale (ACP), which was induced by severe hypoxemia and subsequent pulmonary hypertension. Severe ACP characterized with enlargement of RV would compromise the LV contractility and decrease cardiac output. All these abnormalities improved and disappeared with the improved hypoxemia.
At ICU admission, we noted some abnormal laboratory findings in critically ill patients with COVID-19, which included neutrophilia, lymphopenia, elevated IL-6, and hypoxemia. An elevated level of lactate dehydrogenase and aspartate aminotransferase was also common. In the early stage of MODS induced by COVID-19, the common manifestation was ARDS. Furthermore, the level of IL-6 was higher in nonsurvivors than that in survivors. This indicated that systemic inflammatory response syndrome was more obvious in nonsurvivors and may be one of the mechanisms of MODS induced by COVID-19.
During ICU stay, ARDS and refractory hypoxemia were found to be the main presentation of the enrolled patients in our study. The Cstat and PaO2/FiO2 were lower, particularly in nonsurvivors. In nonsurvivors, the PaO2/FiO2 ranged 100–150 mmHg, despite being on average PEEP level of 10 cmH2 O. To increase oxygenation in severe hypoxemia patients with mechanical ventilation, neuromuscular blockade and prone ventilation were used frequently, especially for the nonsurvivors. Hypercapnia was observed. This was even more obvious among nonsurvivors from day 5 to day 10. Severe and persistent hypercapnia was probably related to increased dead space and decreased Cstat. Thus, ECMO had to be used for improving gas exchange., In the 68 enrolled patients, 20 underwent prone positioning and 17 were initiated on ECMO. Up to March 17, 8 patients were weaned off ECMO successfully. ECMO was used during the H1N1 influenza epidemics and has been considered as a useful management measure to salvage the severe ARDS patients.,
There is currently no treatment recommended for coronavirus infections except for supportive care as needed. Several antivirals and other agents have been used during the COVID-19 outbreak. Herein, most patients were given antiviral and glucocorticoid therapy before ICU admission, but the efficacy of these drugs should be assessed in the future. Secondary infection was common in the late stages of the illness and at least partly due to the prolonged ICU length of stay. Thus, controlling the secondary infection is also critical to reduce hospital mortality.
Diffuse alveolar damage is seen on pathologic examination in patients with SARS as well as COVID-19 who have acute lung injury., For our patents, the PEEP set was relatively low compared to that set for other ARDS patients. We usually set the initial tidal volume at 6 ml/kg. At first, we assessed response to the lung recruitment maneuver. The PEEP was started from 5 to 10 to 15 cmH2 O, and the changes of compliance and driving pressure were monitored. When PEEP increased to above 10 cm H2 O, the Pplat increased more, and subsequently, the diving pressure increased more. Thus, we had to set PEEP at relatively low levels. Moreover, the postmortem examination may be needed to explain the pathogenesis of the COVID-19. We also identified the Cstat of at the 1st h of intubation as a clinical risk factor for death by multivariate logistic regression analysis.
This study has several limitations. Only 68 patients were included in this study. Due to the limited number of patients, the differences between survivors and nonsurvivors should be interpreted carefully. The median of ICU length of stay was 12.50 days, and we tracked some important data during this timeline. Future studies are needed to track temporal changes for longer periods of time to describe the whole clinical progress among critically ill patients with COVID-19. Although we collected cases from two ICU located in Wuhan, multicenter studies are needed to thoroughly describe the comorbidities and clinical features of this illness.
| Conclusion|| |
We have demonstrated that COVID-19-related critical illness predominantly affects older patients and is associated with severe hypoxemic respiratory failure, often requiring prolonged mechanical ventilation. The high APACHE II at ICU admission and low Cstat at the 1st h of intubation indicated poor outcomes.
BH and DW collected the data and wrote the manuscript. CH did the statistical analysis. FZ, MH, HX, and BZ collected the data. KK revised the manuscript. ZP designed and finalized the manuscript.
Financial support and sponsorship
This work was supported by the National Natural Science Foundation (grants 81772046 and 81971816 to Dr. Peng) and the Special Project for Significant New Drug Research and Development in the Major National Science and Technology Projects of China (2020ZX09201007 to Dr. Peng).
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]