Acute Respiratory Distress Syndrome in Critically Ill Patients With Severe Acute Respiratory Syndrome FREE

Severe acute respiratory syndrome (SARS) is a new disease that emerged in November 2002, was initially described in March 2003, and is thought to be caused by a novel coronavirus (SARS CoV).¹ In Singapore, the index case was a traveler who was believed to have been infected in Hong Kong. This patient was admitted to our hospital on March 1, 2003, and subsequently infected 19 health care workers, patients, and their contacts.^{2 - 3} By June 9, 2003, a total of 206 probable SARS cases had been diagnosed in Singapore. To date, more than 8000 individuals have been infected with SARS worldwide, with two thirds of cases reported in China alone.⁴ Toronto is the only city in North America with a major outbreak of SARS.⁵

Approximately 25% of patients with SARS are likely to progress to severe respiratory failure. In Hong Kong, the case-fatality rate is 13.2% for patients younger than 60 years and is 43% for those aged 60 years or older.⁶ In Hong Kong and Canada, outcome data on critically ill SARS patients are available either from very early in the course of the outbreaks or from patients who were treated in many separate intensive care units (ICUs).^{4 ,7} However, to date, no single center has reported a sufficiently large cohort of critically ill patients to accurately characterize the clinical spectrum and outcome of SARS-related critical illness.

Early in the SARS outbreak in Singapore (ie, on March 22, 2003), Tan Tock Seng Hospital, a 1200-bed acute care general hospital where the national Communicable Disease Centre is located, was designated for the intake and solitary isolation of all suspected and probable SARS cases. Except for 5 patients who were too ill to be transferred to Tan Tock Seng Hospital or had only postmortem diagnoses of probable SARS, all critically ill SARS patients were treated in a single dedicated SARS ICU. This report describes the clinical characteristics and outcomes of 46 critically ill patients with probable SARS treated during a 13-week period in this dedicated SARS ICU.

The Tan Tock Seng Hospital research ethics committee approved this study. We reviewed all probable SARS ICU cases diagnosed according to the prevailing World Health Organization definition at the time of admission from March 6 to June 6, 2003.⁸ Patients were transferred to the ICU if they developed signs and symptoms of respiratory failure, arterial oxygen saturation (SaO₂) of less than 92% despite oxygen therapy of at least 50% fraction of inspired oxygen (FIO₂), or if they presented to another hospital with acute respiratory failure and had contact history that was suspicious of SARS.

Patients were treated in a 36-bed ICU. All beds were in individual rooms that had individual air-conditioning systems with negative pressure airflow. A strict personal protection protocol that met or exceeded prevailing World Health Organization guidelines^{9 - 10} was put in place by the first week of the outbreak and was strictly followed by health care workers.

Patients underwent intubation and mechanical ventilation if they deteriorated clinically or could not maintain more than 90% SaO₂ with spontaneous ventilation despite maximal oxygen therapy. A low-tidal-volume lung-protective strategy was used for ventilation, with volume or pressure control ventilation targeting tidal volumes at 6 mL/kg of predicted body weight and plateau pressures of less than 30 cm H₂O. Positive end-expiratory pressure (PEEP), FIO₂, and ventilator rates were then titrated to keep PaO₂ greater than 55 mm Hg (oxygen saturation as measured by pulse oximetry >88%-90%), with normal pH and PaCO₂, if possible. Patients undergoing mechanical ventilation were sedated with a combination of an opioid, benzodiazepine, and/or propofol. Atracurium or pancuronium were used for neuromuscular paralysis to facilitate ventilation when indicated. Standard cardiovascular support to maintain euvolemia, nutritional support, prophylactic and culture-directed antibiotic therapy, continuous renal replacement therapy in renal failure, and euglycemia therapy were administered. Prophylaxis against deep vein thrombosis involved use of stockings, calf sequential compression devices, and subcutaneous low-molecular-weight heparin once daily unless contraindicated.

Antimicrobial therapy was not protocol based, but most patients had been treated with either levofloxacin or a combination of a macrolide and intravenous cephalosporin prior to ICU admission. Antiviral agents were initially used (ribavirin was administered to 96 patients and oseltamivir to 6 patients) but were subsequently discontinued because of lack of clinical efficacy.² An immunomodulation regimen, combining intravenous pulse methylprednisolone (200 mg) and high-dose intravenous immunoglobulin (0.4 g/kg of body weight) administered once daily for 3 consecutive days, was administered within 24 hours of ICU admission to 16 eligible critically ill probable SARS patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) but without any evidence of bacterial or fungal infections (absence of positive microbiologic cultures, marked leukocytosis, or elevated serum procalcitonin levels).

Data on the hospital cohort were drawn from a computerized database maintained by the hospital's Communicable Disease Centre and administered by a clinical epidemiologist. A group of trained physicians collected and regularly updated demographic, clinical, and treatment characteristics in a standardized format. Intensive care unit–related data in this database were predefined by the clinical director of the SARS ICU (D.T.) and regularly reviewed for accuracy and consistency. Additional information used in this study was collected from chart review by a second team of 4 physicians, all of whom had spent at least 14 days or more managing cases in the SARS ICU. Detailed physiological data was also obtained manually from our ICU Clinical Information System (CareVue 2000, version I.2, Philips Medical Systems, Andover, Mass) and entered into a computerized database. Pilot data were initially reviewed by the 2 senior investigators (T.W.K.L. and T.K.K.) for consistency and refinement of definitions before the full data set was collected.

The main outcome measure was mortality at 28 days after symptom onset for patients in the cohort. Deaths were defined as early (<7 days after ICU admission) or late (≥7 days) and were classified based on clinical diagnoses of the proximate cause of death, with postmortem evidence when available (n = 5).

We also classified the patients' clinical course of ARDS, based on clinical observation, into 3 groups: those who survived without need for mechanical ventilator support (early recovery), those who required mechanical ventilation for 14 days or less (intermediate recovery), and those who required mechanical ventilation for more than 14 days (late survival). We compared these groups according to the following characteristics: age and sex, patient demographics, Acute Physiology and Chronic Health Evaluation (APACHE) II score, time from illness onset to ICU admission, baseline (lowest initial) ratio of PaO₂ to FIO₂ as recorded on admission, time from illness onset to requirement of mechanical ventilation, earliest time to reversal of oxygenation shunt and cessation of mechanical ventilation, and peak and time to peak serum lactate dehydrogenase level, a previously described marker of severity.^{2 ,7}

We also examined treatment characteristics for principal ventilator mode used, effectiveness in meeting ventilation targets, maximum PEEP used, management of sedation and muscle paralysis, incidence and treatment of complications, and specific ventilator and caregiver precautions for prevention of spread of aerosolized droplets.

Continuous variables were compared among the 3 survival groups and the nonsurvivors using the Kruskal-Wallis test. Pairwise comparisons were made using the Mann-Whitney test. Categorical variables were compared using the χ² test or the Fisher exact test whenever appropriate. Nonparametric tests were chosen because of the small sample size in each group. The Kaplan-Meier method was used for length of stay in the ICU because there were censored cases (ie, patients still in the ICU as of the last follow-up date). The log-rank test was used to compare length of stay in the ICU. We performed a logistic regression analysis to identify predictors of early and intermediate recovery vs late survival and death. Starting from the most significant variable in the univariate analysis, the log-likelihood ratio test was used to determine whether inclusion of a new variable improved the fit of the multivariate model. All tests were conducted at the P<.05 level of significance, and data analysis was carried out using Stata version 6.0 software (Stata Corp, College Station, Tex).

Of 199 patients with probable SARS treated at our hospital, 46 (23%) were admitted to the SARS ICU. Table 1 shows the comparison of the characteristics of the ICU and non-ICU cohorts. Complete data were available for 149 of 153 non-ICU patients. There were 4 direct transfers from ICUs of other hospitals. Patients admitted to the ICU were older and more likely to have elevated lactate dehydrogenase levels. The main indication for ICU admission for nonventilated patients was hypoxemia (97%). One patient was admitted with posthypoxic encephalopathy after hypoxic cardiopulmonary arrest.

Forty-five patients met the criteria for either ALI (PaO₂/FIO₂ ≤300 mm Hg) or ARDS (PaO₂/FIO₂ ≤200 mm Hg).¹¹ The overall 28-day post–symptom onset mortality rate was 20 (10.1%) of 199 (95% confidence interval [CI], 6.2%-15.1%), and the overall mortality at 13 weeks was 27 (13.6%) of 199 (95% CI, 9.1%-19.1%) for the entire hospital cohort. For SARS patients admitted to the ICU, the 28-day post– symptom onset mortality was 17 (37%) of 46 (95% CI, 23.2%-52.5%) and mortality at 13 weeks was 24 (52.2%) of 46 (95% CI, 36.9%-67.1%). Three patients who died in the hospital declined ICU admission. Five patients died within the first 7 days of ICU admission. All but 1 of the early deaths had significant preexisting comorbidities. The proximate causes of ICU deaths are shown in the Article . The majority of deaths (75%) occurred late in the course of the disease from complications related to severe ARDS, multiorgan failure, thromboembolic complications, or septicemic shock.

Early (<7 Days in ICU; n = 5)

Dilated cardiomyopathy (1)
Cardiac failure with septicemic shock (1)
Ventricular fibrillation and end- stage renal failure (1)
Biliary peritonitis and acute-on- chronic renal failure (1)
ARDS with bacterial pneumonia and pulmonary embolism (1)

Late (≥7 Days in ICU; n = 19)

End-stage renal failure (1)
Late ARDS with multiorgan failure (7)
Late ARDS with intractable hypoxia (single-organ failure)
(2) Acute myocardial infarction (1)
Postanoxic brain ischemia (1)
Massive cerebrovascular accident (2)
ARDS with acute pulmonary embo lism (3)
Septicemic shock (2)

*ICU indicates intensive care unit; ARDS, acute respiratory distress syndrome. Autopsies were performed in 5 of these patients.

Table 2 shows the survival group (n = 22) divided into 3 subgroups based on clinical course: early recovery without mechanical ventilation, intermediate recovery with mechanical ventilation for 14 days or less, and late survival with mechanical ventilation for more than 14 days. In the late survival group, 4 patients had been discharged from the ICU and 2 remained in critical condition. The groups differed in age (P = .03), APACHE II score (P = .002), baseline PaO₂/FIO₂ ratio values, (P<.001), and peak lactate dehydrogenase levels (P = .02).

Patients in the early recovery group had an abbreviated course of ALI and their FIO₂ requirements peaked at a median of day 8 of illness, which coincided with the median day of admission to the ICU. Patients in the intermediate recovery group had improvement in oxygenation and pulmonary compliance after a median of 5 days of mechanical ventilation and were extubated within a median of 4 days of improvement (Figure 1). Patients in the late survival group had a protracted and severe course of ARDS, required the most interventions and treatment, and had the most complications.

In univariate analysis, age, APACHE II score, and baseline PaO₂/FIO₂ ratio were associated with early/intermediate recovery. In multivariate analysis, only APACHE II scores and baseline PaO₂/FIO₂ ratio were independently associated with early/intermediate recovery (Table 3). The odds ratio of recovery decreased by 0.87 (95% CI, 0.78-0.97) for every 1-unit increase in APACHE II score after adjusting for baseline PaO₂/FIO₂ ratio (P = .02). The odds ratio of recovery increased by 1.02 (95% CI, 1.00-1.04) for every 1-unit increase in baseline PaO₂/FIO₂ ratio after adjusting for APACHE II score (P = .02).

Pressure control ventilation was used in 22 patients, volume control in 17 patients, and airway pressure release ventilation in 1 patient. Seven patients underwent ventilation in the prone position for periods ranging from 4 to 9 h/d. Three of these 7 patients had significant improvements in SaO₂ and 1 survived; there were 3 survivors overall from this group. Respiratory tract secretions were minimal and bronchospasm was encountered in only 3 patients who underwent ventilation.

Tidal volumes, minute ventilation, plateau pressures, and PEEP use were not significantly different between the intermediate recovery and late survival/nonsurvival groups on day 1 (data not shown). The mean tidal volumes used were low (6.46 and 6.94 mL/kg of predicted body weight), with plateau pressures kept to less than 30 cm H₂O and pH and PaCO₂ levels within normal limits. On day 7, the late survival and nonsurvival groups had higher mean minute ventilation (P = .02) coupled with higher mean PaCO₂ and higher mean plateau pressures (P = .03), indicative of worsening ARDS in that group. PEEP use was generally high on day 1 (>12 cm H₂O) with a trend toward decreasing requirements by day 7 in the intermediate recovery group, consistent with earlier recovery in that group.

We noted a low incidence of dynamic hyperinflation and auto-PEEP in SARS-related ARDS. In 9 patients undergoing ventilation in whom auto-PEEP was measured, this ranged from 1 to 5 cm H₂O. Two patients received inhaled nitric oxide, up to 30 ppm, as rescue treatment for intractable hypoxia. High-frequency oscillatory ventilation was attempted in 1 patient as a rescue mode after progressive deterioration. These 3 patients did not survive.

Regular lung recruitment maneuvers were necessary as SARS-related ARDS was characterized by hyposecretory airways, probably predisposing them to alveolar derecruitment and desaturation. Twenty-eight of 39 patients who underwent ventilation required muscle paralysis. The longest duration of paralysis was 24 days.

Twelve patients developed positive blood cultures and 24 had positive lung aspirate cultures. Eight patients developed pneumothorax and 1 developed pneumomediastinum. Nine patients developed acute renal failure and required continuous renal replacement therapy (continuous veno-veno hemofiltration or hemodiafiltration). Four patients developed ischemic strokes. There were 11 episodes of deep vein thrombosis and 7 episodes of proven or suspected pulmonary embolism in the cohort. Four patients had both deep vein thrombosis and pulmonary embolism. Two patients received streptokinase for massive pulmonary embolism. There were improvements noted in hemodynamic parameters and pulmonary shunting but one of these patients died after 24 hours and the other died subsequently from progression of ARDS.

In our cohort of critically ill patients with SARS and ALI/ARDS, 28-day mortality was 37% and overall ICU mortality was 52.2% after 13 weeks.

We found that critically ill SARS patients with ARDS experienced a potentially fatal but in some cases self-limiting clinical course. A third of patients recovered early, generally within 14 days of illness. However, the majority of patients underwent a protracted course of ARDS, accompanied by complications of severe hypoxia, multiorgan failure, thromboembolic complications, and sepsis. Mortality in this group was high despite maximal supportive therapy. This pattern is consistent with that reported in the literature, in which mortality in late ARDS is related primarily to the degree of other organ dysfunctions.^{12 - 14}

We modeled our ventilator strategy after the recommendations of the National Institutes of Health ARDS Network,¹⁵ targeting low tidal volumes and plateau pressures of less than 30 cm H₂O and titrating PEEP according to FIO₂. ARDS in SARS was generally severe, with poor compliance and requirement for high PEEP to maintain adequate oxygenation. In patients with progressive disease, we found it increasingly difficult to maintain adequate lung recruitment and had to compromise plateau pressures, exceeding the limit of 30 cm H₂O to keep tidal volumes at 6 mL/kg of predicted body weight. The mean PEEP levels used in our series were higher than those reported by others (8-10 cm H₂O) using similar low-tidal-volume ventilation strategies.^{15 - 17} This may indicate greater severity of ARDS encountered in SARS or may merely reflect local preference for higher PEEP over higher FIO_2.Although viral infections such as respiratory syncytial virus and rhinovirus have been reported to be associated with asthma exacerbations,¹⁸ bronchospasm, dynamic hyperinflation, and auto-PEEP were not common findings in SARS.

We suggest, like others,^{7 ,19} that progression to a severe and protracted course of ARDS is most likely related to patients' hyperimmune response to SARS. This is similar to ARDS associated with sepsis or the systemic inflammatory response syndrome. Our impressions were supported by postmortem pathologic findings of diffuse alveolar damage and pulmonary fibroproliferation, similar to findings from Hong Kong.²⁰

Previous studies of ARDS patients treated with high-dose methylprednisolone did not show lowering of serum complement levels or improvement in outcome.^{21 - 22} The benefit of using steroid therapy (alone) in ARDS thus remains controversial. Immunomodulation also requires exclusion of bacterial suprainfection. This may be difficult in SARS because of routine use of prophylactic antibiotics and where bronchoalveolar lavage or open-circuit plugged telescoping catheter sampling is not routinely performed. Among the subgroup of patients in our study who received the combined immunoglobulin and methylprednisolone regimen daily for 3 days, an interim analysis of the first 15 patients treated revealed an adjusted hazard ratio for mortality of 0.41 (95% CI, 0.14-1.23; P = .11) in the treated group compared with those who did not receive treatment (n = 30). There was also a trend toward earlier recovery in the treated group. However, conclusions about the efficacy of this therapy await a final analysis of the data.

Differences in the virulence of different SARS Co-V strains and viral load may play a role in determining patients more likely to develop a severe ARDS course. This differentiation awaits more precise and quantitative diagnostic tools. Clinically, poor baseline PaO₂/FIO₂ ratios and higher APACHE II scores were the only predictors of late survival or death. This is consistent with more severe disease presentation. We are also studying cytokine levels for potential value as predictors. Attempts to identify patients who may progress to a severe course of ARDS, and to target such patients for early aggressive intervention, are supported in a recent review and in an early-outcome study on ARDS.^{23 - 24}

Although we have presented ICU management of ARDS in SARS as a single retrospective case series, management of this disease had not been standardized from the beginning but evolved rapidly with experience and an improved understanding of its characteristics. This evolution also included an initial period of profound fear and emotional distress experienced by health care workers working with potentially fatal nosocomial transmission.²⁵ However, after implementation of specific, rigorous protective measures, there were no known nosocomial transmission of SARS to the 211 health care workers in our ICU for the period of March 17 to June 9, 2003. After the initial 2 weeks of operation, when powered air-purifying respirator units became available, their use was mandated for procedures in the ICU involving actual or potential ventilator circuit disconnections or "splash" dissemination of body fluids. These procedures included manual lung recruitment, ventilator tubing changes, thoracocentesis, tracheostomies, and interventional radiological procedures. Neither bronchoscopic procedures nor bronchoalveolar lavage was carried out in the 46 patients. In our experience, ensuring the safety of health care workers and providing timely psychological peer support were critical in maintaining staff morale and to secure the delivery of appropriate care. Although no health care worker became ill with SARS in our ICU, we cannot rule out the possibility of subclinical infections.

In this series of critically ill patients with SARS and ARDS, the treatment of patients who progressed to severe and protracted ARDS was challenging and associated with high mortality.