Historically, postinjury multiple organ dysfunction syndrome (MODS) has been the most significant cause of late trauma mortality, causing 51% to 61% of late trauma deaths (1, 2). The incidence of MODS has decreased in the last decade with improvement of trauma care, but its incidence still varies widely and is continuously reported between 13% and 33% (2–8). Further, it still uses significant intensive care unit (ICU) resources and remains an important cause of late deaths (2, 6–8).
To early identify patients at risk for MODS development prediction models have been created. Originally, age, Injury Severity Score (ISS), shock parameters, and packed red blood cells (PRBC) transfusion were independent predictors of MODS (9). A decade later these predictors were tested again and the prediction model was much weaker (2). With improved trauma care also the independent predictors for MODS changed fundamentally; injury severity and shock parameters no longer predicted MODS. Several research groups identified new predictors that are available early after injury (6, 10–12).
Although several studies reported continuously high MODS-related deaths in the last decade (2, 6, 7), we did not observe high MODS-related death rates anymore in our polytrauma population in last few years. Therefore, we conducted a prospective study in polytrauma patients to investigate the current incidence of MODS and its contribution to mortality. We hypothesized that the incidence of MODS was comparable to internationally reported data but that mortality caused by MODS decreased.
The study was conducted at an urban major (Level-1) trauma center. From November 2013 a 3-year prospective population-based cohort study was undertaken including all consecutive trauma patients who were admitted to the ICU of the University Medical Center Utrecht. This major trauma center is the only Level-1 trauma center in the province of Utrecht and covers the central region of the Netherlands with a relatively small, but densely populated service area of 1,500 square kilometers and approximately 1.3 million residents. The service area for neurosurgery facilitates 2.1 million residents. Around 1,300 trauma patients with full activation of a trauma team are annually admitted. Approximately 375 of them are multiply injured (ISS > 15) (13). Patients included in the study were all admitted to ICU either directly from the emergency department (ED) or postoperatively after urgent surgery was performed. Patients <15 years of age, injury caused by asphyxiation, drowning, burns, or isolated traumatic brain injury (TBI) were excluded.
All data were prospectively collected and included patient demographics, ISS, shock, and resuscitation parameters. Admission arterial blood gas analysis, coagulation status, and temperature measurement were performed during resuscitation in ED as part of standard procedures. Arterial blood gas analysis and temperature measurement were repeated on arrival in ICU. Urinary output was measured the first hour after arrival in ICU. Blood product (PRBC, fresh frozen plasma (FFP), and platelets (PLT)) use was recorded in the first 24 h following admission. The Denver Multiple Organ Failure (MOF) scores were registered daily up until 28 days or discharge from ICU. Primary outcome was MODS development. Secondary outcomes were mortality, ICU length of stay (ICU-LOS), ventilator days, in-hospital length of stay (H-LOS), and adult respiratory distress syndrome (ARDS).
MODS was defined by Denver MOF scores of greater than 3, occurring more than 48 h after injury (9). Denver MOF score was chosen over sequential organ failure assessment to avoid difficulties by including the Glasgow Coma Scale (GCS) in the organ failure score. GCS can be challenging to obtain in the trauma patient in ICU, because they are often sedated and intubated for extended periods. This could negatively influence the CNS organ failure score (14).
ARDS was defined by the Berlin criteria; there are three categories of ARDS based on degree of hypoxemia: grade 1 mild (200 mm Hg < PaO2/FIO2 ≤ 300 mm Hg), grade 2 moderate (100 mm Hg < PaO2/FIO2 ≤ 200 mm Hg), and grade 3 severe (PaO2/FIO2 ≤ 100 mm Hg) (15). Only patients with grade 3 severe ARDS were included to ascertain clinical relevant ARDS was studied.
Urgent laparotomy was defined as a laparotomy that was performed in patients who were transported from ED directly (or via computed tomography scan) to the operating room (OR).
The local ethics committee approved this prospective observational study (reference number WAG/mb/16/026664).
Data were analyzed using IBM SPSS Statistics, version 21.0 (Armonk, NY). Graphs were prepared with GraphPad Prism version 6.02 (San Diego, Calif). Results are presented as median and interquartile range. Comparison of variables was done using the Kruksal–Wallis test or the Pearson-Chi-square test in dichotomous data. Variables with univariate statistical significance of less than 0.20 were included in a multivariate logistic regression analysis. These variables were analyzed with backward stepwise selection to identify independent risk factors for MODS and presented as odds ratios and 95% confidence intervals. Statistical significance was defined as P < 0.05.
During the 3-year study period 157 trauma patients who were admitted to ICU were included. Eighty-one (52%) of them were directly admitted to ICU and 76 patients (48%) were transported to the OR for surgery straight from ED and were admitted to ICU postoperatively. Seventy-five percent of the population were male with a median age of 45 (26–61) years. They sustained predominantly blunt injuries (96%) and had a median ISS of 29 (22–37). Even though isolated TBI patients were excluded median AIS head was 3 (0–4). Twenty-one percent of the patients underwent an urgent laparotomy and 42 patients (27%) had a pelvic fracture (Table 1).
Thirty-one patients developed MODS (20%), 20 patients developed ARDS (13%), and 14 patients (9%) developed both MODS and ARDS. Patients stayed on the ventilator for 7 (3–12) days. They spend 8 (4–14) days in ICU and 22 (13.5–34) days in hospital. Twenty-seven patients (17%) died (Table 2). Death in 20 patients was caused by brain injury (74%), four patients died of respiratory failure caused by high cervical spine injury (15%), one patient died of MODS (4%), one patient of hemorrhage (4%), and one patient due to cardiac arrest (4%). Median time to death was 8 (2–16) days after admission. The patient who died of MODS had renal and cardiac organ failure and died on day 6 after injury. None of the other deceased patients died while having multiple organ dysfunction. Seven patients (26%) who later died developed MODS, but only one of them died of MODS. Twenty-four patients who survived (18%) had MODS at some point during admission. There was no statistical significant difference in MODS development between patients who died and patients who survived (P = 0.43).
Patients who died stayed shorter in hospital compared with patients who survived (8 (2–16) days vs. 25 (16–36) days, P < 0.01). This could be expected since the median time to death was 8 days. However, there was no difference between deceased patients and patients who survived regarding ICU length of stay (ICU-LOS; 7 (2–16) days vs. 8 (4–14) days, P = 0.34), ventilator days (7 (2–15) days vs. 7 (3–12) days, P = 0.94), development of MODS (26% vs.18%, P = 0.43), or ARDS (11% vs. 12%, P = 1.0).
Only one of 31 MODS patients (3%) died of MODS. Median highest Denver MOF score was 4 (4–5). Only two patients (6%) had a highest MOF score over 5 (Fig. 1). Nine patients (29%) had MODS more than 3 days and only seven patients (23%) had MODS for more than three consecutive days (Fig. 2). Time to MODS onset was early after trauma; MODS developed 3 (3–4) days from injury (Fig. 3) with a length of 2 (1–3) days. Pulmonary dysfunction was the most common organ dysfunction followed by cardiac dysfunction (Table 3). The onset of individual organ dysfunction was 3 (3–4) days for lung and cardiac dysfunction, 5 (3–5) days for renal dysfunction, and 6.5 (3.3–14.3) days for hepatic dysfunction.
Patients who developed MODS were older than patients who did not develop MODS (56 (34–70) vs. 41 (24–57) years, P = 0.01, Table 1). There was no difference in ED parameters between patients who later developed MODS and patients who did not (Table 4). Patients who later developed MODS had slightly lower oxygen saturations on arrival in ICU (98% (96–99) vs. 99% (98–99), P < 0.01, Table 4). Future MODS patients received more units of PRBC (0.5 (0–3.3) vs. 0 (0–0), P < 0.01), and PLT (0 vs. 0, P < 0.01) in ED, and more PLT < 8 h (0 (0–1) vs. 0 (0–0), P < 0.01) and <24 h (0 (0–3) vs. 0 (0–1), P = 0.02, Table 1). Patients with MODS developed more often ARDS than patients without MODS (45% vs. 5%, P < 0.01, Table 2). They stayed twice as long on the ventilator (12 (7–17) vs. 6 (2–11) days, P < 0.01) and in ICU (13 (11–21) vs. 7 (3–12) days, P < 0.01), but there was no difference in hospital length of stay (26 (18–43) vs. 21 (11–33) days, P = 0.06) or mortality (23% vs.16%, P = 0.43) between both groups (Table 2). In multivariate analysis age, administration of PRBC in ED, <8 h and <24 h, FFP administration in ED, urinary output first hour in ICU, and ARDS were independent predictors of MODS (Table 5). Additionally, a stepwise logistic regression with backward selection (parameters out if P < 0.10) was performed. The backward stepwise logistic regression showed highest Nagelkerke R square (0.584) if all 14 parameters were included.
In this polytrauma population the incidence of MODS was 20% and only one patient died of MODS (3%). None of the other deceased died while having MODS. Even though MODS was still present in this cohort of severely injured polytrauma patients, the severity and length of the multiple organ dysfunction was decreased with low MODS-related mortality.
The overall in-hospital mortality was 17% and predominantly caused by brain injury and/or spinal cord injury (89%). This mortality rate is comparable with reports in the literature; however, the percentage of brain/spinal cord injury-related deaths was higher than most reports about cause of death in polytrauma (1, 16). This could be partly explained by the fact that our level-1 trauma center is the only referral center for brain and spinal cord injury in the state (13).
To clarify low MODS mortality rates one could debate that patients did not die of MODS, because they already expired due to brain injury. However, time to death was 8 days and time to MODS onset was 3 days with a length of 2 days. Further, besides one patient who died of MODS, none of the other deceased died while having MODS. In generally, MODS was treated before patients died, so this does not explain the low MODS mortality rates in our cohort.
Sixteen MODS patients developed grade 3 pulmonary organ dysfunction. By definition these patients had also severe ARDS according to the Berlin criteria (15). In this study 20 patients developed ARDS and 14 developed both ARDS and MODS. This inconsistency in numbers is caused by the differences in definition of pulmonary failure in the Denver MOF score and the Berlin criteria for ARDS; grade 3 pulmonary failure in the Denver MOF score is PaO2/FiO2 ratio < 83 occurring at least 48 h after injury, whereas severe ARDS is defined as PaO2/FiO2 ratio <100. There is no specific time period included in the definition for ARDS according to the Berlin criteria (15). We only included patients who developed severe hypoxemia at least 24 h after injury. This is in line with others studying ARDS (17). Two patients developed severe ARDS on day 2 after admission, but did not develop MODS, since they both had severe ARDS for only 1 day on day 2 after arrival and Denver MOF scores are not calculated until day 3.
The incidence of MODS in our cohort is comparable to most internationally reported studies (2–4, 6, 18, 19). MODS patients still used significantly more resources than non-MODS patients with longer ventilator days, and more days in ICU, although days on the ventilator and in ICU were less than reported in recent literature (6, 7). Further, the severity and duration of MODS also decreased compared with other studies; the length of MODS was 2 days, which was shorter compared with 5 days reported in the literature (2, 6). The median highest MOF score of 4 was also lower than previously reported by others (6). Mortality caused by MODS was virtually nonexistent in our population (3%). This is lower than most published studies (2, 4–7, 9), although low MODS-related mortality rates have been reported in the past as well (3, 18).
The studied population was different compared with most North American studies; our cohort almost exclusively consisted of blunt injuries caused by traffic accidents and falls from height in a relatively small service area with short transport times. In this polytrauma population parameters such as blood pressure and hemoglobin were within normal ranges on arrival in ED. One could argue that these patients were not severely injured at all. This is contradicted by the fact that patients were hypothermic, mildly acidotic, and coagulopathic on arrival. Further, they had an ISS of 29, 27% had a pelvic fracture, 21% needed an urgent laparotomy and they were all admitted to ICU since that was one of the inclusion criteria. The studied cohort included the sickest trauma patients admitted to our major trauma center. This phenomenon in which severely injured patients in smaller service areas with short transport times do not have deranged physiologic parameters on arrival in ED has been described earlier (20). These patients do not have the time to deteriorate, because they are in the hospital before blood pressure, BD and hemoglobin will change distinctly. This might also explain the fact that in this cohort only one patient died of hemorrhagic shock, because shock could be reversed early after trauma. This early reversal of shock however does not prevent the development of MODS since the incidence of MODS in this study was comparable to other studies. Possibly, it does explain the attenuation of the syndrome. It is likely that this attenuation of the multiple organ dysfunction syndrome could also be attributed by a combination of several improvements in trauma care in the last decades such as improved prehospital care, hemostatic resuscitation, damage control surgery, and lung protective ventilation.
Many research groups have identified predictors for MODS (6, 7, 9). Dewar et al. (6) demonstrated in their studied population that previously defined predictors had changed from shock and resuscitation parameters to other parameters such as age and admission platelets. This change in MODS predictors might be related to changes in treatment strategies; however, they are not necessarily causal factors. Predictors are tools for identifying patients at risk for MODS, but do not explain causal mechanisms. This might explain the fact that different research groups have identified different predictors for MODS. Predictors for MODS in this study were age, administration of PRBC in ED, <8 h and <24 h, FFP administration in ED, urinary output first hour in ICU, and ARDS. It is not surprising that ARDS is a predictor for MODS, since severe ARDS is pulmonary organ dysfunction and the origin of organ failure is an inflammatory response caused by ischemia/reperfusion injury. Age has been reported consistently as an independent predictor of MODS in several studies (6, 7, 9). This is an important predictor as the average age of the polytrauma is still increasing (6). In this cohort, the median age of patients developing MODS was 56 years. Further, resuscitation parameters were still important for MODS development. This is in contrast with the study by Dewar et al. (6) but in line with the work by Frohlich et al. (4), Minei et al. (21), and Johnson (22).
One of the limitations of this study is that it was conducted at a single institution in which the clinical treatment and research were conducted by the same clinicians. Another limitation is that patients with isolated head injuries were excluded, because of different physiologic responses to trauma and to be consistent with inclusion/exclusion criteria to other MODS databases (2, 6, 22). In contrast to the Denver MOF database and the Glue Grant database (7), we did include polytrauma patients who had associated head injuries, because these multiply severely injured patients are also prone to MODS and we feel that they should be included in MODS-related morbidity and mortality studies. This has possibly partly guided the use of inotropic agents to maintain blood pressure for brain perfusion and may have influenced MODS scores since inotropic usage is included as cardiac failure in the Denver MOF score. Pulmonary and cardiac dysfunctions were the most common organ failures in this population. Further, lung and cardiac dysfunction developed before renal and hepatic dysfunction. This is in accordance with other studies (3, 7, 19). The patients in this cohort developed rarely renal and frequently pulmonary dysfunction compared with others (23). Kidney dysfunction is a harbinger of adverse outcome (23) and the only patient in our cohort who died of MODS had renal and cardiac dysfunction. Possibly, low kidney dysfunction rates might be an expression of the attenuation of MODS.
In conclusion, in this cohort of severely injured patients the incidence of MODS was comparable to literature reports, but its character has fundamentally changed to an entity that only has an early onset, shorter time period and less severe expression with lower mortality than previously reported. This attenuation of the deadly MODS to a less deleterious disposition could be considered a success of the improvements in trauma and critical care in the last decade.
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