- Email: [email protected]
Liver cirrhosis but not alcohol abuse is associated with impaired outcome in trauma patients – A retrospective, multicentre study
Injury, Int. J. Care Injured 44 (2013) 661–666
Contents lists available at SciVerse ScienceDirect
Injury journal homepage: www.elsevier.com/locate/injury
Liver cirrhosis but not alcohol abuse is associated with impaired outcome in trauma patients – A retrospective, multicentre study Christoph Nau a,1,*, Sebastian Wutzler a,1, Hagen Do¨rr a, Mark Lehnert a, Rolf Lefering b, Helmut Laurer a, Hendrik Wyen a, Ingo Marzi a The Trauma Registry of DGU2 a b
Department of Trauma, Hand and Reconstructive Surgery, Hospital of the Johann Wolfgang, Goethe-University, Frankfurt, Germany Institute for Research in Operative Medicine (IFOM), University of Witten/Herdecke, Cologne, Germany
A R T I C L E I N F O
A B S T R A C T
Article history: Accepted 15 June 2012
Introduction: Liver cirrhosis has been shown to be associated with impaired outcome in patients who underwent elective surgery. We therefore investigated the impact of alcohol abuse and subsequent liver cirrhosis on outcome in multiple trauma patients. Materials and methods: Using the multi-centre population-based Trauma Registry of the German Society for Trauma Surgery, we retrospectively compared outcome in patients (ISS 9, 18) with pre-existing alcohol abuse and liver cirrhosis with healthy trauma victims in univariate and matched-pair analysis. Means were compared using Student’s t-test and analysis of variance (ANOVA) and categorical variables using x2 (p < 0.05 = significant). Results: Overall 13,527 patients met the inclusion criteria and were, thus, analyzed. 713 (5.3%) patients had a documented alcohol abuse and 91 (0.7%) suffered from liver cirrhosis. Patients abusing alcohol and suffering from cirrhosis differed from controls regarding injury pattern, age and outcome. More specific, liver cirrhotic patients showed significantly higher in-hospital mortality than predicted (35% vs. predicted 19%) and increased single- and multi-organ failure rates. While alcohol abuse increased organ failure rates as well this did not affect in-hospital mortality. Conclusions: Patients suffering from liver cirrhosis presented impaired outcome after multiple injuries. Pre-existing condition such as cirrhosis should be implemented in trauma scores to assess the individual mortality risk profile. ß 2012 Elsevier Ltd. All rights reserved.
Keywords: Multiple trauma Alcohol abuse Liver cirrhosis RISC Trauma Registry
Introduction Liver cirrhosis is the 6th leading cause of death in industrialized countries and closely correlated with alcohol abuse.1 Additionally, approximately every 5th patient admitted to a general hospital has a history of alcohol abuse.2 Alcoholism with subsequent liver cirrhosis therefore has to be considered in the management of multiple trauma patients with regard to more frequent coagulatory or inflammatory complications.
* Corresponding author at: Department of Trauma, Hand and Reconstructive Surgery, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60596 Frankfurt, Germany. Tel.: +49 069 6301 83304; fax: +49 069 6301 6439. E-mail address: [email protected] (C. Nau). 1 These authors contributed equally to this work. 2 Committee on Emergency Medicine, Intensive and Trauma Care (Sektion NIS) of the German Society for Trauma Surgery (DGU), Participating Centers of the Trauma Registry: http://www.traumaregister.de. 0020–1383/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.injury.2012.06.013
Due to the higher risk of increased bleeding, metabolic changes and more frequent infections as well as a higher incidence of renal dysfunction and hepatic encephalopathy patients with a verified liver cirrhosis are at maximized risk for fatal outcome.3 This leads to a longer hospitalization, more frequent local and systemic complications and an increased mortality.4 As reported by Wahlstrom et al. mortality in trauma patients with cirrhosis undergoing abdominal surgery is approximately four times higher when compared to patients without liver cirrhosis independent of the individual Child’s classification.5 Similarly, mortality after laparoscopic cholecystectomy is elevated when liver cirrhosis is present (0.9% vs. 0.01% in healthy controls).6 Tinkoff et al.7 showed that mortality of trauma patients with liver disease confirmed by past medical history, clinical exam, operative findings, biopsy and/ or imaging is 30% higher than in healthy controls. Significant adverse outcomes also occurred in patients who underwent a total knee or hip replacement where 20.7% of the cirrhotic patients showed major complications like hepatic decompensation or fatal outcome in contrast to 3.2% in the control group.8
662
C. Nau et al. / Injury, Int. J. Care Injured 44 (2013) 661–666
Against this background we used the Trauma Registry of the German Society for Trauma Surgery (DGU-TR) to analyse the association of liver cirrhosis and alcohol abuse with in-hospital mortality and single organ failure in multiple trauma patients. Materials and methods Trauma Registry of the German Society for Trauma Surgery (TR-DGU) The Trauma Registry was founded in 1993 and contains anonymous datasets on patients with suspicion of multiple injuries assessed by the first treating physician that are prospectively documented and structured into four consecutive phases: (A) pre-hospital phase: mechanism of injury, initial physiology, first therapy, neurological signs, rescue time; (B) emergency room: physiology, laboratory findings, suspected pattern of injury, therapy, time sequence of diagnostics; (C) intensive care unit: status on admission, organ failure, sepsis, duration of ventilation; (D) final outcome: hospital stay, survival, complete list of injuries including anatomic injury assessment using the injury severity score (ISS),9 operative procedures, and pre-existing medical conditions (PMCs) (current documentation sheets and participating centres available on http://www.traumaregister.de). The criterion for inclusion is the potential need for intensive care upon admission. Patients who died at the scene or are dead upon emergency room arrival are excluded as well as patients with minor injuries and burns. Continuous documentation is performed by responsible physicians until the patient is discharged or died in hospital. In 2002, data collection moved from paper based documentation to a central online system with completeness and plausibility checks. Once a year all participating hospitals receive an extended individual audit report during a one-day workshop with presentation of new scientific results. Since data collection is performed anonymously as part of the legal required activities of hospitals for external quality assessment, no informed consent is required. From 1993 until 2007, data of 35,664 trauma patients from 145 hospitals (128 from Germany, 10 from Austria, 4 from Slovenia and one each from Switzerland, the Netherlands and Belgium) were entered into the registry, 68% of those by onlinedocumentation since 2002.
of liver cirrhosis; (C) patients with liver cirrhosis caused by alcohol abuse; (D) patients with any PMC other than alcohol abuse or liver cirrhosis. Clinical and outcome parameters such as days of hospitalization, stay on the ICU, mortality, organ failure, sepsis, circulation and coagulation parameters and rate of mechanical ventilation and transfusion were compared among groups A–C; (ii) a matched-pair analysis between patients with and without liver cirrhosis was performed (ISS 9). Matching criteria were male/ female, shock-index < 1 or 1, AIS 3 or <3 for the body regions abdomen, thorax, head and extremities and age 10 years. For statistical reasons we allocated two corresponding partners that fulfilled all matching criteria to every patient with liver cirrhosis (ratio control/cirrhosis 2:1). Since this is a retrospective study the exact definition of chronic alcohol abuse has to rely on the assessment done by the first treating physician. Indications were given by alcohol-blood concentration (>0%) and liver enzymes (GOT-35 U/L, GPT-45 U/L, g-GT-55 U/L) which are diagnosed with every admission laboratory and information given by the patient if not intubated or by third parties. In any case of doubt patients were allocated into group A. Cirrhosis was verified by elevated liver enzymes, the liver’s appearance during ultrasound and the CT trauma scan which is also performed by every patient upon admission. Comparisons across the three subgroups were performed with one-way ANOVA or x2 test in case of continuous or categorical variables, respectively. In case of a significant overall test result (p < 0.05), pairwise comparisons of the subgroups were performed, using t-test or x2 test. According to the closed testing principle, no adjustment of p-values would be required here since there are only three subgroups. The analysis of the matched pairs was performed with test statistics for independent groups since the paired versions of the tests are based on the difference between the pairs. In this study we have an uneven matching (2:1) which would complicate the calculation of differences. Using standard test procedures here has marginally less power but would not increase type I error. Matching is thus only considered as a tool to generate comparable subgroups of independent individuals. Analyses were performed with SPSS for Windows Version 15.0 (SPSS, Chicago, IL). Coagulation parameters
Inclusion criteria For overall group comparison all patients with primary admission and ISS 9 were eligible (no age restriction). Patients without data entry on PMCs were excluded. Data were restricted to 24,247 patients who were documented online between 2002 and 2006, as a consistent process of PMC documentation was used during this period. For the matched pair analysis age restriction was 18 years and over.
The following parameters were included: (1) platelet count (mL); (2) partial thromboplastin time (PTT, s); (3) prothrombin time test (Quick’s value, PT). The PT, first introduced by A.J. Quick in 1935, is either expressed in Quick % (100% = normal) or as PT ratio. While the international normalized ratio (INR) was introduced as a coagulation test, the PT in Quick % is preferred by the majority of German physicians/medical institutions, in which a value of <70% is equivalent to an INR > 1.3.11
RISC score
Results
The RISC score was developed using Trauma Registry datasets from 1993 to 2000 to precisely quantify the prognosis of severely injured patients upon admission.10 It consists of nine different prognostic variables, including age, injury severity, and coagulation parameters, and has an area under the ROC curve of 0.907 for in-hospital mortality. This score has been used in previous studies to compare observed outcome with mortality prediction.
Overall 13,525 patients met the inclusion criteria and were analysed. Within this collective 9017 (66.6%) data sets were allocated to ‘‘healthy trauma victims’’ without documented PMC and 3704 (27.4%) patients had a PMC other than alcohol abuse or liver cirrhosis. Additionally, 713 (5.3%) patients had a documented alcohol abuse and 91 (0.7%) patients presented verified liver cirrhosis according to the above mentioned criteria. Basic data of our study population are shown in Table 1.
Statistical analysis Overall group comparison We performed a two-step analysis: (i) patients that met the inclusion criteria were subdivided into four groups: (A) patients without PMC; (B) patients with alcohol abuse without the presence
Patients from groups B (mean age 49.5 years) and C (mean age 58.6 years) were older than healthy trauma victims
C. Nau et al. / Injury, Int. J. Care Injured 44 (2013) 661–666
663
Table 1 Overall comparison of healthy trauma victims, patients with alcohol abuse and patients with liver cirrhosis. Healthy trauma victims (group A)
Parameter Hospital stay
ICU (days) Mechanical ventilation (days) Hospitalization (days)
Alcohol abuse (group B) a
9.8 (12.7) 6.2 (10.9) 27.2 (31.8)
12.6 (14.5) 8.1 (12.7)a 26.4 (27.6)
Liver cirrhosis (group C) 14.1 (19.8)a 8.8 (14.0)a 24.7 (28.4)
Primary admitted patients (n)
7468
549
73
Preclinical phase
sBP 90 mmHg Catecholamines Intubation
1283 (19%) 509 (7%) 4044 (55%)
78 (16%) 35 (7%) 267 (51)a
13 (20%) 10 (14%) 34 (49%)
Emergency room
sBP 90 mmHg (%) Thrombocytes 1000/nl TPZ (Quick’s value, %) PTT (s) Blood transfusion pRBC 10 units No. of pRBC units No. of FFP units
883 (13%) 208 (78) 79 (22) 35 (21) 1887 (26%) 532 (7%) 2.1 (6.0) 1.5 (5.0)
80 (16%) 202 (75)a 85 (22)a 32 (11) 120 (22%) 23 (4%)a 1.4 (3.8)a 1.0 (3.2)a
13 (19%) 149 (96)a,b 69 (28)a,b 41 (17) 21 (29%) 2 (3%) 2.2 (8.4) 1.7 (4.9)
Data are given as mean, SD in brackets or n (%); some data were not available in all cases. a p < 0.05 vs. healthy trauma victims. b p < 0.05 vs. alcohol abuse.
(mean age 36.1 years.) while mean ISS (24.2–26) and percentages of male patients (75–83%) and patients suffering from blunt trauma (93–96%) were comparable. Patients with alcohol abuse more often sustained a severe head injury (63% vs. 50% healthy trauma victims and 53% liver cirrhotic patients) and patients with liver cirrhosis had a higher percentage of severe abdominal injuries (26% vs. 20% healthy trauma victims and 13% with alcohol abuse). Both groups B and C presented fewer injuries of the extremities when compared with group A (28% and 27% vs. 39%). During the preclinical phase similar rates of patients with hypotension (RRsystolic 90 mmHg) were observed for groups A and C (19% and 20%) but patients with liver cirrhosis needed circulatory support by administration of catecholamines more often than other patients (6% in groups A and B vs. 13% in group C). However, even with more extensive use of preclinical catecholamine treatment, group C contained the most hypotensive patients upon arrival in the emergency department. For the documented coagulatory parameters thrombocytes, PT and PTT similar values were observed for groups A and B while patients from group C had
fewer mean thrombocytes and worse overall coagulation as expressed by decreased PT and prolonged PTT. However, no overall trend towards more transfusions (PRBC/FFP) or mass transfusion (>10 units) could be found. Both groups B and C had a significantly longer time on mechanical ventilation and in the ICU while mean time in hospital did not reveal significant differences when compared with healthy trauma victims. Fig. 1 illustrates patients’ outcomes across the three groups. Description of outcome parameters demonstrated higher 24-h and in-hospital mortality rates for patients with liver cirrhosis. Alcohol abuse decreased 24-h mortality in comparison with healthy trauma victims. Rates of patients with single-organ failure, multi-organ failure and sepsis showed a steady increase from group A to group C. Matched-pair analysis For the matched-pair analysis 58 patients with liver cirrhosis could be allocated to 116 matching healthy trauma victims as shown in Table 2. Due to the matching criteria no significant
70 60 Healthy trauma vicms
50
Alcohol abuse %
40
Liver cirr hosis
30 20 10 0 24-hour mortali ty
In-hospital mortali ty
Single-organ fail ure
Mul-organ fail ure
Sepsis
Fig. 1. Comparison of outcome parameters in healthy controls, patients with alcohol abuse and patients with liver cirrhosis (percentages and CI95 are shown).
C. Nau et al. / Injury, Int. J. Care Injured 44 (2013) 661–666
664
Table 2 Matched-pair analysis of healthy trauma victims compared with patients with liver cirrhosis. Healthy trauma victims
Parameter Preclinical phase
sBP 90 mmHg Catecholamines Intubation
Emergency room
sBP 90 mmHg Thrombocytes 1000/nl TPZ (Quick’s value, %) PTT (s) Blood transfusion pRBC 10 units No. of pRBC units No. of FFP units
Hospital stay
ICU (days) Mechanical ventilation (days) Length of hospital stay (days) 24 h mortality Single organ failure Multi-organ failure Sepsis Organ failure respiratory system Organ failure coagulation Organ failure liver Organ failure cardio vascular system (%) Organ failure renal system (%) Organ failure nervous system* (%)
Liver cirrhosis
25 (22%) 7 (6%) 71 (61%)
11 (19%) 7 (12%) 26 (45%)
11 (10%) 182 (71) 81 (21) 33 (20) 29 (25%) 8 (7%) 2.3 (8.3) 1.7 (7.4)
10 (18%) 145 (90) 68 (25) 39 (12) 18 (28%) 2 (3%) 2.4 (9.4) 1.9 (5.4)
10.6 (12.7) 6.9 (10.1) 24.5 (28.1) 13 (11%) 45 (45%) 21 (21%) 6 (6%) 20 (20%) 8 (8%) 0 (0%) 27 0 24
11.8 (17.6) 7.4 (12.6) 19.3 (21.0) 8 (14%) 32 (62%) 27 (52%) 6 (12%) 17 (33%) 10 (19%) 6 (12%) 48 12 33
p value 0.84 0.24 0.052 0.22 0.006 <0.001 0.29 0.86 0.50 0.73 0.07 0.59 0.74 0.22 0.63 0.060 <0.001 0.20 0.11 0.061 <0.001 0.011 <0.001 0.25
Data are given as mean, SD in brackets or n (%), actual p-values given for all parameters; some data were not available in all cases.
differences could be observed for basic descriptors as age (56.9 vs. 56.6), ISS (23.9 vs. 27.1), injury pattern (57% head, 40% thorax, 22% abdominal and 22% extremity injuries), rate of male patients (81%) and rate of blunt trauma (98 vs. 97%). Differences in preclinical administration of catecholamines and hypotension upon admission observed in groups A–C comparison above were similar in the matched-pair setting, but not statistically significant. A trend (p = 0.052) towards a higher rate of preclinical mechanical ventilation in healthy trauma victims could also be shown. Worse coagulatory capabilities due to fewer mean thrombocytes and decreased PT were confirmed for liver cirrhotic patients. However; this finding had no statistically significant effect on transfusion strategies (PRBC/FFP). While 24-h mortality was not significantly affected by liver cirrhosis, in-hospital mortality was significantly increased when compared with healthy trauma victims (35% vs. 19%; p = 0.038). Moreover, patients with liver cirrhosis also showed a significantly higher mortality than predicted by the RISC score (observed mortality 35% vs. predicted mortality 19%) while survival in controls was slightly better than predicted (observed mortality 19% vs. predicted mortality 22%) (Fig. 2). The rate of patients with multi organ failure was more than 2fold increased in liver cirrhotic patients (21% vs. 52%). Although the overall rate of patients with single organ failure only showed a trend (p = 0.06) to increase in cirrhotic patients, three of the six organs systems included in the MOF score were significantly affected by liver cirrhosis expressed by increased rates of organ failure. These were ‘‘Organ failure liver’’, ‘‘Organ failure renal system’’ and ‘‘Organ failure cardio vascular system’’. Surprisingly ‘‘Organ failure coagulation’’ only tended to increase in cirrhotic patients (p = 0.061).
elucidated the association of alcohol abuse as one of the major causes for liver cirrhosis, on impaired outcome in trauma patients. The observed predominance of middle aged men (mean age 56 years, 81% male) agree with the fact that the incidence of alcohol abuse and trauma has already been described to be greater in males.12 Since the mechanism of trauma was mainly blunt with an increased rate of severe head injuries we conclude that patients with alcohol abuse and acute intoxication have reduced capability to intercept falls and prevent injuries due to reduced fine motor skills. The reduced rate of relevant extremity injuries is in accordance with this finding. We can only speculate that some
mortality Observed vs. predicted mor tality SMR 1.82 (1.17 - 2.46)
50
40 SMR 0.86 (0.54 - 1.19)
%
30
20
10
0 Healthy trau Healthy trauma ma victims
Liver cirrhos rhosis is
Discussion In the present study we demonstrated the aggravating effect of liver cirrhosis on complications and outcome in patients suffering from severe trauma using a large population-based registry with over 24,000 data sets. With the analysis of a total of 13,527 eligible patients between 2002 and 2006 we also
RISC prognosis Observed in-hospital mortality (95% CI) Fig. 2. Predicted mortality according to the RISC-score vs. observed in-hospital mortality. SMR, standardized mortality ratio; RISC for liver cirrhosis, 19.0% vs. observed mortality 34.5% (95% CI 22.3–46.7); RISC for healthy trauma victims 22.0% vs. observed mortality 19.0% (95% CI 11.8–26.1).
C. Nau et al. / Injury, Int. J. Care Injured 44 (2013) 661–666
patients might receive false diagnosis of severe head injury due to alcohol-induced reduced consciousness. Similarly, the AISAbdomen might be set 3 in patients with liver cirrhosis, pre-existing ascites and hypotension after traumatic impact under suspicion of abdominal bleeding. Impaired coagulation in cirrhotic patients as reflected by the observed decreased thrombocytes and PT and increased PTT can be easily explained. The liver is the central organ for the synthesis of coagulation factors. The missing statistical effect on transfusion and substitution strategies in our setting might simply be due to the case numbers. Obviously chronic alcohol abuse itself does not compromise coagulation in trauma patients enough to affect the three parameters analysed in this study. Moreover a subsequent cirrhotic destruction of hepatic parenchyma to reduce synthetic capability of clotting factors seems necessary. The aggravating effect of cirrhosis on organ failure and mortality can not only be contributed to worse coagulation but also to inflammatory reactions and interactions of organ systems. We conclude this due to the fact that other single organ failure rates (liver, cardiovascular) were increased as well. This association of liver cirrhosis with mortality independent from coagulation disorders is in accordance with previous studies.13 When further interpreting the pathophysiological mechanism of increased organ failure rates we have to consider that clinical studies like this can only show correlations, but not necessarily causalities. For this reason we have to be careful when drawing conclusions. Anyhow, the increased rate of circulatory support in cirrhotic patients via fluids and catecholamine administration corresponds with data published by Moller et al.14 where cirrhotic patients showed characteristic haemodynamic changes with hyperkinetic systemic circulation, abnormal distribution of blood volume and neurohumoral dysregulation. Their plasma and noncentral blood volumes were increased. Splanchnic vasodilatation is a pacemaker to the low systemic vascular resistance and abnormal volume distribution of blood. Significant pathophysiological mechanisms that contribute to impaired circulatory compensation are reduced beta-adrenergic receptor signal transduction, defective cardiac excitation–contraction coupling and conductance abnormalities. Vasodilators such as nitric oxide and calcitonin gene-related peptide are among the candidates in vasodilatation and increased arterial compliance.15 Reflex-induced, enhanced sympathetic nervous system activity, activation of the reninangiotensin aldosterone system, and elevated circulation vasopressin and endothelin-1 are implicated in haemodynamic counter-regulation in cirrhosis. We already know that the host response to injury leads to an activation of the inflammatory cascade which serves to recruit and activate immune cells to the site of damage. The magnitude of this response is directly proportional to the severity of injury.16 We and others demonstrated an increased level of tumour necrosis factor, interleukin 1 b, TGF-b and IL-6 after haemorrhagic shock.17,18 It even appears that the cytokine response varies according to the damaged tissue. The counterregulatory response leads to an increased production and release of anti-inflammatory mediators such as IL-4, IL-10, IL-13, TGF-a and prostaglandin E2. Alcohol, both chronic and acute, can affect these complex pro and anti-inflammatory pathways in many aspects. The overall mortality in patients abusing alcohol is higher than in healthy controls, however, the 24 h survival rate in patients with acute alcohol abuse without liver cirrhosis was significantly better than in healthy patients. This leads to the hypothesis that acute alcohol abuse may decrease mortality but the chance to develop an organ failure during ICU stay is slightly higher than in healthy controls. As already pointed out by various authors19 we found a significant higher mortality, rate of sepsis and a higher incidence of
665
a multi-organ failure, especially liver, heart and kidney in patients with liver cirrhosis. Adequate hepatic function is necessary in physiological response to surgery or traumatic injury. As mentioned earlier, the liver plays an important role in protein synthesis, detoxification and immune response so that any degree of hepatic insufficiency decreases this vital metabolic function in patients with traumatic injury or surgical intervention. One potential confounder of our results may be the mean age of the groups. Assuming at first that this was caused by a difference in age, e.g. that the acutely intoxicated patients are significantly younger than the patients with liver cirrhosis or the healthy controls, this could be disproved easily by a comparison of age (age average of 49.5 in acute intoxicated patients vs. 58.6 in liver cirrhotic patients and 36.1 years in completely healthy patients). It is rather more likely that the immune modulation is different for acute and chronic alcohol abuse. Many studies16,20 show that short term acute alcohol exposure leads to a suppression of proinflammatory cytokine release. The mechanisms are multifactorial and include a greater production and release of IL-10, an inhibition of p38 and extracellular signal-regulated protein kinase activation. It also modulates the toll-like receptor-4 and CD 14 association with lipid rafts and it inhibits the TNF/TNF-alpha-converting enzyme in the cell membrane of monocytes.16,21 Studies performed by Nelson and Zhang demonstrated that acute alcohol exposure results in decreased neutrophil recruitment a phagocytic function which is a key process in the host response to microbial invasion. The better outcome in the first 24 h after trauma in acutely intoxicated patients is reversed in the further posttraumatic course. This may be in part explained by an influence of alcohol on the activation status of inflammatory cells – as shown by Szabo et al. Peripheral mononuclear cells obtained from alcohol intoxicated patients with exclusion of chronic alcoholics have a blunted pro inflammatory response during the first 4 days in comparison to their counterparts but an exaggerated response late post-injury after 9 days.22 However, these differences on a cellular level certainly do not explain the differences in the clinical course of alcoholic and non-alcoholic patients but may provide a reasonable approach to further study cellular mechanisms that result in an adverse clinical outcome. It could be observed that the mortality of cirrhotic patients was underestimated by the RISC system. Usually, as mentioned earlier mortality rates and odds ratios (ORs) are presented with 95% confidence intervals. A difference of 11% between the predicted lethality of 19% and the actual lethality of 31.1% clarifies that the RISC system is not a reliable predictor for cirrhotic trauma victims. Considering parameters of cirrhosis into the Score system has to be debated. Limitations Although we had access to over 24,000 datasets which represents on of the major strength of register studies our study remains a retrospective analysis of prospectively collected data. Hence limitations include the usual suspects such as a variety of documenting physicians with no clear definition of cirrhosis (e.g. Child’s classification) or alcohol abuse (e.g. acute intoxication, liver enzymes). While all hospitals are advised to document ‘‘alcohol abuse’’ and ‘‘liver cirrhosis’’ only when verified, the decision how to verify these PMCs remains with the individual documenting physician. We have to distinguish ‘‘acute alcohol intoxication’’ from ‘‘chronic alcohol abuse’’ and ‘‘chronic alcohol abuse with subsequent liver cirrhosis’’ in future studies since the impact of these entities on post-traumatic inflammation, organ failure and coagulation disorders is different. Due to the inclusion of a relatively small number of patients with liver cirrhosis and statistical methods that do not maximise power we
C. Nau et al. / Injury, Int. J. Care Injured 44 (2013) 661–666
666
might have overlooked some differences in the matched pair analysis. One could assume that with higher case numbers differences concerning e.g. coagulation parameters and blood product substitution may become more apparent. Conclusion Patients with verified liver cirrhosis are at maximized risk for organ failure and mortality after trauma due to their deficiency of protein synthesis, detoxification, synthesis of adequate coagulation parameters and immune response. In contrast, alcohol abuse did not show any significant statistical association with overall inhospital mortality while it showed significant association with a decrease in the first 24-h mortality. Future studies should focus on further subdividing the effect of liver cirrhosis, e.g. on coagulation disorders or the effect of alcohol abuse on post-traumatic inflammation for improved ICU-treatment. Conflicts of interest None. Funding The Trauma Registry of the German Society for Trauma Surgery (Deutsche Gesellschaft fu¨r Unfallchirurgie, DGU) was partly funded by the Deutsche Forschungsgemeinschaft (DFG) Ne 385/5 and by a grant of Novo Nordisk A/S, Bagsvaerd, Denmark. References 1. Maull KI, Turnage B. Trauma in the cirrhotic patient. Southern Medical Journal 2001;94(2):205–7. 2. Moore RD, et al. Prevalence: detection, and treatment of alcoholism in hospitalized patients. Journal of the American Medical Association 1989;261(3):403–7. 3. Friedman LS. The risk of surgery in patients with liver disease. Hepatology 1999;29(6):1617–23. 4. del Olmo JA, et al. Risk factors for nonhepatic surgery in patients with cirrhosis. World Journal of Surgery 2003;27(6):647–52.
5. Wahlstrom K, et al. Trauma in cirrhotics: survival and hospital sequelae in patients requiring abdominal exploration. American Surgeon 2000;66(11): 1071–6. 6. Yeh CN, Chen MF, Jan YY. Laparoscopic cholecystectomy in 226 cirrhotic patients. Experience of a single center in Taiwan. Surgical Endoscopy 2002;16(11):1583–7. 7. Tinkoff G, et al. Cirrhosis in the trauma victim. Effect on mortality rates. Annals of Surgery 1990;211(2):172–7. 8. Cohen SM, Te HS, Levitsky J. Operative risk of total hip and knee arthroplasty in cirrhotic patients. Journal of Arthroplasty 2005;20(4):460–6. 9. Baker SP, et al. The injury severity score: a method for describing patients with multiple injuries and evaluating emergency care. Journal of Trauma 1974;14(3):187–96. 10. Lefering R. Development and validation of the revised injury severity classification score for severely injured patients. European Journal of Trauma and Emergency Surgery 2009:437–47. 11. Wafaisade A, et al. Acute coagulopathy in isolated blunt traumatic brain injury. Neurocritical Care 2010;12(2):211–9. 12. Chen ZB, et al. Pre-existing cirrhosis is associated with increased mortality of traumatic patients: analysis of cases from a trauma center in east China. World Journal of Gastroenterology 2007;13(42):5654–8. 13. Wutzler S, et al. Association of preexisting medical conditions with in-hospital mortality in multiple-trauma patients. Journal of the American College of Surgeons 2009;209(1):75–81. 14. Moller S, Bendtsen F, Henriksen JH. Splanchnic and systemic hemodynamic derangement in decompensated cirrhosis. Canadian Journal of Gastroenterology 2001;15(2):94–106. 15. Cardenas A, et al. Hemodynamic effects of substance P and its receptor antagonist RP67580 in anesthetized rats with carbon tetrachloride-induced cirrhosis. Scandinavian Journal of Gastroenterology 2008;43(3):328–33. 16. Greiffenstein P, Molina PE. Alcohol-induced alterations on host defense after traumatic injury. Journal of Trauma 2008;64(1):230–40. 17. Relja B, et al. Inhibition of c-Jun N-terminal kinase after hemorrhage but before resuscitation mitigates hepatic damage and inflammatory response in male rats. Shock 2009;32(5):509–16. 18. Ackermann M, et al. Cytokine synthesis in the liver of endotoxin-tolerant and normal rats during hemorrhagic shock. Journal of Endotoxin Research 2001;7(2):105–12. 19. von Heymann C, et al. Posttraumatic immune modulation in chronic alcoholics is associated with multiple organ dysfunction syndrome. Journal of Trauma 2002;52(1):95–103. 20. Zhang P, et al. Acute alcohol intoxication inhibits the lineage- c-kit+ Sca-1+ cell response to Escherichia coli bacteremia. Journal of Immunology 2009;182(3): 1568–76. 21. Nelson S, et al. The effects of acute and chronic alcoholism on tumor necrosis factor and the inflammatory response. Journal of Infectious Diseases 1989;160(3):422–9. 22. Szabo G, et al. Acute ethanol consumption synergizes with trauma to increase monocyte tumor necrosis factor alpha production late postinjury. Journal of Clinical Immunology 1994;14(6):340–52.
Contents lists available at SciVerse ScienceDirect
Injury journal homepage: www.elsevier.com/locate/injury
Liver cirrhosis but not alcohol abuse is associated with impaired outcome in trauma patients – A retrospective, multicentre study Christoph Nau a,1,*, Sebastian Wutzler a,1, Hagen Do¨rr a, Mark Lehnert a, Rolf Lefering b, Helmut Laurer a, Hendrik Wyen a, Ingo Marzi a The Trauma Registry of DGU2 a b
Department of Trauma, Hand and Reconstructive Surgery, Hospital of the Johann Wolfgang, Goethe-University, Frankfurt, Germany Institute for Research in Operative Medicine (IFOM), University of Witten/Herdecke, Cologne, Germany
A R T I C L E I N F O
A B S T R A C T
Article history: Accepted 15 June 2012
Introduction: Liver cirrhosis has been shown to be associated with impaired outcome in patients who underwent elective surgery. We therefore investigated the impact of alcohol abuse and subsequent liver cirrhosis on outcome in multiple trauma patients. Materials and methods: Using the multi-centre population-based Trauma Registry of the German Society for Trauma Surgery, we retrospectively compared outcome in patients (ISS 9, 18) with pre-existing alcohol abuse and liver cirrhosis with healthy trauma victims in univariate and matched-pair analysis. Means were compared using Student’s t-test and analysis of variance (ANOVA) and categorical variables using x2 (p < 0.05 = significant). Results: Overall 13,527 patients met the inclusion criteria and were, thus, analyzed. 713 (5.3%) patients had a documented alcohol abuse and 91 (0.7%) suffered from liver cirrhosis. Patients abusing alcohol and suffering from cirrhosis differed from controls regarding injury pattern, age and outcome. More specific, liver cirrhotic patients showed significantly higher in-hospital mortality than predicted (35% vs. predicted 19%) and increased single- and multi-organ failure rates. While alcohol abuse increased organ failure rates as well this did not affect in-hospital mortality. Conclusions: Patients suffering from liver cirrhosis presented impaired outcome after multiple injuries. Pre-existing condition such as cirrhosis should be implemented in trauma scores to assess the individual mortality risk profile. ß 2012 Elsevier Ltd. All rights reserved.
Keywords: Multiple trauma Alcohol abuse Liver cirrhosis RISC Trauma Registry
Introduction Liver cirrhosis is the 6th leading cause of death in industrialized countries and closely correlated with alcohol abuse.1 Additionally, approximately every 5th patient admitted to a general hospital has a history of alcohol abuse.2 Alcoholism with subsequent liver cirrhosis therefore has to be considered in the management of multiple trauma patients with regard to more frequent coagulatory or inflammatory complications.
* Corresponding author at: Department of Trauma, Hand and Reconstructive Surgery, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60596 Frankfurt, Germany. Tel.: +49 069 6301 83304; fax: +49 069 6301 6439. E-mail address: [email protected] (C. Nau). 1 These authors contributed equally to this work. 2 Committee on Emergency Medicine, Intensive and Trauma Care (Sektion NIS) of the German Society for Trauma Surgery (DGU), Participating Centers of the Trauma Registry: http://www.traumaregister.de. 0020–1383/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.injury.2012.06.013
Due to the higher risk of increased bleeding, metabolic changes and more frequent infections as well as a higher incidence of renal dysfunction and hepatic encephalopathy patients with a verified liver cirrhosis are at maximized risk for fatal outcome.3 This leads to a longer hospitalization, more frequent local and systemic complications and an increased mortality.4 As reported by Wahlstrom et al. mortality in trauma patients with cirrhosis undergoing abdominal surgery is approximately four times higher when compared to patients without liver cirrhosis independent of the individual Child’s classification.5 Similarly, mortality after laparoscopic cholecystectomy is elevated when liver cirrhosis is present (0.9% vs. 0.01% in healthy controls).6 Tinkoff et al.7 showed that mortality of trauma patients with liver disease confirmed by past medical history, clinical exam, operative findings, biopsy and/ or imaging is 30% higher than in healthy controls. Significant adverse outcomes also occurred in patients who underwent a total knee or hip replacement where 20.7% of the cirrhotic patients showed major complications like hepatic decompensation or fatal outcome in contrast to 3.2% in the control group.8
662
C. Nau et al. / Injury, Int. J. Care Injured 44 (2013) 661–666
Against this background we used the Trauma Registry of the German Society for Trauma Surgery (DGU-TR) to analyse the association of liver cirrhosis and alcohol abuse with in-hospital mortality and single organ failure in multiple trauma patients. Materials and methods Trauma Registry of the German Society for Trauma Surgery (TR-DGU) The Trauma Registry was founded in 1993 and contains anonymous datasets on patients with suspicion of multiple injuries assessed by the first treating physician that are prospectively documented and structured into four consecutive phases: (A) pre-hospital phase: mechanism of injury, initial physiology, first therapy, neurological signs, rescue time; (B) emergency room: physiology, laboratory findings, suspected pattern of injury, therapy, time sequence of diagnostics; (C) intensive care unit: status on admission, organ failure, sepsis, duration of ventilation; (D) final outcome: hospital stay, survival, complete list of injuries including anatomic injury assessment using the injury severity score (ISS),9 operative procedures, and pre-existing medical conditions (PMCs) (current documentation sheets and participating centres available on http://www.traumaregister.de). The criterion for inclusion is the potential need for intensive care upon admission. Patients who died at the scene or are dead upon emergency room arrival are excluded as well as patients with minor injuries and burns. Continuous documentation is performed by responsible physicians until the patient is discharged or died in hospital. In 2002, data collection moved from paper based documentation to a central online system with completeness and plausibility checks. Once a year all participating hospitals receive an extended individual audit report during a one-day workshop with presentation of new scientific results. Since data collection is performed anonymously as part of the legal required activities of hospitals for external quality assessment, no informed consent is required. From 1993 until 2007, data of 35,664 trauma patients from 145 hospitals (128 from Germany, 10 from Austria, 4 from Slovenia and one each from Switzerland, the Netherlands and Belgium) were entered into the registry, 68% of those by onlinedocumentation since 2002.
of liver cirrhosis; (C) patients with liver cirrhosis caused by alcohol abuse; (D) patients with any PMC other than alcohol abuse or liver cirrhosis. Clinical and outcome parameters such as days of hospitalization, stay on the ICU, mortality, organ failure, sepsis, circulation and coagulation parameters and rate of mechanical ventilation and transfusion were compared among groups A–C; (ii) a matched-pair analysis between patients with and without liver cirrhosis was performed (ISS 9). Matching criteria were male/ female, shock-index < 1 or 1, AIS 3 or <3 for the body regions abdomen, thorax, head and extremities and age 10 years. For statistical reasons we allocated two corresponding partners that fulfilled all matching criteria to every patient with liver cirrhosis (ratio control/cirrhosis 2:1). Since this is a retrospective study the exact definition of chronic alcohol abuse has to rely on the assessment done by the first treating physician. Indications were given by alcohol-blood concentration (>0%) and liver enzymes (GOT-35 U/L, GPT-45 U/L, g-GT-55 U/L) which are diagnosed with every admission laboratory and information given by the patient if not intubated or by third parties. In any case of doubt patients were allocated into group A. Cirrhosis was verified by elevated liver enzymes, the liver’s appearance during ultrasound and the CT trauma scan which is also performed by every patient upon admission. Comparisons across the three subgroups were performed with one-way ANOVA or x2 test in case of continuous or categorical variables, respectively. In case of a significant overall test result (p < 0.05), pairwise comparisons of the subgroups were performed, using t-test or x2 test. According to the closed testing principle, no adjustment of p-values would be required here since there are only three subgroups. The analysis of the matched pairs was performed with test statistics for independent groups since the paired versions of the tests are based on the difference between the pairs. In this study we have an uneven matching (2:1) which would complicate the calculation of differences. Using standard test procedures here has marginally less power but would not increase type I error. Matching is thus only considered as a tool to generate comparable subgroups of independent individuals. Analyses were performed with SPSS for Windows Version 15.0 (SPSS, Chicago, IL). Coagulation parameters
Inclusion criteria For overall group comparison all patients with primary admission and ISS 9 were eligible (no age restriction). Patients without data entry on PMCs were excluded. Data were restricted to 24,247 patients who were documented online between 2002 and 2006, as a consistent process of PMC documentation was used during this period. For the matched pair analysis age restriction was 18 years and over.
The following parameters were included: (1) platelet count (mL); (2) partial thromboplastin time (PTT, s); (3) prothrombin time test (Quick’s value, PT). The PT, first introduced by A.J. Quick in 1935, is either expressed in Quick % (100% = normal) or as PT ratio. While the international normalized ratio (INR) was introduced as a coagulation test, the PT in Quick % is preferred by the majority of German physicians/medical institutions, in which a value of <70% is equivalent to an INR > 1.3.11
RISC score
Results
The RISC score was developed using Trauma Registry datasets from 1993 to 2000 to precisely quantify the prognosis of severely injured patients upon admission.10 It consists of nine different prognostic variables, including age, injury severity, and coagulation parameters, and has an area under the ROC curve of 0.907 for in-hospital mortality. This score has been used in previous studies to compare observed outcome with mortality prediction.
Overall 13,525 patients met the inclusion criteria and were analysed. Within this collective 9017 (66.6%) data sets were allocated to ‘‘healthy trauma victims’’ without documented PMC and 3704 (27.4%) patients had a PMC other than alcohol abuse or liver cirrhosis. Additionally, 713 (5.3%) patients had a documented alcohol abuse and 91 (0.7%) patients presented verified liver cirrhosis according to the above mentioned criteria. Basic data of our study population are shown in Table 1.
Statistical analysis Overall group comparison We performed a two-step analysis: (i) patients that met the inclusion criteria were subdivided into four groups: (A) patients without PMC; (B) patients with alcohol abuse without the presence
Patients from groups B (mean age 49.5 years) and C (mean age 58.6 years) were older than healthy trauma victims
C. Nau et al. / Injury, Int. J. Care Injured 44 (2013) 661–666
663
Table 1 Overall comparison of healthy trauma victims, patients with alcohol abuse and patients with liver cirrhosis. Healthy trauma victims (group A)
Parameter Hospital stay
ICU (days) Mechanical ventilation (days) Hospitalization (days)
Alcohol abuse (group B) a
9.8 (12.7) 6.2 (10.9) 27.2 (31.8)
12.6 (14.5) 8.1 (12.7)a 26.4 (27.6)
Liver cirrhosis (group C) 14.1 (19.8)a 8.8 (14.0)a 24.7 (28.4)
Primary admitted patients (n)
7468
549
73
Preclinical phase
sBP 90 mmHg Catecholamines Intubation
1283 (19%) 509 (7%) 4044 (55%)
78 (16%) 35 (7%) 267 (51)a
13 (20%) 10 (14%) 34 (49%)
Emergency room
sBP 90 mmHg (%) Thrombocytes 1000/nl TPZ (Quick’s value, %) PTT (s) Blood transfusion pRBC 10 units No. of pRBC units No. of FFP units
883 (13%) 208 (78) 79 (22) 35 (21) 1887 (26%) 532 (7%) 2.1 (6.0) 1.5 (5.0)
80 (16%) 202 (75)a 85 (22)a 32 (11) 120 (22%) 23 (4%)a 1.4 (3.8)a 1.0 (3.2)a
13 (19%) 149 (96)a,b 69 (28)a,b 41 (17) 21 (29%) 2 (3%) 2.2 (8.4) 1.7 (4.9)
Data are given as mean, SD in brackets or n (%); some data were not available in all cases. a p < 0.05 vs. healthy trauma victims. b p < 0.05 vs. alcohol abuse.
(mean age 36.1 years.) while mean ISS (24.2–26) and percentages of male patients (75–83%) and patients suffering from blunt trauma (93–96%) were comparable. Patients with alcohol abuse more often sustained a severe head injury (63% vs. 50% healthy trauma victims and 53% liver cirrhotic patients) and patients with liver cirrhosis had a higher percentage of severe abdominal injuries (26% vs. 20% healthy trauma victims and 13% with alcohol abuse). Both groups B and C presented fewer injuries of the extremities when compared with group A (28% and 27% vs. 39%). During the preclinical phase similar rates of patients with hypotension (RRsystolic 90 mmHg) were observed for groups A and C (19% and 20%) but patients with liver cirrhosis needed circulatory support by administration of catecholamines more often than other patients (6% in groups A and B vs. 13% in group C). However, even with more extensive use of preclinical catecholamine treatment, group C contained the most hypotensive patients upon arrival in the emergency department. For the documented coagulatory parameters thrombocytes, PT and PTT similar values were observed for groups A and B while patients from group C had
fewer mean thrombocytes and worse overall coagulation as expressed by decreased PT and prolonged PTT. However, no overall trend towards more transfusions (PRBC/FFP) or mass transfusion (>10 units) could be found. Both groups B and C had a significantly longer time on mechanical ventilation and in the ICU while mean time in hospital did not reveal significant differences when compared with healthy trauma victims. Fig. 1 illustrates patients’ outcomes across the three groups. Description of outcome parameters demonstrated higher 24-h and in-hospital mortality rates for patients with liver cirrhosis. Alcohol abuse decreased 24-h mortality in comparison with healthy trauma victims. Rates of patients with single-organ failure, multi-organ failure and sepsis showed a steady increase from group A to group C. Matched-pair analysis For the matched-pair analysis 58 patients with liver cirrhosis could be allocated to 116 matching healthy trauma victims as shown in Table 2. Due to the matching criteria no significant
70 60 Healthy trauma vicms
50
Alcohol abuse %
40
Liver cirr hosis
30 20 10 0 24-hour mortali ty
In-hospital mortali ty
Single-organ fail ure
Mul-organ fail ure
Sepsis
Fig. 1. Comparison of outcome parameters in healthy controls, patients with alcohol abuse and patients with liver cirrhosis (percentages and CI95 are shown).
C. Nau et al. / Injury, Int. J. Care Injured 44 (2013) 661–666
664
Table 2 Matched-pair analysis of healthy trauma victims compared with patients with liver cirrhosis. Healthy trauma victims
Parameter Preclinical phase
sBP 90 mmHg Catecholamines Intubation
Emergency room
sBP 90 mmHg Thrombocytes 1000/nl TPZ (Quick’s value, %) PTT (s) Blood transfusion pRBC 10 units No. of pRBC units No. of FFP units
Hospital stay
ICU (days) Mechanical ventilation (days) Length of hospital stay (days) 24 h mortality Single organ failure Multi-organ failure Sepsis Organ failure respiratory system Organ failure coagulation Organ failure liver Organ failure cardio vascular system (%) Organ failure renal system (%) Organ failure nervous system* (%)
Liver cirrhosis
25 (22%) 7 (6%) 71 (61%)
11 (19%) 7 (12%) 26 (45%)
11 (10%) 182 (71) 81 (21) 33 (20) 29 (25%) 8 (7%) 2.3 (8.3) 1.7 (7.4)
10 (18%) 145 (90) 68 (25) 39 (12) 18 (28%) 2 (3%) 2.4 (9.4) 1.9 (5.4)
10.6 (12.7) 6.9 (10.1) 24.5 (28.1) 13 (11%) 45 (45%) 21 (21%) 6 (6%) 20 (20%) 8 (8%) 0 (0%) 27 0 24
11.8 (17.6) 7.4 (12.6) 19.3 (21.0) 8 (14%) 32 (62%) 27 (52%) 6 (12%) 17 (33%) 10 (19%) 6 (12%) 48 12 33
p value 0.84 0.24 0.052 0.22 0.006 <0.001 0.29 0.86 0.50 0.73 0.07 0.59 0.74 0.22 0.63 0.060 <0.001 0.20 0.11 0.061 <0.001 0.011 <0.001 0.25
Data are given as mean, SD in brackets or n (%), actual p-values given for all parameters; some data were not available in all cases.
differences could be observed for basic descriptors as age (56.9 vs. 56.6), ISS (23.9 vs. 27.1), injury pattern (57% head, 40% thorax, 22% abdominal and 22% extremity injuries), rate of male patients (81%) and rate of blunt trauma (98 vs. 97%). Differences in preclinical administration of catecholamines and hypotension upon admission observed in groups A–C comparison above were similar in the matched-pair setting, but not statistically significant. A trend (p = 0.052) towards a higher rate of preclinical mechanical ventilation in healthy trauma victims could also be shown. Worse coagulatory capabilities due to fewer mean thrombocytes and decreased PT were confirmed for liver cirrhotic patients. However; this finding had no statistically significant effect on transfusion strategies (PRBC/FFP). While 24-h mortality was not significantly affected by liver cirrhosis, in-hospital mortality was significantly increased when compared with healthy trauma victims (35% vs. 19%; p = 0.038). Moreover, patients with liver cirrhosis also showed a significantly higher mortality than predicted by the RISC score (observed mortality 35% vs. predicted mortality 19%) while survival in controls was slightly better than predicted (observed mortality 19% vs. predicted mortality 22%) (Fig. 2). The rate of patients with multi organ failure was more than 2fold increased in liver cirrhotic patients (21% vs. 52%). Although the overall rate of patients with single organ failure only showed a trend (p = 0.06) to increase in cirrhotic patients, three of the six organs systems included in the MOF score were significantly affected by liver cirrhosis expressed by increased rates of organ failure. These were ‘‘Organ failure liver’’, ‘‘Organ failure renal system’’ and ‘‘Organ failure cardio vascular system’’. Surprisingly ‘‘Organ failure coagulation’’ only tended to increase in cirrhotic patients (p = 0.061).
elucidated the association of alcohol abuse as one of the major causes for liver cirrhosis, on impaired outcome in trauma patients. The observed predominance of middle aged men (mean age 56 years, 81% male) agree with the fact that the incidence of alcohol abuse and trauma has already been described to be greater in males.12 Since the mechanism of trauma was mainly blunt with an increased rate of severe head injuries we conclude that patients with alcohol abuse and acute intoxication have reduced capability to intercept falls and prevent injuries due to reduced fine motor skills. The reduced rate of relevant extremity injuries is in accordance with this finding. We can only speculate that some
mortality Observed vs. predicted mor tality SMR 1.82 (1.17 - 2.46)
50
40 SMR 0.86 (0.54 - 1.19)
%
30
20
10
0 Healthy trau Healthy trauma ma victims
Liver cirrhos rhosis is
Discussion In the present study we demonstrated the aggravating effect of liver cirrhosis on complications and outcome in patients suffering from severe trauma using a large population-based registry with over 24,000 data sets. With the analysis of a total of 13,527 eligible patients between 2002 and 2006 we also
RISC prognosis Observed in-hospital mortality (95% CI) Fig. 2. Predicted mortality according to the RISC-score vs. observed in-hospital mortality. SMR, standardized mortality ratio; RISC for liver cirrhosis, 19.0% vs. observed mortality 34.5% (95% CI 22.3–46.7); RISC for healthy trauma victims 22.0% vs. observed mortality 19.0% (95% CI 11.8–26.1).
C. Nau et al. / Injury, Int. J. Care Injured 44 (2013) 661–666
patients might receive false diagnosis of severe head injury due to alcohol-induced reduced consciousness. Similarly, the AISAbdomen might be set 3 in patients with liver cirrhosis, pre-existing ascites and hypotension after traumatic impact under suspicion of abdominal bleeding. Impaired coagulation in cirrhotic patients as reflected by the observed decreased thrombocytes and PT and increased PTT can be easily explained. The liver is the central organ for the synthesis of coagulation factors. The missing statistical effect on transfusion and substitution strategies in our setting might simply be due to the case numbers. Obviously chronic alcohol abuse itself does not compromise coagulation in trauma patients enough to affect the three parameters analysed in this study. Moreover a subsequent cirrhotic destruction of hepatic parenchyma to reduce synthetic capability of clotting factors seems necessary. The aggravating effect of cirrhosis on organ failure and mortality can not only be contributed to worse coagulation but also to inflammatory reactions and interactions of organ systems. We conclude this due to the fact that other single organ failure rates (liver, cardiovascular) were increased as well. This association of liver cirrhosis with mortality independent from coagulation disorders is in accordance with previous studies.13 When further interpreting the pathophysiological mechanism of increased organ failure rates we have to consider that clinical studies like this can only show correlations, but not necessarily causalities. For this reason we have to be careful when drawing conclusions. Anyhow, the increased rate of circulatory support in cirrhotic patients via fluids and catecholamine administration corresponds with data published by Moller et al.14 where cirrhotic patients showed characteristic haemodynamic changes with hyperkinetic systemic circulation, abnormal distribution of blood volume and neurohumoral dysregulation. Their plasma and noncentral blood volumes were increased. Splanchnic vasodilatation is a pacemaker to the low systemic vascular resistance and abnormal volume distribution of blood. Significant pathophysiological mechanisms that contribute to impaired circulatory compensation are reduced beta-adrenergic receptor signal transduction, defective cardiac excitation–contraction coupling and conductance abnormalities. Vasodilators such as nitric oxide and calcitonin gene-related peptide are among the candidates in vasodilatation and increased arterial compliance.15 Reflex-induced, enhanced sympathetic nervous system activity, activation of the reninangiotensin aldosterone system, and elevated circulation vasopressin and endothelin-1 are implicated in haemodynamic counter-regulation in cirrhosis. We already know that the host response to injury leads to an activation of the inflammatory cascade which serves to recruit and activate immune cells to the site of damage. The magnitude of this response is directly proportional to the severity of injury.16 We and others demonstrated an increased level of tumour necrosis factor, interleukin 1 b, TGF-b and IL-6 after haemorrhagic shock.17,18 It even appears that the cytokine response varies according to the damaged tissue. The counterregulatory response leads to an increased production and release of anti-inflammatory mediators such as IL-4, IL-10, IL-13, TGF-a and prostaglandin E2. Alcohol, both chronic and acute, can affect these complex pro and anti-inflammatory pathways in many aspects. The overall mortality in patients abusing alcohol is higher than in healthy controls, however, the 24 h survival rate in patients with acute alcohol abuse without liver cirrhosis was significantly better than in healthy patients. This leads to the hypothesis that acute alcohol abuse may decrease mortality but the chance to develop an organ failure during ICU stay is slightly higher than in healthy controls. As already pointed out by various authors19 we found a significant higher mortality, rate of sepsis and a higher incidence of
665
a multi-organ failure, especially liver, heart and kidney in patients with liver cirrhosis. Adequate hepatic function is necessary in physiological response to surgery or traumatic injury. As mentioned earlier, the liver plays an important role in protein synthesis, detoxification and immune response so that any degree of hepatic insufficiency decreases this vital metabolic function in patients with traumatic injury or surgical intervention. One potential confounder of our results may be the mean age of the groups. Assuming at first that this was caused by a difference in age, e.g. that the acutely intoxicated patients are significantly younger than the patients with liver cirrhosis or the healthy controls, this could be disproved easily by a comparison of age (age average of 49.5 in acute intoxicated patients vs. 58.6 in liver cirrhotic patients and 36.1 years in completely healthy patients). It is rather more likely that the immune modulation is different for acute and chronic alcohol abuse. Many studies16,20 show that short term acute alcohol exposure leads to a suppression of proinflammatory cytokine release. The mechanisms are multifactorial and include a greater production and release of IL-10, an inhibition of p38 and extracellular signal-regulated protein kinase activation. It also modulates the toll-like receptor-4 and CD 14 association with lipid rafts and it inhibits the TNF/TNF-alpha-converting enzyme in the cell membrane of monocytes.16,21 Studies performed by Nelson and Zhang demonstrated that acute alcohol exposure results in decreased neutrophil recruitment a phagocytic function which is a key process in the host response to microbial invasion. The better outcome in the first 24 h after trauma in acutely intoxicated patients is reversed in the further posttraumatic course. This may be in part explained by an influence of alcohol on the activation status of inflammatory cells – as shown by Szabo et al. Peripheral mononuclear cells obtained from alcohol intoxicated patients with exclusion of chronic alcoholics have a blunted pro inflammatory response during the first 4 days in comparison to their counterparts but an exaggerated response late post-injury after 9 days.22 However, these differences on a cellular level certainly do not explain the differences in the clinical course of alcoholic and non-alcoholic patients but may provide a reasonable approach to further study cellular mechanisms that result in an adverse clinical outcome. It could be observed that the mortality of cirrhotic patients was underestimated by the RISC system. Usually, as mentioned earlier mortality rates and odds ratios (ORs) are presented with 95% confidence intervals. A difference of 11% between the predicted lethality of 19% and the actual lethality of 31.1% clarifies that the RISC system is not a reliable predictor for cirrhotic trauma victims. Considering parameters of cirrhosis into the Score system has to be debated. Limitations Although we had access to over 24,000 datasets which represents on of the major strength of register studies our study remains a retrospective analysis of prospectively collected data. Hence limitations include the usual suspects such as a variety of documenting physicians with no clear definition of cirrhosis (e.g. Child’s classification) or alcohol abuse (e.g. acute intoxication, liver enzymes). While all hospitals are advised to document ‘‘alcohol abuse’’ and ‘‘liver cirrhosis’’ only when verified, the decision how to verify these PMCs remains with the individual documenting physician. We have to distinguish ‘‘acute alcohol intoxication’’ from ‘‘chronic alcohol abuse’’ and ‘‘chronic alcohol abuse with subsequent liver cirrhosis’’ in future studies since the impact of these entities on post-traumatic inflammation, organ failure and coagulation disorders is different. Due to the inclusion of a relatively small number of patients with liver cirrhosis and statistical methods that do not maximise power we
C. Nau et al. / Injury, Int. J. Care Injured 44 (2013) 661–666
666
might have overlooked some differences in the matched pair analysis. One could assume that with higher case numbers differences concerning e.g. coagulation parameters and blood product substitution may become more apparent. Conclusion Patients with verified liver cirrhosis are at maximized risk for organ failure and mortality after trauma due to their deficiency of protein synthesis, detoxification, synthesis of adequate coagulation parameters and immune response. In contrast, alcohol abuse did not show any significant statistical association with overall inhospital mortality while it showed significant association with a decrease in the first 24-h mortality. Future studies should focus on further subdividing the effect of liver cirrhosis, e.g. on coagulation disorders or the effect of alcohol abuse on post-traumatic inflammation for improved ICU-treatment. Conflicts of interest None. Funding The Trauma Registry of the German Society for Trauma Surgery (Deutsche Gesellschaft fu¨r Unfallchirurgie, DGU) was partly funded by the Deutsche Forschungsgemeinschaft (DFG) Ne 385/5 and by a grant of Novo Nordisk A/S, Bagsvaerd, Denmark. References 1. Maull KI, Turnage B. Trauma in the cirrhotic patient. Southern Medical Journal 2001;94(2):205–7. 2. Moore RD, et al. Prevalence: detection, and treatment of alcoholism in hospitalized patients. Journal of the American Medical Association 1989;261(3):403–7. 3. Friedman LS. The risk of surgery in patients with liver disease. Hepatology 1999;29(6):1617–23. 4. del Olmo JA, et al. Risk factors for nonhepatic surgery in patients with cirrhosis. World Journal of Surgery 2003;27(6):647–52.
5. Wahlstrom K, et al. Trauma in cirrhotics: survival and hospital sequelae in patients requiring abdominal exploration. American Surgeon 2000;66(11): 1071–6. 6. Yeh CN, Chen MF, Jan YY. Laparoscopic cholecystectomy in 226 cirrhotic patients. Experience of a single center in Taiwan. Surgical Endoscopy 2002;16(11):1583–7. 7. Tinkoff G, et al. Cirrhosis in the trauma victim. Effect on mortality rates. Annals of Surgery 1990;211(2):172–7. 8. Cohen SM, Te HS, Levitsky J. Operative risk of total hip and knee arthroplasty in cirrhotic patients. Journal of Arthroplasty 2005;20(4):460–6. 9. Baker SP, et al. The injury severity score: a method for describing patients with multiple injuries and evaluating emergency care. Journal of Trauma 1974;14(3):187–96. 10. Lefering R. Development and validation of the revised injury severity classification score for severely injured patients. European Journal of Trauma and Emergency Surgery 2009:437–47. 11. Wafaisade A, et al. Acute coagulopathy in isolated blunt traumatic brain injury. Neurocritical Care 2010;12(2):211–9. 12. Chen ZB, et al. Pre-existing cirrhosis is associated with increased mortality of traumatic patients: analysis of cases from a trauma center in east China. World Journal of Gastroenterology 2007;13(42):5654–8. 13. Wutzler S, et al. Association of preexisting medical conditions with in-hospital mortality in multiple-trauma patients. Journal of the American College of Surgeons 2009;209(1):75–81. 14. Moller S, Bendtsen F, Henriksen JH. Splanchnic and systemic hemodynamic derangement in decompensated cirrhosis. Canadian Journal of Gastroenterology 2001;15(2):94–106. 15. Cardenas A, et al. Hemodynamic effects of substance P and its receptor antagonist RP67580 in anesthetized rats with carbon tetrachloride-induced cirrhosis. Scandinavian Journal of Gastroenterology 2008;43(3):328–33. 16. Greiffenstein P, Molina PE. Alcohol-induced alterations on host defense after traumatic injury. Journal of Trauma 2008;64(1):230–40. 17. Relja B, et al. Inhibition of c-Jun N-terminal kinase after hemorrhage but before resuscitation mitigates hepatic damage and inflammatory response in male rats. Shock 2009;32(5):509–16. 18. Ackermann M, et al. Cytokine synthesis in the liver of endotoxin-tolerant and normal rats during hemorrhagic shock. Journal of Endotoxin Research 2001;7(2):105–12. 19. von Heymann C, et al. Posttraumatic immune modulation in chronic alcoholics is associated with multiple organ dysfunction syndrome. Journal of Trauma 2002;52(1):95–103. 20. Zhang P, et al. Acute alcohol intoxication inhibits the lineage- c-kit+ Sca-1+ cell response to Escherichia coli bacteremia. Journal of Immunology 2009;182(3): 1568–76. 21. Nelson S, et al. The effects of acute and chronic alcoholism on tumor necrosis factor and the inflammatory response. Journal of Infectious Diseases 1989;160(3):422–9. 22. Szabo G, et al. Acute ethanol consumption synergizes with trauma to increase monocyte tumor necrosis factor alpha production late postinjury. Journal of Clinical Immunology 1994;14(6):340–52.