Thrombocytopenia in critically ill surgical patients: a case-control study evaluating attributable mortality and transfusion requirements

Abstract

platelets/l were carefully matched for the severity of underlying disease and other important variables. < 0.04). The estimated attributable transfusion requirement was 25% (95% confidence interval 5.4⌓44.6), and the estimated odds ratio was 1.52 (95 confidence interval 1.05⌓2.20). platelets/l may be a marker for more severe illness and increased risk of death, rather than causative, because a true causal relationship is not established. Thrombocytopenia also leads to an excess of blood product consumption.

Background:

platelets/l were carefully matched for the severity of underlying disease and other important variables.

Results:

< 0.04). The estimated attributable transfusion requirement was 25% (95% confidence interval 5.4⌓44.6), and the estimated odds ratio was 1.52 (95 confidence interval 1.05⌓2.20).

Conclusion:

platelets/l may be a marker for more severe illness and increased risk of death, rather than causative, because a true causal relationship is not established. Thrombocytopenia also leads to an excess of blood product consumption.

Introduction

]. Previous studies have not clearly demonstrated that thrombocytopenia results in increased mortality or increased transfusion requirements, however. Two independent factors have made this important and seemingly straightforward issue difficult to resolve.

was responsible for the poorer prognosis, or whether this higher mortality simply reflected more severe underlying illness.

platelets/l is indicative of platelet transfusion requirement in surgical patients.

One of the commonest methods to evaluate excess mortality is to perform a case-control study in which confounding variables (eg severity of underlying illness, reason for hospitalization, and so forth) are carefully matched in the two populations. To date, however, no case-control studies that have evaluated morbidity and mortality associated with thrombocytopenia in ICU patients have been published in which these important variables have been carefully matched.

platelets/l) increases mortality and blood product requirements in surgical ICU patients.

Study design

We performed a matched cohort study, with a matched control patient without thrombocytopenia for each thrombocytopenic patient (1:1 matching). The study was conducted in the Service de Réanimation Chirurgicale of Tenon University Hospital in Paris. This 8-bed ICU admits patients from all surgical departments and operating rooms of the hospital. The study period ran from January 1, 1996 to December 31, 1996, during which time 298 patients were admitted to the ICU and thrombocytopenic patients were prospectively identified.

Case identification

].

None of patients with a history of platelet disorders, haematologic malignancies or chemotherapy, splenectomy, mechanical heart valves, or patients undergoing cardiopulmonary bypass surgery were included in the patient population.

Matching and selection of control patients

platelets/l) at any time during hospitalization in the ICU. A computer-generated list of eligible control patients was obtained from a database that included 695 patients hospitalized between November, 1995 and March, 1998. Control patients were selected according to the following matching criteria: age (± 5 years), Acute Physiology and Chronic Health Evaluation (APACHE) II score calculated on the first day of ICU admission (± 5 points), primary diagnosis and duration of stay in the ICU (± 5 days). The list of potential control patients was reviewed for the best possible match, giving highest priority to primary diagnosis, duration of stay in the ICU, APACHE II score and age. In the case of multiple acceptable control patients, the one with the date of ICU admission closest to that of the patient was chosen.

Collection of data

].

]. Shock was defined as a decrease in systolic blood pressure (< 90 mmHg) despite adequate vascular filling or the need for vasoactive drugs (dopamine > 5μ g/kg per min, dobutamine, epinephrine, or norepinephrine).

/l; a decrease in prothrombin level activity to less than 50%; a decrease in the level of factor V to less than 50%; and the presence of fibrin degradation products (D-dimers).

Statistical analysis

].

].

< 0.05 was considered statistically significant.

Study population

platelets/l, producing a global incidence rate of 12 episodes of thrombocytopenia per 100 admissions. Thrombocytopenia occurred 3.2 ± 4.8 days (median 2 days, interquartile range 2.5 days, range 0⌓26 days) after ICU admission, for a mean duration of 3.4 ± 2.9 days (median 2 days, interquartile range 4 days, range 1⌓13 days). Thrombocytopenia was related to sepsis in eight patients; sepsis and DIC in 11 patients; bleeding in nine patients; bleeding and DIC in six patients; undetermined shock and DIC in one patient; and haemolysis-elevated liver enzymes-low platelets syndrome with DIC in one patient. Matching was performed for these 36 patients.

< 0.01).

Closeness of matching

). The median APACHE II score of cases was 21 (range 5⌓41, mean 20.8) versus 21 for control patients (range 4⌓37, mean 22.7). The median duration of ICU stay of cases was 5 days (range 1⌓35 days, mean 8.3 days) versus 4 days for control patients (range 1⌓26 days, mean 6.4 days). Thirty-five (97%) of the pairs were matched for primary diagnosis. Overall, matching was successful for 243 out of 288 (84.3%) variables.

). No significant differences in these indices were observed between cases and control patients. This was particularly the case when comparing the four variables that were individually predictive of survival for all patients: mean SAPS II score, mean number of organ-system failures, number of patients with cardiac failure on admission, and number of patients with renal failure on admission. The sex ratio of the two groups was also similar. Finally, the dates of admission of cases and control patients differed by less than 1 year in 27 pairs (75%).

Mortality

). Twenty-seven matched pairs had a concordant outcome (18 lived and nine died). Nine pairs had a discordant outcome, and in eight of these pairs the case died (exact binomial probabilities: 0.037). The estimated attributable mortality was 19.5% (95% CI 3.2⌓35.8), and the estimated odds ratio was 2.7 (95% CI 1.02⌓7.10).

Primary diagnosis in the nine discordant case-control pairs was septic shock in six pairs, acute pancreatitis in one pair, undetermined shock in one pair and haemorrhagic shock in one pair. Causes of mortalities included refractory septic shock in eight cases (47%) and four control patients (40%); multiple organ failure-related sepsis in five cases (29%) and three control patients (30%); uncontrolled bleeding in four cases (24%) and two control patients (20%); and one undetermined shock in one contol (10%).

= 0.008).

).

Blood product consumption

< 0.04). The estimated attributable transfusion requirement was 25% (95% CI 5.4⌓44.6), and the estimated odds ratio was 1.52 (95% CI 1.05⌓2.20).

/l, with a correction of thrombocytopenia a few days later. In eight patients (seven died), only a transient rise of platelet count was noted and thrombocytopenia persisted during the entire ICU stay, despite platelet transfusion. After onset of thrombocytopenia, 4.4 ± 7.2 units of RBCs and 2.5 ± 5.4 units of fresh frozen plasma were transfused. This represents about 50% of the total transfusion requirements.

Discussion

platelets/l in ICU patients is associated with increased mortality, with a relative risk of 2.7 (95%CI 1.02-7.10), and with excess blood product consumption, with a relative risk of 1.52 (95%CI 1.05-2.20).

].

]. These discrepencies may be attributable to differences in the variables and analytical methods used, and could also result from the complex interactions noted in multivariate analysis.

]: age, a severity of disease scoring system (APACHE II), and specific diagnostic categories according to the one main reason for admission. Matching was 84.3% successful for 288 possible variables. To verify the adequacy of matching for severity of underlying illness and primary diagnosis independently, we compared the cases and control patients with respect to another seven potentially confounding variables. No statistically significant differences in these indices were observed between cases and control patients. It may be argued that we matched patients at the time of admission. We realize that this does not reflect the severity of illness at the time of thrombocytopenia, and that matching on variables recorded at the time or just before the diagnosis of thrombocytopenia may have yielded different results. The reliability of systems such as APACHE II, SAPS II and ODIN is not sufficiently defined to study the daily probability of death, however. Moreover, thrombocytopenia is linked to admission characteristics and/or diagnosis, because nearly 60% of patients with thrombocytopenia occurred during the first 2 days after ICU admission.

].

] that indicated that late mortality is essentially associated with the characteristics of the underlying disease.

].

Conclusion

platelets/l is associated with excess mortality that is independent of the patient's age and initial severity of illness, and leads to excess blood product consumption, thus imposing a significant economic burden. Thrombocytopenia appears to be mostly a marker of severity of underlying processes, rather than causally related to death. Thus, the exact relationship between thrombocytopenia and mortality has yet to be elucidated, especially in septic patients. Further studies of the specific role of thrombocytopenia in shock and infections are necessary. Moreover, the risks and benefits of the various strategies for the management of thrombocytopenic ICU patients should be reevaluated in a variety of clinical settings.

Acknowledgments

The authors thank Prof Jean-Yves Fagon for his critical review of the manuscript.

Figures and Tables

Results of matching of cases to control patients using four major criteria

APACHE, Acute Physiology and Chronic Health Evaluation; ICA, intensive care unit.

Matching criteria and clinical characteristics of the study population

] APACHE, Acute Physiology and Chronic Health Evaluation; ODIN, organ dysfunstion and/or infection; ICU, intensive care unit; SAP, Simplified Acute Physiology Score.

Crude mortality, attributable mortality, and odds ratio of death due to severe thrombocytopenia in intensive care unit patients

CI, confidence interval.

Comparison of illness severity scores between cases and control patients on the day of admission and on the day of onset of thrombocytopenia in the nine discordant pairs

].

Crude transfusion requirements, attributable transfusion requirements, and odds ratio of transfusion requirements due to severe thrombocytopenia in intensive care unit patients

CI, confidence interval.

Keywords

• APACHE II score
• bleeding
• case-control study
• intensive care unit
• mortality
• prognosis
• sepsis
• transfusion
• thrombocytopenia
• underlying disease