Impact of a Recent Chemotherapy on the Duration and Intensity of the Norepinephrine Support During Septic Shock
Schnell, David; Besset, Sébastien; Lengliné, Etienne; Maziers, Nicolas; Zafrani, Lara; Reuter, Danielle; Moreau, Anne-Sophie; Canet, Emmanuel; Lemiale, Virginie; Azoulay, Élie
Medical ICU, AP-HP, Hôpital Saint-Louis; and UFR de Médecine, University Paris-7–Paris-Diderot, Paris, France
Received 7 Aug 2012; first review completed 21 Aug 2012; accepted in final form 3 Dec 2012
Address reprint requests to David Schnell, AP-HP, Hôpital Saint-Louis, Réanimation Médicale, 1 Avenue Claude Vellefaux, 75010 Paris, France. E-mail: firstname.lastname@example.org.
The authors did not receive any financial support.
No potential conflicts of interest occur for any of the authors.
Authors’ contribution to the study: study’s mentoring: S.B. and É.A.; study design, data collection and analysis: É.A., S.B., E.L., and D.S.; preparation and critical reviewing of the manuscript: all authors.
ABSTRACT: The objective of this study was to compare the dose and the duration of vasopressor during septic shock in recently treated cancer patients, untreated cancer patients, and patients without malignancy. This was a retrospective single-center study. This study was performed on a 12-bed medical intensive care unit at a teaching hospital. There were 147 patients admitted to the intensive care unit with septic shock: 82 cancer patients recently treated (TCPs), 20 untreated cancer patients (UCPs), and 45 without malignancy (NPs). The primary outcomes were the maximal dose and the duration of vasopressor support. Treated cancer patients were younger (P < 0.0001) and compared with NPs had less comorbidity (P = 0.003), had more frequently an intra-abdominal source of sepsis (P = 0.011), less frequently a gram-positive bacteria (P = 0.036), and a shorter delay for antibiotics (P = 0.029). All patients received norepinephrine with similar maximal doses (0.66 [0.29–1.5] µg · kg−1 · min−1 in TCPs vs. 0.82 [0.41–1.4] µg · kg−1 · min−1 in NPs and 0.79 [0.48–1.7] µg · kg−1 · min−1 in UCPs; P = 0.61) and duration in the three groups (2 [2–4] days in TCPs vs. 3 [2–4] days in NPs and 3 [2–5] days in UCPs; P = 0.13). Mechanical ventilation (P = 0.11), renal replacement therapy (P = 0.19), and 28-day mortality (43% in TCPs vs. 49% in NPs, and 50% in UCPs; P = 0.77) were similar between the three groups. Cancer patients recently treated with chemotherapy had similar needs in vasopressor support during septic shock compared with untreated cancer patients and patients without malignancy. Mortality was not different in cancer and noncancer patients with septic shock.
Over the last decades, the increasing use of intensive curative regimens and the advances in supportive care have improved outcomes and prolonged survival of cancer patients (1–6). Indeed, this survival gain has been made at the price of a higher incidence of infectious and treatment-related complications (7, 8).
Septic shock is a life-threatening condition driven by an ongoing infectious process responsible for an uncontrolled systemic inflammatory response and ultimately resulting in acute circulatory and multiorgan failures (9). It is associated with a high mortality of about 30% to 40% (9, 10). In cancer patients, mortality in the intensive care unit (ICU) may reach 50% (11, 12). However, the respective attributability of underlying malignancy and shock-related severity has never been assessed. Indeed, the disease- and therapy-driven immune deficiencies could explain increased mortality rate (13). During septic shock, observed hypotension can be determined by three distinct mechanisms: hypovolemia, cardiac dysfunction, and vascular dysfunction (14, 15). Cancer- and therapy-related conditions may exacerbate every one of these mechanisms in cancer patients: neutropenic enterocolitis by itself can induce hypovolemia; anthracyclines are a well-known cause of cardiac dysfunction through oxidative stress in cancer patients (16, 17); both chemotherapy and the illness by itself can injure endothelial cells and may promote vascular dysfunction during septic shock (18, 19). These conditions may participate to the higher severity of septic shock in cancer patients. Yet, comparison of cancer and noncancer patients with septic shock has never been reported.
We therefore conducted a retrospective single-center cohort study in patients with septic shock admitted to ICU to evaluate the impact of a recent chemotherapy on the dose and the duration of the vasopressor agents.
PATIENTS AND METHODS
Adult patients admitted from January 2008 to December 2010 with septic shock to our 12-bed closed ICU in a teaching hospital were eligible for the study. Our institutional review board approved the study and waived the need for informed consent because this study was retrospective and observational. Septic shock was defined as an acute circulatory failure (systolic blood pressure <90 mmHg or mean blood pressure <60 mmHg combined to clinical signs of acute circulatory failure [cold extremities, skin mottling, oliguria, mental confusion]) persisting despite adequate fluid resuscitation and requiring vasopressors in patients with a proven (positive microbiological test from a sterile body fluid) or a clinically documented (an obvious infectious foci at physical examination or fever of unknown origin and no other obvious etiology than sepsis for the acute circulatory failure) infection (20). All included patients received vasopressor support. For patients with more than one ICU admission during the study period, only the first episode of septic shock was analyzed.
All data reported in Tables 1, 2, 3 and 4 and in Figures 1 and 2 were extracted from medical charts. Neutropenia was defined as a neutrophil count less than 500 cells/µL within 24 h after ICU admission (21). Neutropenia recovery was defined as correction of neutrophil count in the 72 h following ICU admission. Sequential Organ Failure Assessment was collected at admission (22). Maximal Acute Kidney Injury grade during ICU stay was recovered as previously described (23).
Patients were separated into three groups: (a) NPs: patients with no malignancy; (b) UCPs: untreated cancer patients (patients with newly diagnosed/untreated malignancy [solid tumor or hematological malignancy]); (c) TCPs: treated cancer patients (patients who received intravenous chemotherapy in the month preceding ICU admission). This 1-month cutoff was selected arbitrarily when we designed the study to allow the inclusion of highly immunocompromised patients with or without neutropenia at ICU admission.
All patients are admitted to our ICU based on a policy of broad admission with frequent reassessments of the benefits of intensive care. Only patients with uncontrolled underlying disease or total disability are not admitted. All patients received a comprehensive medical assessment at ICU admission. Microbiological tests and radiographs were performed as deemed appropriate by the attending physician. Antibiotics were administered as soon as possible in hypotensive patients, before ICU admission whenever possible. We collected the time to antibiotic therapy that was defined as the delay from the first signs of circulatory failure to the first administration of an adapted antibiotic therapy. It generally consisted in a combination therapy of a broad-spectrum β-lactam with an aminoglycoside, and vancomycin was administered according to international guidelines (21). During the whole study period, admission and every medical decisions were not influenced by the study. No protocol of goal-directed therapy for the management of the patient with septic shock has been implemented in our ICU. Clinicians are, however, strongly encouraged to promptly administer fluids and vasopressors as needed with early reassessment (during the first hour) of their efficiency based on clinical signs of acute circulatory failure and arterial lactate measurements. All patients received lung-protective ventilation.
Quantitative parameters are reported as median and interquartile range (IQR; 25th–75th percentiles), and qualitative parameters as number and percentage. Categorical variables were compared using the χ2 test. Continuous variables were compared using the Kruskal-Wallis test. P < 0.05 was considered significant. In case of a global statistically significant difference, post hoc pairwise comparisons between each three groups were performed with adjusted P value using Hochberg correction. Statistical analyses were performed using Statview 5.0 (SAS Institute, Cary, NC).
One hundred forty-seven patients were included in the study: 45 NPs (31%), 20 UCPs (14%), and 82 TCPs (55%). The median delay between chemotherapy and ICU admission was 11 (IQR, 7–16) days. In UCPs, 12 patients (60%) had newly diagnosed malignancies, and eight (40%) had relapsing malignancies that had not been treated in the last month. The mean delay since the last chemotherapy course was 6 (IQR, 4–13) months. Study patients characteristics and comparison between the three groups are reported in Table 1.
Of the 147 patients, 91 patients (62%) had a proven infection, without difference between the three groups (67%, 60%, and 60%, respectively, in NPs, UCPs, and TCPs; P = 0.73). Fifty-six (38%) had only clinically documented infection without difference between the three groups (33%, 40%, and 40%, respectively, in NPs, UCPs, and TCPs; P = 0.73). Infectious foci, microbiological documentation, and comparison between the three groups are displayed in Table 2. In TCPs, intra-abdominal sepsis originated from neutropenic enterocolitis in 24 patients (96%) and acute cholecystitis in one patient (4%). Two patients (8%) (one with neutropenic enterocolitis and the patient with cholecystitis) needed urgent abdominal surgery for source control.
The vasopressor used was norepinephrine for all study patients. Figure 1 represents the maximal dose of norepinephrine that was similar in the three groups (0.66 [IQR, 0.29–1.5] µg · kg−1 · min−1 in TCPs vs. 0.82 [IQR, 0.41–1.4] µg · kg−1 · min−1 in NPs, and 0.79 [IQR, 0.48–1.7] µg · kg−1 · min−1 in UCPs; P = 0.61). Also, Figure 2 depicts the duration of the vasopressor support that was comparable in the three groups (2 [IQR, 2–4] days in TCPs vs. 3 [IQR, 2–4] days in NPs and 3 [IQR, 2–5] days in UCPs; P = 0.13). When considering only the 38 patients with no comorbidity (4 in NPs) or no other comorbidity than the underlying malignancy (3 in UCPs and 31 in TCPs), there was no difference in norepinephrine maximal dose (1.1 [IQR, 0.49–2.1] µg · kg−1 · min−1 in TCPs vs. 0.63 [IQR, 0.28–1.7] µg · kg−1 · min−1 in NPs and 0.48 [IQR, 0.43–0.77] µg · kg−1 · min−1 in UCPs; P = 0.41), nor in the duration of this vasopressor support (2 [IQR, 2–4] days in TCPs vs. 2 [IQR, 2–3] days in NPs and 3 [IQR, 2–8] days in UCPs; P = 0.55). Comparison of neutropenic and nonneutropenic patients found no difference in norepinephrine dose (0.72 [IQR, 0.34–1.5] µg · kg−1 · min−1 in neutropenic patients vs. 0.77 [IQR, 0.36–1.5] µg · kg−1 · min−1 in nonneutropenic patients; P = 0.93) nor in its duration (2 [IQR, 2–4] days in neutropenic patients vs. 3 [IQR, 2–4] days in non-neutropenic patients; P = 0.3).
Thirty-seven patients (25%) had refractory shock with similar proportion in the three groups (24%, 25%, and 26%, respectively, in NPs, UCPs, and TCPs; P = 0.99). Fifty patients (34%) had received corticosteroids in the 3 preceding months, all of them belonging to TCPs. Patients with refractory shock were not more prone than the other to have received corticosteroids in the last 3 months (24% vs. 26%; P = 0.97). Norepinephrine doses were similar between patients who had received corticosteroids and those who had not (0.66 [IQR, 0.31–1.5] µg · kg−1 · min−1 vs. 0.77 [IQR, 0.36–1.5] µg · kg−1 · min−1; P = 0.38).
Hemodynamic severity, the need for life-sustaining therapies, and outcomes of study patients are described in Table 3. Twenty-six (32%) of the TCPs were already receiving effective antibiotics at onset of septic shock compared with five (11%) in NPs and three (15%) in UCPs (overall P = 0.02; post hoc analyses showed a significant difference for TCPs compared with NPs; Table 4). Not surprisingly, 14 of the 26 patients already on antibiotics in TCPs had neutropenia compared with none of those in NPs and UCPs. Because this may have decreased the time to antibiotics in TCPs, we performed another analysis in the subgroup of patients with newly introduced antibiotics at the onset of septic shock. In these patients, the times to antibiotics were similar between the three groups (4 [IQR, 2–7] h in TCPs vs. 4 [IQR, 2–9] h in NPs and 4 [IQR, 3–6] h in UCPs; P = 0.81). Twenty-six (87%) of the 30 patients with limitations of active therapeutics had died at day 28. After exclusion of these patients, 39 (33%) of the 117 remaining patients had died at day 28, without difference between the three groups (12 [32%], 8 [46%], and 19 [30%] in NPs, UCPs, and TCPs, respectively; P = 0.54).
Post hoc pairwise comparisons for variables with a significant difference in the overall analysis are displayed in Table 4.
The main result of the present study is that there was no impact of a recent chemotherapy either on the intensity or in the duration of the vasopressor support in a cohort of patients admitted to the ICU with septic shock. Moreover, mortality during septic shock was not different between cancer and noncancer patients and between treated and untreated cancer patients.
Septic shock is a dreaded complication in cancer patients. It is associated with a high mortality rate (11, 12). Of course, disease- and therapy-driven immune deficiencies are probably the main reason for this high fatality rate (13). However, there is some evidence that both cancer and chemotherapy may have consequences enhancing the hemodynamic insults during septic shock or alter the organism’s adaptation during septic shock (16–19). We therefore hypothesize that patients with cancer and especially those recently treated with chemotherapy may need a higher dose of vasopressor for a longer duration during septic shock. Consistently with the results of a recent experimental study (24), our hypothesis was, however, not confirmed in this retrospective cohort of patients admitted to the ICU with septic shock: cancer patients recently treated with chemotherapy needed the same dose and duration of vasopressor support compared with the patients with untreated cancer and those without malignancy. Our hypothesis was based on a higher mortality rate of cancer patients with septic shock compared with those without malignancy. Actually, we did not observe such an increased mortality. This study is the first to compare outcomes in patients with septic shock with and without cancer. Patients had similar severity and percentages of organ dysfunction. The better outcome previously reported of patients with septic shock who recently received chemotherapy probably reflected the selection of these patients (25). Indeed, the preadmission triage of cancer patients who are the most likely to benefit from ICU management led to the admission of a large proportion of young people with no or few comorbidities (26).
Intensive care unit admission of cancer patients has long been considered futile. This reluctance was based on the results of studies in the 1990s showing high mortality rates (27). Both progress in organ support therapies and use of intensive curative regimens led to improved outcome and better survival of cancer patients (1–6, 11, 12). Early ICU admission to prevent further deterioration in organ dysfunctions may also partly explain the better outcome of the patients in the last years (26). Recent studies have shown that satisfactory survival rates can be achieved even in the most severely ill cancer patients (11, 12, 28–30). As a consequence, mentalities have now evolved, and we believe ICU admission must be for every cancer patient with a life span extending curative regimen who is not bedridden (26, 29, 31). To our knowledge, the most striking result of our study is that there was no increased mortality during septic shock in cancer patients, either treated or untreated, compared with those without malignancy. This encouraging finding may have several explanations. First, the preadmission triage of cancer patients who are the most likely to benefit from ICU management led to the admission of a large proportion of young people with no or few comorbidities. In these selected patients, mortality associated with septic shock may be more related to the sepsis itself and its prompt management rather than to cancer-related characteristics. This may at least partly explain the similar mortality rates compared with patients without malignancy. Second, our patients have probably benefited from the recent advances in the ICU management of septic shock made in the last decade (i.e., early antibiotics administration, early goal-directed therapy, hydrocortisone replacement therapy, and lung-protective ventilation) (20). Third, Vandijck et al. (25) reported better outcomes in patients with septic shock receiving chemotherapy, probably because of patient selection. Finally, our center is a highly experienced, high-volume cancer center with highly skilled intensivists and close collaboration between hematologists and intensivists. Undoubtedly, all these factors must have positively affected the outcome of cancer patients with septic shock in the present study. We believe these results confirm that cancer-specific characteristics are no longer determinants in the short-term outcome in ICU (1, 32, 33).
Our study has several limitations. First, it was a retrospective study. However, this design seemed adapted to the main objective that was only to compare vasopressor dose and duration between patients. Second, we cannot exclude that our study lacked power to detect any difference in mortality or norepinephrine dose and duration between groups, given the small sample size and the unequal group sizes. Third, we did not match patients with and without cancer and with and without recent chemotherapy. The fact that both the disease and its treatment may impact the outcome of septic shock rendered such a study design difficult. Also, the study was based on our clinical knowledge that recently treated cancer patients needed higher doses of vasopressors, and we simply tried to demonstrate this point. Fourth, the 1-month delay to define recent chemotherapy was arbitrarily chosen and may be criticized. Fifth, the preadmission triage of cancer patients who are the most likely to benefit from ICU management led to the admission of a large proportion of young people with no or few comorbidities (26). This probably has impacted our results. Finally, our results are obtained in a highly experienced, high-volume cancer center and may not be reproducible in other settings.
In the present study, we did not show an impact of a recent chemotherapy either on the intensity or on the duration of the vasopressor support in a cohort of patients admitted to the ICU with septic shock. Moreover, we did not find increased mortality during septic shock in cancer and noncancer patients and of treated and untreated cancer patients. The selected population and the single-center design in a highly experienced, high-volume cancer center have probably impacted our results. The observed advances in the management of septic shock in cancer patients are encouraging, and further improvement will probably arise from studies investigating specific therapeutics of septic shock in this specific subgroup of patients that is usually excluded from the studies (34, 35).
ICU — intensive care unit
NP — patient with no malignancy
TCP — treated cancer patient
UCP — untreated cancer patient
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Cancer; chemotherapy; hematological malignancy; intensive care unit; septic shock
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