Clinical features of pulmonary emboli in patients following cytoreductive surgery (peritonectomy) and hyperthermic intraperitoneal chemotherapy (hipec), a single centre experience

Available online at www.sciencedirect.com

ScienceDirect EJSO xx (2015) 1e5

www.ejso.com

Clinical features of pulmonary emboli in patients following cytoreductive surgery (peritonectomy) and hyperthermic intraperitoneal chemotherapy (hipec), a single centre experience V. Vukadinovic a,*, J.D. Chiou a, D.L. Morris a,b a

St George Public Hospital, Gray Street, Kogarah, NSW 2217, Australia b UNSW Department of Surgery, St George Clinical School, Australia Accepted 22 January 2015 Available online - - -

Abstract Background: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) can be complicated by pulmonary emboli (PE). Patients are at high risk due to surgery, underlying malignancy, immobility and indwelling lines. Objectives: This paper aims to identify clinically significant signs and symptoms preceding acute PE in post CRS-HIPEC patients, assess the PE investigative approach in this population and the significance of PE on patient management. Method: 25 cases with a positive and 50 controls with a negative CTPA for PE were isolated from the peritonectomy database at St George Hospital Sydney, January 2006 to July 2013. Vital signs, patient symptoms, adjunct investigation findings and patient outcomes were collected and graphed in Microsoft Excel. P values and 95% confidence intervals were calculated using GraphPad Prism version 6. Results: 25 of 562 (4.4%) CRS-HIPEC patients were diagnosed with acute PE. Raised body temperature was the only statistically significant clinical finding that differentiated cases from controls ( p value 0.02). Arterial blood gas results did not correlate with PE ( p values 0.62; 0.29; 0.55, 0.84). Troponin, ECG and CXR were not routinely conducted. CXR and CTPA findings were similar between cases and controls (Table 4). PE patients required lower supplementary oxygen and escalation of care. Conclusion: Body temperature is the only statistically significant clinical finding observed with PE. We recommend a standardised investigative approach consisting of troponin, ECG and CXR. PE in CRS-HIPEC does not cause significant cardio-respiratory dysfunction, or escalation of care. PE rates are higher than other major surgeries, thus we propose a trial with increased chemical prophylaxis in CRSHIPEC patients. Ó 2015 Elsevier Ltd. All rights reserved.

Keywords: Pulmonary emboli; Symptoms; Signs; Cytoreductive surgery

Introduction Peritonectomy is cytoreductive surgery (CRS) performed to remove malignancy from the peritoneum and pelvicabdominal viscera in combination with hyperthermic intraperitoneal chemotherapy (HIPEC), as per the Sugarbaker method first described in 1995.1 Pulmonary embolism (PE) is a common post surgical complication causing major * Corresponding author. PO Box 342, Coogee, NSW 2034, Australia. Tel.: þ61 0407 061 083. E-mail address: [email protected] (V. Vukadinovic).

morbidity and mortality.2 CRS-HIPEC confers an increased risk of PE due to long operative hours, extensive resection, postoperative immobility and the hypercoagulable state of malignancy. Cancer, chemotherapy and indwelling lines common to peritonectomy patients are independent risk factors for venous thromboembolism (VTE).3 The Wells prediction rule4 places patients in the ‘intermediate risk’ for the aforementioned reasons, and does not distinguish who should be investigated for PE in this population group. PE have variable clinical presentations with signs and symptoms of low sensitivity and specificity.3 To date, there are no studies on the clinical presentation of PE in CRS-HIPEC

http://dx.doi.org/10.1016/j.ejso.2015.01.016 0748-7983/Ó 2015 Elsevier Ltd. All rights reserved. Please cite this article in press as: Vukadinovic V, et al., Clinical features of pulmonary emboli in patients following cytoreductive surgery (peritonectomy) and hyperthermic intraperitoneal chemotherapy (hipec), a single centre experience, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.01.016

2

V. Vukadinovic et al. / EJSO xx (2015) 1e5

surgical patients. Furthermore at our institute there is no standardised diagnostic approach for PE, and the significance of resulting PE on cardio-respiratory reserve has not been assessed. This paper aims to identify the clinically significant signs and symptoms preceding acute PE in post CRS-HIPEC patients, assess the PE investigative approach in this population group and assess the impact of PE on patient management. Methods The peritonectomy database at St George Hospital Sydney was reviewed for CTPA findings from January 1996 to July 2013. PE was defined as a clot seen obstructing a pulmonary vessel on computer tomography pulmonary angiogram (CTPA). CRS-HIPEC patients with a positive CTPA for PE were identified as ‘cases’, while CRS-HIPEC patients with a negative CTPA were identified and randomly selected as ‘controls’, in a 2:1 ratio relative to cases. Patients’ medical record entries at the time of the clinical decision to investigate for acute PE were reviewed by two independent investigators V.V and J.D.C. De-identified data was collected on vital signs, symptoms, catheter lines, antibiotic use and adjunct investigations; arterial blood gases (ABG), troponin T, chest roentgenograms (CXR) and electrocardiograms (ECG). Patient deterioration requiring admission to intensive care units and supplementary oxygen use was recorded. Symptoms for investigation; pleuritic chest pain, dyspnoea at rest, calf swelling or pain, were chosen based on findings from the multicentre medical study PIOPED II which identified these symptoms in up to 98% of patients.5 Palpitations and dizziness at rest were also assessed as patients were often bed-bound and could not experience orthostatic symptoms. Data was tabulated and graphed using Microsoft Excel. P values and 95% confidence intervals were calculated in GraphPad Prism using unpaired t-tests and Fisher’s exact test. All CRS-HIPEC patients operated between January 1996 and July 2013 who had a CTPA investigating for PE were considered for the study. Exclusion criteria included patients under 18yrs (N ¼ 0), pregnant women (N ¼ 0), re-do peritonectomy (N ¼ 127), personal history of PE/DVT (N ¼ 0), and cases where data were lacking (N ¼ 3).

Table 1 Patient characteristics for cases and controls. Patient characteristics

Sex Age

PCI

Tumour

Male Female 20e40 41e60 61e80 0e10 11e20 21e30 31e40 n/a CRC PMP Appendiceal Meso Ovarian Small bowel

Cases

Controls

11 (44%) 14 (56%) 3 (12%) 13 (52%) 9 (36%) 6 (24%) 4 (16%) 5 (20%) 10 (40%) 0 6 (24%) 8 (32%) 8 (32%) 2 (8%) 1 (4%) 0

17 33 5 27 18 10 10 9 20 1 9 16 13 7 3 2

(34%) (66%) (10%) (54%) (36%) (20%) (20%) (18%) (40%) (2%) (18%) (32%) (26%) (14%) (6%) (4%)

in cases and controls (48% vs 22%; 54% vs 32%; 36% vs 34%; 4% vs 14% respectively). However, none of these symptoms were statistically significant for PE ( p values 0.59; 0.58; 0.60, 0.66 Table 2). Calf tenderness or swelling could not be assessed as data was only available for two patients of the seventy-five investigated. Body temperatures of 37.5e38.5 degrees Celsius occurred more frequently in cases than controls and were the only statistically significant clinical sign observed in this study ( p value 0.02, Table 2, Fig. 1). No association between heart rate, systolic or diastolic blood pressure and PE was observed ( p values 0.33; 0.25; 0.39, Table 2). Likewise oxygen saturation levels (Sa02), fraction of inspired oxygen (Fi02) and respiratory rates were similar in cases and controls ( p values 0.15; 0.11; 0.46, Table 2). There was no significant difference in arterial blood gas results between cases and controls for pH, p02, pC02 or alveolarearterial gradient (Aea) at the time of the clinical decision to investigate for PE ( p values 0.62; 0.29; 0.55, 0.84, Table 3). Adjunct investigations of troponin T, ECG and CXR were conducted infrequently in the case group Table 2 Signs and symptoms in cases versus controls. Signs and symptoms

Results Signs

Twenty five CTPA positive cases met inclusion criteria from 562 post-peritonectomy patients (4.4% incidence). Of PEs that occurred, two were ‘massive’ affected a main pulmonary artery, while ‘minor’ PE involved two segmental arteries in nine cases, and one segmental artery in fourteen cases. Controls were randomly selected but were matched for patient characteristics with cases, Table 1. Dyspnoea at restpalpitations, pleuritic chest pain then dizziness were the most common symptoms experienced

Symptoms

Systolic BP Diastolic BP Heart Rate Oxygen saturation FiO2 Respiratory rate Temperature Shortness of breath Pleuritic chest pain Palpitations Dizziness

P Value

95% CI

0.26 0.39 0.33 0.15 0.11 0.46 0.02 0.59 0.60 0.58 0.66

18.64 to 5.019 9.491 to 3.781 17.03 to 5.749 0.6624 to 4.402 1.559 to 14.39 4.979 to 2.263 0.8640 to 0.07202 N/A

Please cite this article in press as: Vukadinovic V, et al., Clinical features of pulmonary emboli in patients following cytoreductive surgery (peritonectomy) and hyperthermic intraperitoneal chemotherapy (hipec), a single centre experience, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.01.016

V. Vukadinovic et al. / EJSO xx (2015) 1e5

3

Discussion

Figure 1. Temperature range in cases and controls.

compared to control ( p values 0.02; 0.04; 0.05, Table 3). Central venous and peripherally inserted central catheters were common to both groups, however no significant difference was found between cases and controls ( p values 0.46; 1.0, Table 3). Antibiotics with pulmonary cover used prior to and at time of CTPA investigation were not statistically significant in this study ( p value 0.11, Table 3). Lung pathology; collapse/consolidation, atelectasis, unilateral and bilateral effusions were present relatively equally in cases and controls, such that no statistical difference in imaging modality findings were seen between the groups per modality (Table 4). Interestingly, CTPA findings of collapse/consolidation differed significantly from CXR in both cases and controls ( p values 0.02, 0.02), and for bilateral effusions in control patients ( p value 0.01, Table 4). Oxygen requirements of Fi02 27e33% were observed in five cases and seven controls. Two PE patients required Fi02 80%, however greater oxygen demands were seen in the control patients; 1 required re-intubation, 4 received non-invasive ventilation, 4 needed Fi02 80e100% and 4 required Fi02 35e50%. One case patient needed escalation of care to the high dependency unit, whereas eight control patients moved to intensive care and two were escalated to coronary care units.

Table 3 Arterial blood gases, investigations and exogenous features in cases versus controls.

Arterial blood gas

Investigation

Exogenous feature

pH p02 pC02 Aea gradient ECG Troponin CXR CVC PICC Antibiotic

P value

95% CI

0.62 0.29 0.55 0.84 0.02 0.04 0.05 0.46 1.00 0.11

0.05247 to 0.03160 11.84 to 38.81 6.011 to 3.271

N/A

N/A

Detection of acute pulmonary emboli continues to be challenging in the post CRS-HIPEC population. Dyspnoea at rest, and pleuritic chest pain were common symptoms in our population group, and reflect observations of the PIOPED II medical trial.5 Unfortunately no symptom differentiated cases from controls ( p values 0.59; 0.58; 0.6; 0.66 Table 2), thus we surmise patient symptoms are not a useful predictor of PE in post CRS-HIPEC patients. Body temperatures between 37.5 and 38.5 degrees Celsius predominated in PE cases and significantly differed from controls ( p values 0.02, Table 2, Fig. 1). Similar temperatures have been reported in 57% of patients with PE, rarely exceeding 38.3  C and normalising over 7 days.6 Interestingly, the use of antibiotics with pulmonary cover for presumed or known infection did not statistically differ between cases and controls ( p value 0.11, Table 3). Thus, raised body temperature in post CRS-HIPEC patients should prompt consideration of PE as a cause. Body temperature was the only clinical sign found statistically significant in PE post CRS-HIPEC patients. Cardiac reserve markers of heart rate, systolic and diastolic blood pressure, did not statistically differ between cases and controls ( p values 0.33; 0.25; 0.39, Table 2). This is likely multi-factorial and dependent upon patients’ premorbid cardiac function, medications, pain control and fluid status. These vital signs parameters may direct patient management but do not aid in the assessment for PE. Sa02, Fi02 and respiratory rates did not significantly differ between cases and controls ( p values 0.15; 0.11; 0.46, Table 2). Similarly arterial blood gas values for pH, p02, pC02 and Aea gradient did not distinguish cases from controls ( p values 0.62; 0.29; 0.55, 0.84 Table 3). Several studies have shown Pa02 and PaC02 levels decrease while the Aea gradient increases following PE.5,7 The discrepancy in our study may be due to respiratory rates of 20 and above affecting both cases and controls (12 and 24 patients respectively), thereby affecting gas results in both. Furthermore only two PEs were ‘massive’ causing main pulmonary artery obstruction. It has been shown that the severity of arterial gas derangement depends on the degree of pulmonary vascular obstruction, such that ‘minor’ PE may not show any derangement in partial pressures.7 An elevated troponin following PE is associated with a high risk of death.8 Furthermore Becattini et al., found right ventricular dysfunction following significant PE is more common in patients with an elevated troponin. While sinus tachycardia is common in minor PE, right ventricular dysfunction on ECG can occur with massive pulmonary emboli.9 Adjunct investigation with troponin, ECG and CXR were not routinely performed at our institute and may be useful to aid in the diagnosis of PE in post CRSHIPEC patients.

Please cite this article in press as: Vukadinovic V, et al., Clinical features of pulmonary emboli in patients following cytoreductive surgery (peritonectomy) and hyperthermic intraperitoneal chemotherapy (hipec), a single centre experience, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.01.016

4

V. Vukadinovic et al. / EJSO xx (2015) 1e5

Table 4 Computer tomography scan versus chest roentenogram in cases and controls. Cases vs control

CT

CXR

Collapse Unilateral Effusion Eilateral effusion Atelectasis Collapse Unilateral Effusion Bilateral effusion Atelectasis

Cases

Controls

CT

CXR

vs CXR

vs CT

p value

p value

p value

p value

0.02 0.67 0.18 0.07

fx1

0.62 1.00 0.09 1.00 0.17 0.48 0.15 0.29

was no delay in discharge due to PE diagnosis, and only one death within three months of peritonectomy occurred however this was not attributable to PE. This study was limited by the study number, subjective and retrospective nature of the investigation. However it remains the largest PE peritonectomy study to date. Conclusion

0.02 1.00 0.01 0.31

CXR abnormalities of atelectasis, pleural effusions and parenchymal abnormalities can accompany an acute PE.10 Likewise ground-glass attenuation, consolidation and wedge-shaped opacities observed on CT.11 While small unilateral pleural effusions are common in PE, moderate-large or bilateral effusions suggest other lung pathology.12 The presence of atelectasis, collapse/consolidation, unilateral and bilateral effusions seen on CXR or CTPA was common to both groups such that imaging findings did not show statistical significance for PE (Table 4). We recommend post CRSHIPEC patients undergo an initial CXR to identify and consider other differentials; pneumonia, empyema, cardiac failure and pneumothorax before performing CTPA. The morbidity and mortality of PE depends upon the degree of vascular obstruction and has significant implications on patient management.11 Mortality rates ranges from 30% for massive PE causing circulatory collapse, to 1% for small PE but rising to 30% if left untreated.13,14 Despite these statistics, in our study only one patient required escalation of care to a high dependency unit, and of the twentyfive patients, two temporarily required increased Fi02 to 80% and five required 30e33%. This suggests that PEs following CRS-HIPEC are minor, can generally be managed in a ward setting and have lower oxygen requirements than other cardio-respiratory complications. We found a PE incidence of 4.4% (25 of 562) post CRSHIPEC, a rate similar to other CRS-HIPEC studies of 4.2%.15 In comparison, isolated major surgeries carry PE incidence rates of; 3.1% cystectomy, 2.4% esophagectomy and 1.0e1.3% for colectomy, gastrectomy, or hepatectomy.16 In consideration of these findings, we propose a clinical trial at a higher chemical prophylaxis dose to assess PE prevention rates in CRS-HIPEC patients. Currently at our institute CRS-HIPEC patients receive heparin 5000units twice daily from the day of surgery til discharge and continue prophylactic enoxaparin 40 mg subcutaneously for a total of six weeks from day of surgery if discharged prior. Patients diagnosed with PE either continued on a total of three months therapeutic daily enoxaparin or warfarin (following heparin infusion loading) depending on patient preference, hepatic and renal function. In our study there

CRS-HIPEC post operative patients are high risk for PE, however body temperature is the only statistically significant clinical finding that correlates with PE in this population. At St George Hospital Sydney, adjunct investigations are not routinely performed. Considering the mortality risk stratification troponin values and ECG findings provide, we recommend their use in a standardised investigative approach for all patients suspected of PE. Furthermore the similarity of CXR and CTPA findings in this study illustrates CXRs are often sufficient in identifying differential diagnoses and should part of the standardised investigative approach for PE. PE in post CRS-HIPEC patients generally do not cause significant cardio-respiratory dysfunction, or escalation of care. However they do occur more frequently than following other major surgery, thus we propose a trial of increased chemical prophylaxis to reduce the complication rate of small PE. Conflict of interest I, Vladana Vukadinovic, on behalf of my colleagues certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.

Acknowledgements No funding was allocated for this research. There were no conflicts of interest in this research.

References 1. Virzı S, L D, Bonomi S, Grassi A. Pseudomyxoma peritonei treated with cytoreductive surgery and hyperthermic chemotherapy: a 7-year single-center experience. Tumori 2012;Sep-Oct;98(5):588–93. 2. Young MD, D AH, Evangelista PT, et al. Predicting pulmonary embolus in orthopedic trauma patients using the wells score. Orthopedics 2013;36(5):e642–7. 3. Torbicki A, P A, Konstantinides S, et al. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J 2008;29:2276–315. 4. Boka K, OD, Harrington A, et al. Pulmonary embolism clinical scoring systems. New York: WebMD; 2014. [cited 2014]. 5. Stein PD, BA, Matta F, et al. Clinical characteristics of patients with acute pulmonary embolism: data from PIOPED II. Am J Med 2007; 1(20):871–9.

Please cite this article in press as: Vukadinovic V, et al., Clinical features of pulmonary emboli in patients following cytoreductive surgery (peritonectomy) and hyperthermic intraperitoneal chemotherapy (hipec), a single centre experience, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.01.016

V. Vukadinovic et al. / EJSO xx (2015) 1e5 6. Nucifora G, BL, Hysko F, et al. Pulmonary embolism and fever. When should right-sided infective endocarditis be considered? Circulation 2007;115:e173–6. 7. Metafratzi ZM, V MP, Maglaras GC, et al. Acute pulmonary embolism: correlation of CT pulmonary artery obstruction index with blood gas values. AJR 2006;186(January):213–9. 8. Becattini C, V MC, Agnelli G. Prognostic value of troponins in acute pulmonary embolism. A meta-analysis. Circulation 2007;116:427–33. 9. M R. Diagnosising pulmonary embolism. Postgrad Med J 2004;80: 309–19. 10. Stein PD, T ML, Hales CA, et al. Clinical, laboratory, roentgenographic, and electrocardiographic findings in patients with acute pulmonary embolism and no pre-exisiting cardiac or pulmonary disease. Chest 1991;100:598–603. 11. Karabulut N, K Y. Relationship of parenchymal and pleural abnormalities with acute pulmonary embolism: CT findings in patients with and without embolism. Diagn Interv Radiol 2008;14:189–96.

5

12. Yap E, A G, Donald J, et al. Pleural effusion in patients with pulmonary embolism. Respirology 2008;13:832–6. 13. Stein PD, H JW. Clinical characteristics of patients with acute pulmonary embolism stratified according to their presenting syndromes. Chest 1997;112(4):974–9. 14. Belohlavek J, D V, Linhart A. Pulmonary embolism part 1; epidemiology, risk factors and risk stratification, pathophysiology, clinical presentation, diagnosis and nonthrombotic pulmonary embolism. Exp Clin Cardiol 2013;18(2):129–38. 15. Verwaal VJ, B S, Boot H, et al. 8-year follow-up of randomized trial: cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy in patients with peritoneal carcinomatosis of colorectal cancer. Ann Surg Oncol 2008;15:2426–32. 16. De Martino RR, G PP, Spangler EL, et al. Variation in thromboembolic complications among patients undergoing commonly performed cancer operations. J Vasc Surg 2012;55(4):1035–40.

Please cite this article in press as: Vukadinovic V, et al., Clinical features of pulmonary emboli in patients following cytoreductive surgery (peritonectomy) and hyperthermic intraperitoneal chemotherapy (hipec), a single centre experience, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.01.016