To Örebro University

BACKGROUND: Intensive care unit (ICU) admissions among older patients are increasing, posing significant challenges to already strained healthcare systems. Decision-making around ICU admission in times of limited resources may provide important knowledge about difficult prioritisations, particularly for older patients. Thus, the aim was to investigate ICU-admission decisions for older patients with COVID-19.

METHODS: A mixed-methods approach. We audio-recorded ten COVID Rounds and nine Moral Case Deliberations for 34 patients across three Swedish hospitals during the pandemic, and collected data from medical records of 329 patients aged ≥ 65 diagnosed with COVID-19. Data were analysed using qualitative content analysis and multiple regression.

RESULTS: Among 239 patients with documented decisions in medical records, 56% included explicit justifications. The justifications included considerations of medical benefit (not-too- ill/too-ill), general condition (good/frail), age (not-too-old/high age), professional duty (benefit of the doubt/do no harm) and "worth giving it a go" (grit and will to live/lack of will and coping). A minority (31%) of decisions favoured ICU admission. Justifications supporting admission were predominantly drawn from discussions in COVID Rounds and MCDs, where patient grit was a recurring argument. In regression analyses, age ≥ 80 years was the only factor significantly associated with not being admitted to ICU and having a documented justification. Few decisions explicitly referred to COVID-19-specific factors.

CONCLUSION: Our findings reflect patterns similar to pre-pandemic ICU decision-making, suggesting continuity in clinical reasoning. However, the limited documentation of justifications-especially in favour of admission-warrants attention, emphasising the need for clearer reasoning in medical records. Our findings identify chronological age as a key triage factor, normatively supported by the ethical principles of non-maleficence, justice, and Sweden's legal priority-setting principle of Needs and Solidarity-which emphasises care only when benefit is likely. We therefore advocate for national (and potentially international) guidance on triage systems that support a palliative approach for very old patients. While grit may be relevant to ICU admission due to its link to potential benefit, its use raises ethical concerns, particularly in relation to Needs and Solidarity and Human Dignity. We recommend its cautious application pending further research.

BACKGROUND: Thoracic epidural analgesia (TEA) has been suggested to improve survival after curative surgery for colorectal cancer compared with systemic opioid analgesia. The evidence, exclusively based on retrospective studies, is contradictory.

METHODS: In this prospective, multicentre study, patients scheduled for elective colorectal cancer surgery between June 2011 and May 2017 were randomised to TEA or patient-controlled i.v. analgesia (PCA) with morphine. The primary endpoint was disease-free survival at 5 yr after surgery. Secondary outcomes were postoperative pain, complications, length of stay (LOS) at the hospital, and first return to intended oncologic therapy (RIOT).

RESULTS: We enrolled 221 (110 TEA and 111 PCA) patients in the study, and 180 (89 TEA and 91 PCA) were included in the primary outcome. Disease-free survival at 5 yr was 76% in the TEA group and 69% in the PCA group; unadjusted hazard ratio (HR): 1.31 (95% confidence interval [CI]: 0.74-2.32), P=0.35; adjusted HR: 1.19 (95% CI: 0.61-2.31), P=0.61. Patients in the TEA group had significantly better pain relief during the first 24 h, but not thereafter, in open and minimally invasive procedures. There were no differences in postoperative complications, LOS, or RIOT between the groups.

CONCLUSIONS: There was no significant difference between the TEA and PCA groups in disease-free survival at 5 yr in patients undergoing surgery for colorectal cancer. Other than a reduction in postoperative pain during the first 24 h after surgery, no other differences were found between TEA compared with i.v. PCA with morphine.

Background: Epidural analgesia (EA) has been the standard of care after major abdominal surgery for many years. This study aimed to correlate EA with postoperative complications, short- and long-term mortality in patients with and without EA after open surgery (OS) and minimally invasive surgery (MIS) for colorectal cancer.

Methods: Patient, clinical and outcome data were obtained from the Swedish Colorectal Cancer Registry and the Swedish Perioperative Registry. All adult patients diagnosed with colorectal cancer without metastases who underwent elective curative MIS or OS for colorectal cancer between January 2016 and December 2018 and who had data recorded in both registries, were included in the study. Data were analyzed for OS and MIS procedures separately. A Poisson regression model was used to investigate the association between EA and the outcomes of interest.

Results: Five thousand seven hundred sixty-two patients were included in the study, 2712 in the MIS and 3050 patients in the OS group. After adjusting for patient specific and clinically relevant variables in the regression model, no statistically significant difference in risk for complications; 30-day, 90-day, and up to 3-year mortality following either MIS or OS could be detected between the EA+ and EA-cohorts.

Conclusions: In this large study cohort, EA as part of the comprehensive care provided was not associated with a reduction in postoperative complications risk or improved 30-day, 90-day, or 3-year survival after MIS or OS for colorectal cancer.

Epidural analgesia (EA) with local anaesthetics and opioids is used for pain management after colorectal cancer (CRC) surgery. In recent years, a possible beneficial effect of EA on cancer recurrence and survival after surgery has been proposed. The aim of this thesis was to study the effects of EA on short- and long-term postoperative outcomes after CRC surgery with curative intent.

Study I, an in vitro study, investigated the effects of two different local anaesthetics, lidocaine and ropivacaine, on cell viability and cell proliferation in colon cancer cell lines SW480 and SW620. Neither lidocaine nor ropivacaine reduced cell viability or proliferation at systemically, by epidural administration achievable concentrations.

In study II, the effect of EA on the systemic level of different cytokines as a marker of inflammation was studied. Except for a reduced level of the anti-inflammatory cytokine IL-10, no other significant effects of EA on the systemic cytokine levels at two time points postoperatively could be shown, when compared to patients receiving intravenous morphine.

Study III was an epidemiological study, examining the question if EA affects postoperative complications and mortality after surgery using data from the Swedish Colorectal Cancer Registry and the Swedish Perioperative Registry. No association between EA and a reduction in postoperative complications or mortality could be established.

Study IV, a randomised, controlled trial, the effects of EA on diseasefree survival (DFS), postoperative complications and pain after surgery were compared to patient-controlled intravenous analgesia with morphine. Apart from superior pain relief during the first postoperative day, no significant effects of EA on the occurrence of postoperative complications, length of hospital stay or DFS were found.

Regional anesthesia may prolong survival following surgery for different types of cancers. The mechanisms behind this are unclear but direct effects on cancer cells by local anesthetics (LA) have been suggested. The aim of this study was to investigate if lidocaine or ropivacaine have a dose-dependent effect on the cell viability and proliferation of a primary and a secondary colon carcinoma cell line in vitro. The colon cancer cell lines SW480 derived from primary tumor and SW620 from a metastatic site in the same patient were exposed to increasing concentrations of lidocaine and ropivacaine (5-1,000 mu M). Cell viability was measured using CellTiter-Blue((R)) and cell proliferation by PKH67 after exposure for up to 72 h. Cell viability was significantly reduced by ropivacaine at the highest concentration (1,000 mu M) after 48 and 72 h in the cell line SW480 and at 72 h in SW620. Exposure to lidocaine did not show any significant reduction in cell viability. Notably, low concentrations of both lidocaine and ropivacaine significantly increased cell viability after 48 and 72 h in SW620. Cell proliferation was significantly reduced by 1,000 mu M lidocaine in SW480 and by 1,000 mu M ropivacaine in SW620. In summary, both lidocaine and ropivacaine showed an anti-proliferative effect in the colon cancer cell lines at high concentrations and after prolonged exposure to LA in vitro. Our findings also indicate that lower concentrations promote cell viability in the metastatic cell line.

The question of whether anesthetic, analgesic or other perioperative intervention during cancer resection surgery might influence long-term oncologic outcomes has generated much attention over the past 13 years. A wealth of experimental and observational clinical data have been published, but the results of prospective, randomized clinical trials are awaited. The European Union supports a pan-European network of researchers, clinicians and industry partners engaged in this question (COST Action 15204: Euro-Periscope). In this narrative review, members of the Euro-Periscope network briefly summarize the current state of evidence pertaining to the potential effects of the most commonly deployed anesthetic and analgesic techniques and other non-surgical interventions during cancer resection surgery on tumor recurrence or metastasis.

Background: Cancer cells change phenotypes and properties when evolving from primary tumor cells to metastatic cells. These changes might affect the response to local anesthetics (LA). The aim of this study was to investigate if lidocaine or ropivacaine have a dose- dependent effect on cell viability and proliferation of a primary and a secondary colon carcinoma cell line in vitro.

Methods: The colon cancer cell lines SW 480, derived from primary tumor and SW620 from metastatic tumor in the same patient, were exposed to increasing log-concentrations of lidocaine and ropivacaine. Cell viability was measured using CellTiter Blue, and cell proliferation by PKH67, after exposure for up to 72 h.

Results: Cell viability was not affected after 24 h of exposure. However, the metastatic cell line SW620 showed a significant increase in cell viability at low concentrati ons after 48 and 72 h. Exposure to the higher, but clinically relevant, concentrations of both LA resulted in decreased cell viability in both cell lines. These higher concentrations also showed an inhibitory effect on cell proliferation after 72 h, which was more pronounced for ropivacaine.

Conclusions: Low concentrations of lidocaine and ropivacaine, as achieved in plasma by epidural infusion of LA, do not have direct antiproliferative effects on these colon cancer cell lines in vitro. Higher concentrations of LA, as during continuous local infiltration into tissues over 72 h, inhibit proliferation of both cancer cell lines. The increase in cell viability seen in SW620 should be investigated and underlying mechanisms further elucidated in future studies.

AIM: Epidural analgesia reduces the surgical stress response. However, its effect on pro- and anti-inflammatory cytokines in the genesis of inflammation following major abdominal surgery remains unclear. Our main objective was to elucidate whether perioperative epidural analgesia prevents the inflammatory response following colorectal cancer surgery.

METHODS: 96 patients scheduled for open or laparoscopic surgery were randomized to epidural analgesia (group E) or patient controlled intravenous analgesia (group P). Surgery and anaesthesia were standardized in both groups. Plasma cortisol, insulin and serum cytokines (IL-1β,IL-4,IL-5,IL-6,IL-8,IL-10,IL-12p70,IL-13,TNFα,IFNγ,GM-CSF,PGE2 and VEGF) were measured preoperatively (T0), 1-6 hours postoperatively (T1) and 3-5 days postoperatively (T2). Mixed model analysis was used, after logarithmic transformation when appropriate, for analyses of cytokines and stress markers.

RESULTS: There were no significant differences in any serum cytokine concentration between groups P and E at any time point except in IL-10 which was 87% higher in group P (median and range 4.1 (2.3-9.2) pg/ml,) compared to group E (2.6 (1.3-4.7) pg/ml) (p=0.002) at T1. There was no difference in plasma cortisol and insulin between the groups at any time point after surgery. Significant difference in median serum cytokine concentration was found between open and laparoscopic surgery with higher levels of IL-6,IL-8 and IL-10 at T1 in patients undergoing open surgery compared to laparoscopic surgery. No difference in serum cytokine concentration was detected between the groups or between the surgical technique at T2.

CONCLUSIONS: Open surgery, compared to laparoscopic surgery, has greater impact on these inflammatory mediators than epidural analgesia vs. intravenous analgesia. This article is protected by copyright. All rights reserved.