Elevated Thrombin Generation and Venous Thromboembolism Incidence in Patients Undergoing Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy Compared with Minimally Invasive Rectal Surgery.

INTRODUCTION: Surgical treatment of colorectal cancer carries a risk for venous thromboembolism (VTE). We investigated changes in coagulation and fibrinolysis and the VTE incidence within 30 days in patients undergoing open cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) for peritoneal metastases from colorectal cancer and minimally invasive surgery (MIS) for localized rectal cancer. METHODS: This cohort study included 45 CRS + HIPEC and 45 MIS patients. Blood samples were obtained preoperatively, at the end of surgery, and postoperative day (POD) 1, 3 to 4, and 5 to 7. Systematic ultrasonographic screening for VTE was performed between POD 3 and 7. Computed tomography scan was performed if complications were suspected. The primary endpoint was the difference in mean change (Δ) with [95% confidence intervals] from preoperative to end of surgery in prothrombin fragment 1 + 2 (F1 + 2) levels. Secondary endpoints were the difference in mean change in biomarkers of coagulation and fibrinolysis from preoperative to POD 5 to 7 and the VTE incidence. RESULTS: F1 + 2 levels increased from preoperative to the end of surgery in both groups. The mean increase from preoperative to end of surgery in F1 + 2 levels was significantly greater in CRS + HIPEC patients than MIS patients: Δ1,322 [1,040:1,604] pmol/L, p < 0.01. The VTE incidence was significantly higher after CRS + HIPEC than MIS (24 vs. 5%, p = 0.01). CONCLUSION: F1 + 2 levels were increased after both procedures, but to a far greater extent following CRS + HIPEC. The VTE incidence within 30 days was significantly higher in patients treated with CRS + HIPEC than in MIS patients.

The effects of respiratory rate and tidal volume on pulse pressure variation in healthy lungs-a generalized additive model approach may help overcome limitations.

Pulse pressure variation (PPV) is a well-established method for predicting fluid responsiveness in mechanically ventilated patients. The predictive accuracy is, however, disputed for ventilation with low tidal volume (VT) or low heart-rate-to-respiratory-rate ratio (HR/RR). We investigated the effects of VT and RR on PPV and on PPV's ability to predict fluid responsiveness. We included patients scheduled for open abdominal surgery. Prior to a 250 ml fluid bolus, we ventilated patients with combinations of VT from 4 to 10 ml kg-1 and RR from 10 to 31 min-1. For each of 10 RR-VT combinations, PPV was derived using both a classic approach and a generalized additive model (GAM) approach. The stroke volume (SV) response to fluid was evaluated using uncalibrated pulse contour analysis. An SV increase > 10% defined fluid responsiveness. Fifty of 52 included patients received a fluid bolus. Ten were fluid responders. For all ventilator settings, fluid responsiveness prediction with PPV was inconclusive with point estimates for the area under the receiver operating characteristics curve between 0.62 and 0.82. Both PPV measures were nearly proportional to VT. Higher RR was associated with lower PPV. Classically derived PPV was affected more by RR than GAM-derived PPV. Correcting PPV for VT could improve PPV's predictive utility. Low HR/RR has limited effect on GAM-derived PPV, indicating that the low HR/RR limitation is related to how PPV is calculated. We did not demonstrate any benefit of GAM-derived PPV in predicting fluid responsiveness.Trial registration: ClinicalTrials.gov, reg. March 6, 2020, NCT04298931.

Waking Up in Pain: a prospective unselected cohort study of pain in 3702 patients immediately after surgery in the Danish Realm.

BACKGROUND: Acute and persistent pain after surgery is well described. However, no large-scale studies on immediate postoperative pain in the operating room (OR) exist, hindering potential areas of research to improve clinical outcomes. Thus, we aimed to describe the occurrence and severity of immediate postoperative pain in a large, unselected cohort. METHODS: This was a prospective cohort study, encompassing all procedures in 31 public hospitals in the Danish Realm, during a 5-day period including the weekend. Data on procedures and anesthesia were collected and the main outcome was occurrence of moderate or severe pain in the OR. Secondary outcomes included pain, sedation and nausea in the OR or during the first 15 min in the postanesthesia care unit (PACU) including relevant risk factors. Descriptive and logistic regression statistics were used. RESULTS: A total of 3675 procedures were included for analysis (87% inclusion rate). Moderate or severe pain occurred in 7.4% (95% CI 6.5% to 8.3%) of cases in the OR immediately after awakening, rising to 20.2% in the OR and/or PACU. Large intraprocedure and interprocedure variations occurred (0.0%-37.5%), and in 20% of cases with epidural-general anesthesia patients experienced moderate or severe pain. Independent risk factors were female sex, younger age, preoperative pain, daily opioid use and major surgical procedures. CONCLUSION: Moderate or severe pain in the immediate postoperative phase occurred in 20% of all cases with procedure and anesthesiological technique variations, suggesting a need for identification of relevant procedure-specific risk factors and development of preventive treatments. TRIAL REGISTRATION NUMBER: RoPR ID 43191.

Persistent pain is common 1-2 years after shoulder replacement.

BACKGROUND AND PURPOSE: Persistent postsurgical pain is a well-recognized problem after various types of surgery such as amputation and thoracotomy. The prevalence of persistent pain, and the extent to which it involves neuropathic pain, is highly dependent on the type of surgery. We investigated the prevalence of, characteristics of, and risk factors for persistent pain 1-2 years after shoulder replacement. PATIENTS AND METHODS: A questionnaire was sent to patients who underwent primary shoulder replacement between April 2011 and April 2012, and whose data were recorded in the Danish Shoulder Arthroplasty Register. Patients who had undergone reoperation or bilateral replacements were excluded. Persistent pain was defined as constant or daily pain within the last month, which interfered much or very much with daily activities. Multivariate logistic regression was used to assess risk factors. RESULTS: 538 patients were available for analysis. The prevalence of persistent pain was 22% (CI: 18-25), and the prevalence of presumed neuropathic pain was 13% (CI: 10-16). Persistent pain was more frequent in fracture patients (29%) than in osteoarthritis patients (16%), while the prevalence of neuropathic pain was similar. Severe pain during the first postoperative week increased the risk of persistent pain. Risk also increased with hemiprosthesis (as compared to total prosthesis) in osteoarthritis patients, and with previous osteosynthesis and pain elsewhere in fracture patients. INTERPRETATION: Persistent pain after shoulder replacement is a daily burden for many patients. Further studies should address patient and prosthesis selection, postoperative pain management, and follow-up of these patients.

Pain following hysterectomy: epidemiological and clinical aspects.

It is well known that different surgical procedures like amputation, thoracotomy, inguinal herniotomy, and mastectomy are associated with a risk of developing chronic postsurgical pain. Hysterectomy is the most frequent gynecological procedure with an annual frequency of 5000 hysterectomies for a benign indication in Denmark, but is has not previously been documented in detail to what extent this procedure leads to chronic pain. The aim of this PhD thesis was therefore to describe the epidemiology, type of pain, risk factors, and predictive factors associated with chronic pain after hysterectomy for a benign indication. The thesis includes four papers, of which one is based on a questionnaire study, two are based on a prospective clinical study, and one is a review of chronic pain after hysterectomy. The questionnaire paper included 1135 women one year after hysterectomy. A postal questionnaire about pain before and after hysterectomy was combined with data from the Danish Hysterectomy Database. Chronic postoperative pain was described by 32%, and the identified risk factors were preoperative pelvic pain, previous cesarean section, other pain problems and pain as an indication for hysterectomy. Spinal anesthesia was associated with a decreased risk of having pain after one year. The type of surgery (i.e. abdominal or vaginal hysterectomy) did not influence chronic pain. The prospective paper included 90 women referred for a hysterectomy on benign indication. The tests were performed before, on day 1, and 4 months after surgery and included questionnaires about pain, coping, and quality of life together with quantitative sensory testing of pain thresholds. Seventeen percent had pain after 4 months, and the risk factors were preoperative pain problems elsewhere and a high intensity of acute postoperative pain. Type of surgery was not a risk factor. Preoperative brush-evoked allodynia, pinprick hyperalgesia, and vaginal pain threshold were associated with a high intensity of acute postoperative pain, and preoperative brush-evoked allodynia was also associated with pelvic pain after 4 months. This PhD thesis shows that chronic postoperative pain is present after hysterectomy in 17-32% of women. The identified main risk factors are described above. The findings indicate that it is not the nerve injury itself, but more likely the underlying individual susceptibility to pain that is important for the development of chronic pain after hysterectomy.

A prospective study of risk factors for pain persisting 4 months after hysterectomy.

OBJECTIVES: Chronic pain after hysterectomy is reported by 5% to 32% of women, but it is unknown whether the pain is a result of surgery or can be attributable to other factors such as preoperative and postoperative pain, physical, and psychosocial status. The aim of this prospective study was therefore to study the role of surgery and other possible predictors for pain 4 months after hysterectomy. METHODS: Ninety women referred for hysterectomy for benign conditions completed the study. The women were interviewed and completed pain questionnaires before surgery and after 3 weeks and 4 months. Questions were about pain location, intensity, and frequency, as well as medical treatment and impact on daily living. In addition, the Short Form-36 General Health Status Questionnaire and Coping Strategies Questionnaire were completed before surgery. RESULTS: Fifteen women (16.7%) had persistent pain 4 months after hysterectomy. In 11 women, the pain resembled their preoperative pain, whereas 4 women had pain likely to be related to surgery. Preoperative "pain problems elsewhere" and a high "acute postoperative pain intensity" were associated with having pain 4 months after hysterectomy (P = 0.004 and P = 0.034). A similar tendency was seen for preoperative "pelvic pain" (P = 0.059). Women with pain at 4 months reported lower quality of life in 4 Short Form-36 subscales and less control of pain preoperatively (P < 0.05 and P = 0.023). DISCUSSION: Pain persisting 4 months after hysterectomy is most often related to preoperative factors and acute postoperative pain. The relative contribution of surgery itself is small.

Risk factors for chronic pain after hysterectomy: a nationwide questionnaire and database study.

BACKGROUND: Women scheduled to undergo hysterectomy for benign indications frequently have preoperative pelvic pain, but it is largely unknown why pain in some cases persists or even develops after surgery. This nationwide questionnaire and database study describes pain and identifies risk factors for chronic postsurgical pain 1 yr after hysterectomy for benign indications. METHODS: A pain questionnaire was mailed to 1,299 women 1 yr after hysterectomy. The response rate was 90.3%, and the presence of persistent pain was correlated to indication for surgery, surgical procedure, type of anesthesia, and other perioperative data. RESULTS: Pain was reported by 31.9% 1 yr after hysterectomy (chronic pain), and 13.7% had pain more than 2 days a week. Pain was not present before surgery in 14.9% of women with chronic postsurgical pain. Risk factors for chronic pain were preoperative pelvic pain (odds ratio [OR], 3.25; 95% confidence interval [CI], 2.40-4.41), previous cesarean delivery (OR, 1.54; CI, 1.06-2.26), pain as the main indication for surgery (OR, 2.98; CI, 1.54-5.77), and pain problems elsewhere (OR, 3.19; CI, 2.29-4.44). Vaginal hysterectomy versus total abdominal hysterectomy was not significantly associated with a lower risk of chronic pain (OR, 0.70; CI, 0.46-1.06). Importantly, spinal versus general anesthesia was associated with less chronic pain (OR, 0.42; CI, 0.21-0.85). CONCLUSIONS: Thirty-two percent had chronic pain after hysterectomy, and risk factors were comparable to those seen in other operations. Interestingly, spinal anesthesia was associated with a lower frequency of chronic pain, justifying prospective study of spinal anesthesia for patients with a high risk for development of chronic postsurgical pain.

Increased production of granulocyte-macrophage colony-stimulating factor in Crohn's disease--a possible target for infliximab treatment.

BACKGROUND: The presence of neutrophils among epithelial cells is one of the major features of the inflammation in Crohn's disease, and has been used to indicate disease activity. The survival of neutrophils outside the blood vessels is limited and their longevity is influenced by granulocyte-macrophage colony-stimulating factor (GM-CSF), which probably reduces neutrophil apoptosis. OBJECTIVE: To study GM-CSF production in intestinal cell cultures from Crohn's disease patients before and after infliximab treatment. PATIENTS: Colonic mucosal biopsies were obtained from 29 Crohn's disease patients before and after three infliximab infusions (5 mg/ml) and from ten healthy subjects. METHODS: Biopsies were cultured in RPMI at high concentrations of interleukin-2 (IL-2) (2000 U/ml) and IL-4 (500 U/ml), but without antigen addition. GM-CSF content was analysed after 5 days culture and related to the Crohn's disease activity index (CDAI) and compared with the GM-CSF production from healthy subjects. Peripheral leucocyte count, C-reactive protein and the degree of mucosal inflammation, evaluated histologically, were determined. In-vitro T cell GM-CSF production was studied with/without addition of infliximab and after stimulation. RESULTS: GM-CSF production was increased in Crohn's disease patients compared with healthy controls (P = 0.02) and correlated with the CDAI (Spearman rho = 0.65, P = 0.001). GM-CSF levels and mucosal histology score decreased (P = 0.007 and P = 0.01 respectively) after three infliximab infusions, as did the peripheral blood leucocyte count (P < 0.001). Infliximab inhibited in-vitro T cell GM-CSF production. CONCLUSION: In-vitro cell culture production of GM-CSF was increased in Crohn's disease and related to inflammation, but decreased after infliximab treatment, probably because intestinal T cell GM-CSF production was reduced.