Abnormal Iron Status and Adverse Outcome After Elective Cardiac Surgery: A Prospective, Observational Multicenter Study.

OBJECTIVES: To investigate the incidence of preoperative abnormal iron status and its association with packed red blood cell (PRBC) transfusion, postoperative major complications, and new onset of clinically significant disability in patients undergoing elective cardiac surgery. DESIGN: A prospective, observational multicenter cohort study. SETTING: Three cardiac surgical centers in the Netherlands between 2019 and 2021. Recruitment was on hold between March and May 2020 due to COVID-19. PATIENTS: A total of 427 patients aged 60 years and older who underwent elective on-pump cardiac surgery. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was a 30-day PRBC transfusion. Secondary endpoints were postoperative major complications within 30 days (eg, acute kidney injury, sepsis), and new onset of clinically significant disability within 120 days of surgery. Iron status was evaluated before surgery. Abnormal iron status was present in 45.2% of patients (n = 193), and most frequently the result of iron deficiency (27.4%, n = 117). An abnormal iron status was not associated with PRBC transfusion (adjusted relative risk [ARR] 1.2; 95% CI 0.9-1.8: p = 0.227) or new onset of clinically significant disability (ARR 2.0; 95% CI 0.9-4.6: p = 0.098). However, the risk of postoperative major complications was increased in patients with an abnormal iron status (ARR 1.7; 95% CI 1.1-2.5: p = 0.012). CONCLUSIONS: An abnormal iron status before elective cardiac surgery was associated with an increased risk of postoperative major complications but not with PRBC transfusion or a new onset of clinically significant disability.

Drug-induced liver injury following a repeated course of ketamine treatment for chronic pain in CRPS type 1 patients: a report of 3 cases.

Studies on the efficacy of ketamine in the treatment of chronic pain indicate that prolonged or repetitive infusions are required to ensure prolonged pain relief. Few studies address ketamine-induced toxicity. Here we present data on the occurrence of ketamine-induced liver injury during repeated administrations of S(+)-ketamine for treatment of chronic pain in patients with complex regional pain syndrome type 1 as part of a larger study exploring possible time frames for ketamine re-administration. Six patients were scheduled to receive 2 continuous intravenous 100-hour S(+)-ketamine infusions (infusion rate 10-20mg/h) separated by 16 days. Three of these patients developed hepatotoxicity. Patient A, a 65-year-old woman, developed an itching rash and fever during her second exposure. Blood tests revealed elevated liver enzymes (alanine transaminase, alkaline phosphatase, aspartate transaminase, and γ-glutamyl transferase, all ≥ 3 times the upper limit of normal) and modestly increased eosinophilic leukocytes. Patient E, a 48-year-old woman, developed elevated liver enzymes of similar pattern as Patient A during her second ketamine administration and a weakly positive response to antinuclear antibodies. In a third patient, Patient F, a 46-year-old man, elevated liver enzymes (alanine transaminase and γ-glutamyl transferase) were detected on the first day of his second exposure. In all patients, the ketamine infusion was promptly terminated and the liver enzymes slowly returned to reference values within 2 months. Our data suggest an increased risk for development of ketamine-induced liver injury when the infusion is prolonged and/or repeated within a short time frame. Regular measurements of liver function are therefore required during such treatments.

Effect of ketamine on endogenous pain modulation in healthy volunteers.

Inhibitory and facilitatory descending pathways, originating at higher central nervous system sites, modulate activity of dorsal horn nociceptive neurons, and thereby influence pain perception. Dysfunction of inhibitory pain pathways or a shift in the balance between pain facilitation and pain inhibition has been associated with the development of chronic pain. The N-methyl-d-aspartate receptor antagonist ketamine has a prolonged analgesic effect in chronic pain patients. This effect is due to desensitization of sensitized N-methyl-d-aspartate receptors. Additionally, ketamine may modulate or enhance endogenous inhibitory control of pain perception. Diffuse noxious inhibitory control (DNIC) and offset analgesia (OA) are 2 mechanisms involved in descending inhibition. The present study investigates the effect of a ketamine infusion on subsequent DNIC and OA responses to determine whether ketamine has an influence on descending pain control. Ten healthy subjects (4 men/6 women) received a 1-hour placebo or S(+)-ketamine (40mg per 70kg) infusion on 2 separate occasions in random order. Upon the termination of the infusion, DNIC and OA responses were obtained. After placebo treatment, significant descending inhibition of pain responses was present for DNIC and OA. In contrast, after ketamine infusion, no DNIC was observed, but rather a significant facilitatory pain response (P<0.01); the OA response remained unchanged. These findings suggest that the balance between pain inhibition and pain facilitation was shifted by ketamine towards pain facilitation. The absence of an effect of ketamine on OA indicates differences in the mechanisms and neurotransmitter influences between OA and DNIC. Diffuse noxious inhibitory control responses following a 1-hour low-dose ketamine treatment displayed facilitation of pain in response to experimental noxious thermal stimulation.

Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1.

Complex Regional Pain Syndrome Type 1 (CRPS-1) responds poorly to standard pain treatment. We evaluated if the N-methyl-D-aspartate receptor antagonist S(+)-ketamine improves pain in CRPS-1 patients. Sixty CRPS-1 patients (48 females) with severe pain participated in a double-blind randomized placebo-controlled parallel-group trial. Patients were given a 4.2-day intravenous infusion of low-dose ketamine (n=30) or placebo (n=30) using an individualized stepwise tailoring of dosage based on effect (pain relief) and side effects (nausea/vomiting/psychomimetic effects). The primary outcome of the study was the pain score (numerical rating score: 0-10) during the 12-week study period. The median (range) disease duration of the patients was 7.4 (0.1-31.9) years. At the end of infusion, the ketamine dose was 22.2+/-2.0 mg/h/70 kg. Pain scores over the 12-week study period in patients receiving ketamine were significantly lower than those in patients receiving placebo (P<0.001). The lowest pain score was at the end of week 1: ketamine 2.68+/-0.51, placebo 5.45+/-0.48. In week 12, significance in pain relief between groups was lost (P=0.07). Treatment did not cause functional improvement. Patients receiving ketamine more often experienced mild to moderate psychomimetic side effects during drug infusion (76% versus 18%, P<0.001). In conclusion, in a population of mostly chronic CRPS-1 patients with severe pain at baseline, a multiple day ketamine infusion resulted in significant pain relief without functional improvement. Treatment with ketamine was safe with psychomimetic side effects that were acceptable to most patients.

Morphine-6beta-glucuronide rapidly increases pain sensitivity independently of opioid receptor activity in mice and humans.

BACKGROUND: Previous data indicate that morphine-6beta-glucuronide (M6G), a morphine metabolite with analgesic properties, can paradoxically increase pain sensitivity in mice and humans. The authors tested mice and humans for M6G hyperalgesia and assessed the contribution of N-methyl-D-aspartate receptor activity in mice. METHODS: Nociception after acute injection (10 mg/kg) and chronic infusion (1.6 mg/kg per 24 h) of M6G or saline was assayed using the tail-withdrawal test in CD-1 mice implanted with pellets containing the opioid antagonist naltrexone or placebo and in knockout mice lacking mu-, kappa-, and delta-opioid receptors and their B6129F(1) controls. In volunteers, responses to heat pain were tested after a M6G (0.4 mg/kg) injection in the presence of a continuous high naloxone (0.04-mg/kg bolus followed by 0.04 mg/kg per hour) or saline background infusion. RESULTS: Acute M6G injection evoked analgesia in CD-1 mice implanted with placebo pellets and B6129F(1) control mice, whereas it caused hyperalgesia in CD-1 mice treated concurrently with naltrexone and in knockout mice. Continuous M6G infusion produced hyperalgesia within 24 h, lasting for a minimum of 6 days, in both placebo- and naltrexone-pelleted mice. The N-methyl-D-aspartate receptor antagonist MK-801 (0.05 mg/kg) blocked and reversed hyperalgesia after the acute injection and continuous infusion of M6G, respectively. In humans, M6G increased heat pain sensitivity for at least 6 h independently of simultaneous naloxone infusion. CONCLUSIONS: These data indicate that M6G causes hyperalgesia independent of previous or concurrent opioid receptor activity or analgesia. In mice, a causal role for the N-methyl-D-aspartate receptor is also indicated.

Polymorphism of mu-opioid receptor gene (OPRM1:c.118A>G) does not protect against opioid-induced respiratory depression despite reduced analgesic response.

BACKGROUND: The effect of a single nucleotide polymorphism of the mu-opioid receptor at nucleotide position 118 (OPRM1:c.118A>G) was investigated on morphine-6-glucuronide (M6G)-induced analgesia and respiratory depression in a group of healthy volunteers. METHODS: Sixteen subjects of either sex received 0.4 mg/kg (n = 8) or 0.6 mg/kg M6G (n = 8). At regular time intervals, the isocapnic acute hypoxic ventilatory response, pain tolerance (derived from a transcutaneous electrical acute pain model), and arterial blood samples were obtained. Data acquisition continued for 14 h after drug infusion. Population pharmacokinetic-pharmacodynamic sigmoid Emax models were applied to the respiratory and pain data. All collected data were analyzed using the statistical program NONMEM (San Francisco, CA). RESULTS: Four of the subjects were OPRM1:c.118GA heterozygotes, and the remainder of the subjects were OPRM1:c.118AA homozygotes. M6G analgesia: In contrast to analgesic responses in OPRM1:c.118AA homozygotes, responses were small and inconsistent in OPRM1:c.118GA heterozygotes and best described by the function Effect(t) = baseline (P < 0.01 vs. OPRM1:c.118AA homozygotes). Emax and C50 values in heterozygotes equaled 0.55 +/- 0.18 (or a 55% increase in current above baseline) and 161 +/- 42 ng/ml, respectively. M6G-induced respiratory depression: For the acute hypoxic response, neither Emax nor C50 (value = 282 +/- 72 ng/ml) differed between genotypes. CONCLUSIONS: The data indicate that the OPRM1:c.118A>G polymorphism affects opioid analgesic and respiratory effects differentially. Despite reduced analgesic responses to M6G the OPRM1:c.118A>G single-nucleotide polymorphism does not protect against the toxic effects of the tested opioid. However, some caution in the interpretation of the data is needed because of the small sample size. Further studies are needed to explore the link between this polymorphism and respiratory/analgesic responses beyond the small human sample. In OPRM1:c.118AA homozygotes, the potency parameters differed by a factor of 2 for analgesic versus respiratory effect. In this respect, M6G differs favorably from morphine.