Effect of time of day on outcomes in elective surgery: a systematic review.

BACKGROUND: The timing of elective surgery could affect clinical outcome because of diurnal rhythms of patient physiology as well as surgical team performance. Waiting times for elective surgery are increasing in many countries, leading to increasing interest in undertaking elective surgery in the evening or at night. We aimed to systematically review the literature on the effect of the timing of elective (but not urgent or emergency) surgery on mortality, morbidity and other clinical outcomes. METHODS: We searched databases for relevant studies combining the terms 'circadian rhythm' and 'anaesthesia/surgery'. Additional relevant articles were found by hand-searching the references. All studies were screened for bias. Included studies examined daytime vs. evening/night-time surgery, morning vs. afternoon surgery, multiple timeslots or used time as a continuous variable. RESULTS: Nineteen retrospective cohort studies, one prospective cohort study and one randomised controlled trial were included (n = 798,914). Evening/night-time elective surgery was associated with a higher risk of mortality when compared with daytime procedures in three studies (n = 611,230), with odds ratios (95%CI) for mortality ranging from 1.35 (1.16-1.56) to 3.98 (1.54-10.30), while no differences were found in three other studies (n = 142,355). No differences were found for morning vs. afternoon surgery (four studies, n = 3277). However, most studies had a low quality of evidence due to their retrospective nature and because not all studies corrected for patient characteristics. Moreover, the studies were heterogeneous in terms of the reported time slots and clinical outcomes. CONCLUSIONS: We found that evening/night-time elective surgery is associated with a higher risk of mortality compared with daytime surgery. However, the quality of evidence was graded as low, and thus, future prospective research should publish individual patient data and standardise outcome measures to allow firm conclusions and facilitate interventions.

The effect of spinal versus general anaesthesia on perioperative muscle weakness in patients having bilateral total hip arthroplasty: a single center randomized clinical trial.

BACKGROUND: Perioperative neuro-endocrine stress response may contribute to acquired muscle weakness. Regional anaesthesia has been reported to improve the outcome of patients having total hip arthroplasty. In this study, it was hypothesized that spinal anaesthesia (SA) decreases the perioperative neuro-endocrine stress response and perioperatively acquired muscle weakness (PAMW), as compared to general anaesthesia (GA). METHODS: Fifty subjects undergoing bilateral total hip arthroplasty (THA) were randomly allocated to receive a standardized SA (n = 25) or GA (n = 25). Handgrip strength was assessed preoperatively, on the first postoperative day (primary endpoint) and on day 7 and 28. Respiratory muscle strength was measured by maximal inspiratory pressure (MIP). Stress response was assessed by measuring levels of Adrenocorticotropic hormone (ACTH), cortisol and interleukin-6 (IL-6). RESULTS: Handgrip strength postoperatively (day 1) decreased by 5.4 ± 15.9% in the SA group, versus 15.2 ± 11.7% in the GA group (p = 0.02). The handgrip strength returned to baseline at day 7 and did not differ between groups at day 28. MIP increased postoperatively in patients randomized to SA by 11.7 ± 48.3%, whereas it decreased in GA by 12.2 ± 19.9% (p = 0.04). On day 7, MIP increased in both groups, but more in the SA (49.0 ± 47.8%) than in the GA group (14.2 ± 32.1%) (p = 0.006). Postoperatively, the levels of ACTH, cortisol and IL-6 increased in the GA, but not in the SA group (p < 0.004). CONCLUSION: In patients having bilateral THA, SA preserved the postoperative respiratory and peripheral muscle strength and attenuated the neuro-endocrine and inflammatory responses. TRIAL REGISTRATION: clinicaltrials.gov NCT03600454.

Development of muscle weakness in a mouse model of critical illness: does fibroblast growth factor 21 play a role?

BACKGROUND: Critical illness is hallmarked by severe stress and organ damage. Fibroblast growth factor 21 (FGF21) has been shown to rise during critical illness. FGF21 is a pleiotropic hormone that mediates adaptive responses to tissue injury and repair in various chronic pathological conditions. Animal studies have suggested that the critical illness-induced rise in FGF21 may to a certain extent protect against acute lung, liver, kidney and brain injury. However, FGF21 has also been shown to mediate fasting-induced loss of muscle mass and force. Such loss of muscle mass and force is a frequent problem of critically ill patients, associated with adverse outcome. In the present study, we therefore investigated whether the critical illness-induced acute rise in FGF21 is muscle-protective or rather contributes to the pathophysiology of critical illness-induced muscle weakness. METHODS: In a catheterised mouse model of critical illness induced by surgery and sepsis, we first assessed the effects of genetic FGF21 inactivation, and hence the inability to acutely increase FGF21, on survival, body weight, muscle wasting and weakness, and markers of muscle cellular stress and dysfunction in acute (30 h) and prolonged (5 days) critical illness. Secondly, we assessed whether any effects were mirrored by supplementing an FGF21 analogue (LY2405319) in prolonged critical illness. RESULTS: FGF21 was not required for survival of sepsis. Genetic FGF21 inactivation aggravated the critical illness-induced body weight loss (p = 0.0003), loss of muscle force (p = 0.03) and shift to smaller myofibers. This was accompanied by a more pronounced rise in markers of endoplasmic reticulum stress in muscle, without effects on impairments in mitochondrial respiratory chain enzyme activities or autophagy activation. Supplementing critically ill mice with LY2405319 did not affect survival, muscle force or weight, or markers of muscle cellular stress/dysfunction. CONCLUSIONS: Endogenous FGF21 is not required for sepsis survival, but may partially protect muscle force and may reduce cellular stress in muscle. Exogenous FGF21 supplementation failed to improve muscle force or cellular stress, not supporting the clinical applicability of FGF21 supplementation to protect against muscle weakness during critical illness.

On the Role of Illness Duration and Nutrient Restriction in Cholestatic Alterations that Occur During Critical Illness.

BACKGROUND AND AIMS: Elevated markers of cholestasis are common in response to critical illness, and associated with adverse outcome. The role of illness duration and of nutrient restriction on underlying molecular pathways of such cholestatic responses have not been thoroughly investigated. METHODS: In a mouse model of surgery- and sepsis-induced critical illness, molecular pathways of cholestasis were investigated up to 7 days. To assess which changes are explained by illness-induced lack of feeding, nutrient-restricted healthy mice were studied and compared with ad libitum fed healthy mice. Furthermore, serum bile acid (BA) concentrations were quantified in 1,114 human patients with either short or long intensive care unit (ICU) stay, matched for type and severity of illness, up to ICU-day-7. RESULTS: In critically ill mice, either evoked by surgery or sepsis, circulating and hepatic BA-levels progressively increased with time from day-3 onward, preceded by unsuppressed or upregulated CYP7A1 and CYP27A1 protein expression. From 30 h onward, nuclear farnesoid-X-receptor-retinoid-X-receptor staining was significantly suppressed in both critically ill groups, followed from day-3 onward by decreased gene expression of the apical exporter BA-specific export pump and increased expression of basolateral exporters multidrug resistance-associated protein 3 (MRP3) and MRP4. Nutrient restriction in healthy mice only partly mirrored illness-induced alterations in circulating BA and BA-transporters, without changing nuclear receptors or synthesis markers expression. Also in human critically ill patients, serum BA increased with time in long-stay patients only, similarly for patients with or without sepsis. CONCLUSIONS: Circulating BA concentrations rose days after onset of sepsis- and surgery-induced, critical illness, only partially explained by lack of feeding, preceded by suppressed nuclear feedback-sensors and ongoing BA synthesis. Expression of transporters suggested ongoing reversed BA-flow toward the blood.

The Role of Autophagy in Critical Illness-induced Liver Damage.

Mitochondrial dysfunction and endoplasmic reticulum (ER) stress, which activates the unfolded protein response (UPR), mediate critical illness-induced organ failure, often affecting the liver. Autophagy is known to alleviate both and suppressed or insufficiently activated autophagy in prolonged illness has shown to associate with organ failure. Whether insufficient autophagy contributes to organ failure during critical illness by affecting these underlying mechanisms is incompletely understood. In this study, we investigated whether the inability to acutely activate hepatic autophagy during critical illness aggravates liver damage by increasing hepatic mitochondrial dysfunction and affecting the UPR. In a mouse model of critical illness, induced by surgery and sepsis, we investigated the impact of inactivating hepatic autophagy on markers of hepatic mitochondrial function, the UPR and liver damage in acute (1 day) and prolonged (3 days) critical illness. Hepatic autophagy inactivation during critical illness acutely worsened mitochondrial dysfunction and time-dependently modulated the hepatic UPR. Furthermore, autophagy inactivation aggravated markers of liver damage on both time points. In conclusion, the inability to acutely activate autophagy in liver during critical illness worsened hepatic mitochondrial damage and dysfunction, partially prohibited acute UPR activation and aggravated liver damage, indicating that autophagy is crucial in alleviating critical illness-induced organ failure.

Premorbid obesity, but not nutrition, prevents critical illness-induced muscle wasting and weakness.

BACKGROUND: The 'obesity paradox' of critical illness refers to better survival with a higher body mass index. We hypothesized that fat mobilized from excess adipose tissue during critical illness provides energy more efficiently than exogenous macronutrients and could prevent lean tissue wasting. METHODS: In lean and premorbidly obese mice, the effect of 5 days of sepsis-induced critical illness on body weight and composition, muscle wasting, and weakness was assessed, each with fasting and parenteral feeding. Also, in lean and overweight/obese prolonged critically ill patients, markers of muscle wasting and weakness were compared. RESULTS: In mice, sepsis reduced body weight similarly in the lean and obese, but in the obese with more fat loss and less loss of muscle mass, better preservation of myofibre size and muscle force, and less loss of ectopic lipids, irrespective of administered feeding. These differences between lean and obese septic mice coincided with signs of more effective hepatic fatty acid and glycerol metabolism, and ketogenesis in the obese. Also in humans, better preservation of myofibre size and muscle strength was observed in overweight/obese compared with lean prolonged critically ill patients. CONCLUSIONS: During critical illness premorbid obesity, but not nutrition, optimized utilization of stored lipids and attenuated muscle wasting and weakness.

Glycemic control and outcome related to cardiopulmonary bypass.

Perioperative hyperglycemia, aggravated by cardiopulmonary bypass, is associated with adverse outcome in adult and pediatric patients. Whereas hyperglycemia was originally perceived as an adaptive response to surgical stress, it is now clear that glycemic control is a strategy to reduce adverse outcomes after cardiac surgery and cardiopulmonary bypass. The optimal blood glucose target, whether or not glycemic control should be initiated already intraoperatively, and whether or not perioperative glucose administration affects the impact of glycemic control on ischemia-reperfusion damage remain open questions. Hypoglycemia, the risk of which is increased with glycemic control, is also associated with adverse outcomes. However, it remains controversial whether brief episodes of hypoglycemia, rapidly corrected during glycemic control, have adverse effects on outcome. This review gives an overview of the currently available literature on glycemic control during and after cardiac surgery and focuses on the indicated open questions about this intervention for this specific patient population.

The impact of resuscitated fecal peritonitis on the expression of the hepatic bile salt transporters in a porcine model.

Sepsis is often associated with cholestatic liver dysfunction caused by changes in the expression profile of hepatic bile salt transporters. However, in rodent endotoxin models, the role of ischemic hepatitis caused by liver hypoperfusion cannot be delineated. We hypothesized that hepatocytes change their expression pattern of bile salt transporters during early severe sepsis despite adequate resuscitation. Fifteen anesthetized and instrumented pigs were randomized to either fecal peritonitis (n = 8) or control (n = 7). Resuscitation was performed by hydroxyethyl starch and norepinephrine infusion. Hemodynamic parameters and markers of cholestatic and ischemic hepatic dysfunction were recorded. At baseline and after 21 h, messenger RNA (mRNA) and protein expression of bile salt transporters was determined by quantitative real-time polymerase chain reaction and immunohistochemistry, respectively, on in vivo liver biopsies. All resuscitated septic pigs developed a normotensive hyperdynamic circulation with increased portal flow. After 21 h of peritonitis, no signs of biochemical or histological cholestasis were present. Na-taurocholate cotransporting polypeptide and bile salt export pump mRNA were downregulated by 83% (P = 0.001) and 67% (P = 0.001), respectively, in comparison with controls, whereas multidrug resistance-associated protein 4 (MRP4) mRNA was upregulated by 85% (P = 0.02). Bile salt export pump and MRP2 staining were downregulated in septic pigs. During early porcine fluid-resuscitated sepsis, hepatic basolateral influx (Na-taurocholate cotransporting polypeptide) and canalicular efflux (bile salt export pump) of bile salts were downregulated without hemodynamic signs of hepatic hypoperfusion or biochemical signs of cholestasis. In parallel, the basolateral escape transport (MRP4) was markedly upregulated, possibly as an early adaptive response to counteract hepatocellular accumulation of toxic bile acids.