Risks of serious adverse events with non-steroidal anti-inflammatory drugs in gastrointestinal surgery: A systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly recommended for perioperative opioid-sparing multimodal analgesic treatments. Concerns regarding the potential for serious adverse events (SAEs) associated with perioperative NSAID treatment are especially relevant following gastrointestinal surgery. We assessed the risks of SAEs with perioperative NSAID treatment in patients undergoing gastrointestinal surgery. METHODS: We conducted a systematic review of randomised clinical trials assessing the harmful effects of NSAIDs versus placebo, usual care or no intervention in patients undergoing gastrointestinal surgery. The primary outcome was an incidence of SAEs. We systematically searched for eligible trials in five major databases up to January 2024. We performed risk of bias assessments to account for systematic errors, trial sequential analysis (TSA) to account for the risks of random errors, performed meta-analyses using R and used the Grading of Recommendations Assessment, Development and Evaluation framework to describe the certainty of evidence. RESULTS: We included 22 trials enrolling 1622 patients for our primary analyses. Most trials were at high risk of bias. Meta-analyses (risk ratio 0.78; 95% confidence interval [CI] 0.51-1.19; I2 = 4%; p = .24; very low certainty of evidence) and TSA indicated a lack of information on the effects of NSAIDs compared to placebo on the risks of SAEs. Post-hoc beta-binomial regression sensitivity analyses including trials with zero events showed a reduction in SAEs with NSAIDs versus placebo (odds ratio 0.73; CI 0.54-0.99; p = .042). CONCLUSION: In adult patients undergoing gastrointestinal surgery, there was insufficient information to draw firm conclusions on the effects of NSAIDs on SAEs. The certainty of the evidence was very low.

Deviating vital signs in continuous monitoring prior to discharge and risk of readmission: an observational study.

Premature discharge may result in readmission while longer hospitalization may increase risk of complications such as immobilization and reduce hospital capacity. Continuous monitoring detects more deviating vital signs than intermittent measurements and may help identify patients at risk of deterioration after discharge. We aimed to investigate the association between deviating vital signs detected by continuous monitoring prior to discharge and risk of readmission within 30 days. Patients undergoing elective major abdominal surgery or admitted with acute exacerbation of chronic obstructive pulmonary disease were included in this study. Eligible patients had vital signs monitored continuously within the last 24 h prior to discharge. The association between sustained deviated vital signs and readmission risk was analyzed by using Mann-Whitney's U test and Chi-square test. A total of 51 out of 265 patients (19%) were readmitted within 30 days. Deviated respiratory vital signs occurred frequently in both groups: desaturation < 88% for at least ten minutes was seen in 66% of patients who were readmitted and in 62% of those who were not (p = 0.62) while desaturation < 85% for at least five minutes was seen in 58% of readmitted and 52% of non-readmitted patients (p = 0.5). At least one sustained deviated vital sign was detected in 90% and 85% of readmitted patients and non-readmitted patients, respectively (p = 0.2). Deviating vital signs prior to hospital discharge were frequent but not associated with increased risk of readmission within 30 days. Further exploration of deviating vital signs using continuous monitoring is needed.

Lactate acidosis and cardiac output during initial therapeutic cooling in asphyxiated newborn infants.

AIM: We hypothesized that compromised cardiac output in asphyxiated infants may influence on the rate of disappearance of lactate due to insufficient perfusion. METHODS: The study was a prospective, observational study, where infants with perinatal asphyxia who met the criteria for therapeutic hypothermia were included. Cardiac output, stroke volume and heart rate were measured by electrical velocimetry in 15 newborn infants with perinatal asphyxia during the first six hours of active therapeutic hypothermia. Results from routine blood samples were collected retrospectively. Cardiac parameters were also measured in 10 healthy, term infants after caesarian section. Cardiac parameters were compared between the asphyxiated group and the control group prior to and during hypothermia. Rate of disappearance of lactate was correlated to cardiac output in the asphyxiated infants. RESULTS: Cardiac output was stable in the healthy infants from 0.5 to 6 hours postnatally. The infants with perinatal asphyxia had lower cardiac output prior to and during therapeutic hypothermia compared to the control group. Rate of disappearance of lactate was not related to cardiac output. CONCLUSION: An association between disappearance of lactate acidosis and low cardiac output was not confirmed. A low rate of disappearance of lactate may rather be an indicator of organ injury due to asphyxia.

Dopamine plasma clearance is increased in piglets compared to neonates during continuous dopamine infusion.

AIM: Piglets models have often been used to study the effects of dopamine infusion on hypotension in neonates. However, piglets need higher doses of dopamine than neonates to increase blood pressure. We investigated whether this difference was due to interspecific difference in dopamine pharmacokinetics. METHODS: Arterial blood samples were drawn from six neonates admitted to the neonatal intensive care unit of Copenhagen University Hospital and 20 newborn piglets during continuous dopamine infusion. Furthermore, to estimate the piglet plasma dopamine half-life, blood samples were drawn at 2.5-minute intervals after the dopamine infusion was discontinued. The plasma dopamine content was analysed by high-performance liquid chromatography with electrochemical detection. RESULTS: The dopamine displayed first-order kinetics in piglets and had a half-life of 2.5 minutes, while the median plasma clearance was 627.9 mL/kg/minute (interquartile range 452.6-1914.4). Both piglets and neonates showed large interindividual variations in plasma clearance, but the median tended to be lower in neonates (384.9, interquartile range 114.2-480.2 mL/kg/minute). CONCLUSION: Our results suggest that pharmacokinetic differences may explain the interspecific difference in required doses of dopamine infusion to increase blood pressure. This is important when translating the results obtained in piglet models to treating neonatal hypotension with dopamine.

Rational use of dopamine in hypotensive newborns: Improving our understanding of the effect on cerebral autoregulation.

Hypotension in critically ill newborn infants is associated with higher mortality and higher risk of cerebral injuries. Yet treating hypotension has never been shown to improve outcomes. In fact, some studies have found that hypotensive newborn infants who were treated with dopamine fared worse than a comparable group of newborn infants who were not. Therefore, a concern has been raised that dopamine might cause the observed adverse outcomes. Cerebral autoregulation is a protective mechanism that maintains a fairly constant cerebral blood flow despite fluctuations in blood pressure. We hypothesized that dopamine might impair the cerebral autoregulation by inducing a rightward shift of the cerebral autoregulation curve. An increased cerebrovascular resistance due to a dopaminergic stimulation of α-adrenoceptors might cause this effect. The main focus of this thesis is to clarify whether dopamine induces a rightward shift of the cerebral autoregulatory pressure curve. The thesis is based on four papers: (I) A methodological study comparing the two most commonly used methods of estimating cerebral autoregulation: time-domain analysis and frequency-domain analysis. We found that the consistency between the two methods was poor, and that time-domain analysis appeared a more robust - and simpler - method for describing cerebral autoregulation when estimates of cerebral autoregulation are based on spontaneous changes in blood pressure. (II) A retrospective study estimating cerebral autoregulation in very preterm infants by time domain analysis. This study found an association between dopamine therapy and impaired cerebral autoregulation. (III) An experimental animal study examining whether dopamine affected cerebral autoregulation in newborn piglets with low blood pressure. We found that dopamine did not negatively affect cerebral venous saturation, cerebral blood flow, or cerebral autoregulation capacity in hypotensive newborn piglets. (IV) An in vitro experiment where middle cerebral arteries from newborn piglets were examined by wire myography and pressure myography. In the wire myograph, increasing concentrations of dopamine caused a biphasic response: starting with vasodilation at low concentrations followed by vasoconstrictions at higher concentrations. In the pressure myograph, dopamine mainly induced vasodilation and the internal arterial diameter only tended to decrease at the highest concentrations. In summary, dopamine has been associated with impaired cerebral autoregulation and our conclusions in study II accorded with this. However, other work has found that initiation of dopamine infusion does not affect cerebral autoregulation. This may indicate that dopamine itself does not lead to impaired cerebral autoregulation. In support of these counter-observations, we did not find any causal relationship between dopamine therapy and impaired cerebral autoregulation in newborn piglets in study III. Also, dopamine in therapeutic concentrations did not induce vasoconstriction in pial arteries in study IV. Based on a review of the current literature, and on the studies included in this thesis, the answer to the central question in this thesis is: "No, dopamine did not induce a rightward shift of the cerebral autoregulation curve".

Mechanical and vasomotor properties of piglet isolated middle cerebral artery.

Piglets are often used as experimental models for studying cerebrovascular responses in newborn infants. However, the mechanical characteristics of piglets' middle cerebral arteries (MCA) are not well characterized. Additionally, the vessels' response to dopamine, the most commonly used vasopressor in newborns, is not characterized in piglets' MCA. Finally, the influence of preterm birth on the dopamine response is not known. The aim of this current was to compare by wire myography the active and passive mechanical characteristics and dopamine concentration-response relations of MCAs isolated from preterm and term newborn piglets. Second-order branches of the MCA with a diameter <400 µm were chosen for study. The active and passive mechanical properties were comparable between vessels from six preterm (90% gestation, nsegments = 11) and nine term (nsegments = 22) newborn piglets. The response to increasing concentrations of dopamine was biphasic, starting with vasodilation in the 1 nmol/L-0.3 µmol/L concentration range followed by vasoconstriction at higher concentrations. The response was very similar between the two groups. In conclusion, the mechanical properties of the MCA as well as the response to dopamine were comparable between term and 90% gestation preterm piglets.

Dopamine therapy does not affect cerebral autoregulation during hypotension in newborn piglets.

BACKGROUND: Hypotensive neonates who have been treated with dopamine have poorer neurodevelopmental outcome than those who have not been treated with dopamine. We speculate that dopamine stimulates adrenoceptors on cerebral arteries causing cerebral vasoconstriction. This vasoconstriction might lead to a rightward shift of the cerebral autoregulatory curve; consequently, infants treated with dopamine would have a higher risk of low cerebral blood flow at a blood pressure that is otherwise considered "safe". METHODS: In anaesthetized piglets, perfusion of the brain, monitored with laser-doppler flowmetry, and cerebral venous saturation was measured at different levels of hypotension. Each piglet was studied in two phases: a phase with stepwise decreases in MAP and a phase with stepwise increases in MAP. We randomized the order of the two phases, whether dopamine was given in the first or second phase, and the infusion rate of dopamine (10, 25, or 40 µg/kg/min). In/deflation of a balloon catheter, placed in vena cava, induced different levels of hypotension. At each level of hypotension, fluctuations in MAP were induced by in/deflations of a balloon catheter in descending aorta. RESULTS: During measurements, PaCO2 and arterial saturation were stable. MAP levels ranged between 14 and 82 mmHg. Cerebral autoregulation (CA) capacity was calculated as the ratio between %-change in cerebrovascular resistance and %-change in MAP induced by the in/deflation of the arterial balloon. A breakpoint in CA capacity was identified at a MAP of 38±18 mmHg without dopamine and at 44±18, 31±14, and 24±14 mmHg with dopamine infusion rates of 10, 25, and 40 µg/kg/min (p = 0.057). Neither the index of steady-state cerebral perfusion nor cerebral venous saturation were affected by dopamine infusion. CONCLUSION: Dopamine infusion tended to improve CA capacity at low blood pressures while an index of steady-state cerebral blood flow and cerebral venous saturation were unaffected by dopamine infusion. Thus, dopamine does not appear to impair CA in newborn piglets.

Quantifying cerebral hypoxia by near-infrared spectroscopy tissue oximetry: the role of arterial-to-venous blood volume ratio.

Tissue oxygenation estimated by near-infrared spectroscopy (NIRS) is a volume-weighted mean of the arterial and venous hemoglobin oxygenation. In vivo validation assumes a fixed arterial-to-venous volume-ratio (AV-ratio). Regulatory cerebro-vascular mechanisms may change the AV-ratio. We used hypotension to investigate the influence of blood volume distribution on cerebral NIRS in a newborn piglet model. Hypotension was induced gradually by inflating a balloon-catheter in the inferior vena cava and the regional tissue oxygenation from NIRS ( rStO 2 , NIRS ) was then compared to a reference ( rStO 2 , COX ) calculated from superior sagittal sinus and aortic blood sample co-oximetry with a fixed AV-ratio. Apparent changes in the AV-ratio and cerebral blood volume (CBV) were also calculated. The mean arterial blood pressure (MABP) range was 14 to 82 mmHg. PaCO 2 and SaO 2 were stable during measurements. rStO 2 , NIRS mirrored only 25% (95% Cl: 21% to 28%, p < 0.001 ) of changes in rStO 2 , COX . Calculated AV-ratio increased with decreasing MABP (slope: ? 0.007 · mmHg ? 1

Cerebral autoregulation in the preterm newborn using near-infrared spectroscopy: a comparison of time-domain and frequency-domain analyses.

The aim was to compare two conventional methods used to describe cerebral autoregulation (CA): frequency-domain analysis and time-domain analysis. We measured cerebral oxygenation (as a surrogate for cerebral blood flow) and mean arterial blood pressure (MAP) in 60 preterm infants. In the frequency domain, outcome variables were coherence and gain, whereas the cerebral oximetry index (COx) and the regression coefficient were the outcome variables in the time domain. Correlation between coherence and COx was poor. The disagreement between the two methods was due to the MAP and cerebral oxygenation signals being in counterphase in three cases. High gain and high coherence may arise spuriously when cerebral oxygenation decreases as MAP increases; hence, time-domain analysis appears to be a more robust­and simpler­method to describe CA.

The development of diabetes among Danish cystic fibrosis patients over the last two decades.

OBJECTIVE: Cystic fibrosis (CF)-related diabetes (CFRD) is correlated with age and has been associated with a decline in body mass index (BMI), pulmonary function, and survival. Over the last two decades, the focus has been on the early diagnosis and treatment of diabetes; therefore, in this study, we evaluated the status of the current clinical condition and survival in our CF population. In addition, we also aimed to investigate the incidence of diabetes among adolescence over time and to identify characteristics associated with early diabetes onset. METHODS: A retrospective chart review of a birth cohort consisting of 161 CF patients born between 1975 and 1994 and followed until 2011. RESULTS: Over two decades, the incidence of CFRD among 11- to 16-year-old children remained unchanged at 12-14%, while the proportion of children with chronic pulmonary infection at age 10 declined from 31 to 8% (p < 0.001). Severe CF-mutation, i.e., group I and II mutations, were associated with diabetes (p = 0.003). Female gender was borderline associated with diabetes among adolescents (p = 0.06). No significant worsening in pulmonary function, BMI or survival was identified when comparing CFRD patients to CF patients without CFRD. CONCLUSIONS: The incidence of diabetes among adolescence with CF has not changed over the last two decades. Severe CF mutations are a risk factor for CFRD, and female gender is borderline associated with CFRD among adolescents. Pulmonary function, BMI and survival were comparable regardless of the onset of CFRD.

Dopamine therapy is associated with impaired cerebral autoregulation in preterm infants.

AIM: Hypotension is a common problem in newborn infants and is associated with increased mortality and morbidity. Dopamine is the most commonly used antihypotensive drug therapy, but has never been shown to improve neurological outcomes. This study tested our hypothesis that dopamine affects cerebral autoregulation (CA). METHODS: Near-infrared spectroscopy was used to measure the cerebral oxygenation index in 60 very preterm infants, and mean arterial blood pressure was monitored towards the end of their first day of life. Measurements were performed continuously for two to three hour periods. CA was quantified as the cerebral oximetry index (COx). RESULTS: We treated 13 of the 60 infants (22%) with dopamine during the measurements. COx was higher in the dopamine group than the untreated group (0.41 ± 0.25 vs. 0.08 ± 0.25, p < 0.001). Blood pressure tended to be lower in the dopamine group, but the anticipated difference in cerebral oxygenation was not detected. The need for mechanical ventilation in the first day of life and incidences of mortality was higher in the dopamine group. CONCLUSION: Dopamine therapy was associated with decreased CA in preterm infants. We were unable to determine whether dopamine directly impaired CA or was merely an indicator of illness.

Follow-up of 5- to 11-year-old children treated for persistent pulmonary hypertension of the newborn.

AIM: Determine the prevalence of sensorineural hearing loss (SNHL) and relate this to cumulative exposure to hypoxia, hypocapnia and hypotension. Describe chronic health problems among 5- to 11-year-old children treated for persistent pulmonary hypertension of the newborn (PPHN). METHODS: The index group consisted of 85 children and a reference group was matched for age, sex and municipality of current residence. Questionnaires were sent to the families. The families in the index group were asked to participate in an examination of their child's hearing. RESULTS: Seven children (11%) had SNHL. SNHL was not associated with hypoxia, hypocapnia or hypotension during treatment for PPHN. In the index group chronic health problems were reported in 42% compared with 17% in the reference group (chi-square test, p = 0.001). Twenty-one percent in the index group were treated with bronchodilator therapy compared with 8% in the reference group (chi-square test, p = 0.028). In the index group five children had cerebral palsy and two had developmental delay. Nineteen percent in the index group and 5% in the reference group had remedial education (chi-square test, p = 0.008). CONCLUSION: Children treated for PPHN are at high risk for SNHL. Exposure to hypoxia, hypocapnia or hypotension did not predict SNHL. The incidence of chronic health problems and use of remedial education was high.

[Results after ECMO-treatment of newborn babies and infants in Denmark from 1995-2004]. / Resultater efter ekstrakorporal membranoxygeneringsbehandling af nyfødte og spaedbørn i Danmark 1995-2004.

INTRODUCTION: In 1995 extracorporeal membrane oxygenation (ECMO) was introduced in Denmark as a treatment for critically ill infants. ECMO is primarily used in infants with severe meconium aspiration, but can be used for all kinds of pulmonary and cardiac failures as well. The purpose of our work was to evaluate the Danish ECMO-treatment. MATERIALS AND METHODS: We performed a retrospective study of 55 infants receiving ECMO, and the parents of the surviving children were sent questionnaires. All the completed questionnaires were returned except for one from a family that emigrated from Denmark. The statistical analyses are based on chi2-tests and 95% CI. RESULTS: Only in four cases was the treatment without complications. Thirty-one infants had technical complications and 48 had medical complications. Cerebral complications arose in 28 infants. Thirty-nine (71%) infants were alive at the time of the survey. 42% of the parents reported sequels or suspicion of sequels. The primary sequels were reduced hearing, which was observed in eight infants, and chronic lung disease, which was observed in seven. Only one child was severely disabled. CONCLUSION: The underlying diagnoses, mortality and disability correspond to the results in an English randomised study.