Noninvasive Measurements of Renal Perfusion During Cardiac Surgery
Noninvasive Measurements of Renal Perfusion During Cardiac Surgery
The purpose of this study is to assess the feasibility of measuring urine oxygen tension in
 cardiac surgery patient and the ability of peri-operative urine oxygen measurements to
 predict post-operative acute kidney injury. The hypothesis is that a small oxymeter placed in
 a urinary catheter will provide reliable measurement of urine oxygenation and that these
 measurements will predict post-operative acute kidney injury in cardiac surgery patients.
Acute kidney injury (AKI) is an unfortunately common complication of cardiac surgery that
 occurs in up to 40% of patients and results in increased mortality, prolonged ICU and
 hospital length of stay. AKI after cardiac surgery is not a benign complication, increasing
 mortality from 1% to 19% in those with AKI and to 63% mortality in those who required renal
 replacement therapy (RRT). In another study, patients with AKI with RRT after cardiac surgery
 had 39 times the mortality as patients without AKI (95% CI 32-48).[6] AKI has also been
 associated with increased morbidity and a larger number of patients requiring discharge to an
 extended care facility.

 The pathophysiology of AKI after cardiac surgery is multifactorial. Patients undergoing
 cardiac surgery are likely more susceptible to AKI given their tendency to be older patients
 with multiple co-morbidities including pre-existing chronic kidney disease, cardiac
 dysfunction, diabetes mellitus, and advanced age. Cardiac surgery patients are also exposed
 to multiple nephrotoxic agents in the peri-operative period including radiocontrast dyes used
 for angiography, angiotensin converting enzyme inhibitors, and diuretics. Hemodynamically
 unstable patients may be subject to low cardiac output and low systemic blood pressure
 because of the pathological condition that brings them to the cardiac operating room in the
 first place. Low cardiac output and systemic blood pressure can result in reduced renal
 perfusion. Induction and the maintenance of anesthesia can result in myocardial depression
 and hemodynamic instability, reducing renal perfusion even further. In most cases, cardiac
 surgery is facilitated by cardiopulmonary bypass (CPB) which is the process of placing the
 patient on a heart and lung machine that pumps, oxygenates, and removes CO2 from the
 patient's blood for them while the heart is arrested. The CPB circuit itself is known to
 cause significant inflammation and hemodynamic changes that may cause renal injury
 particularly with prolonged CPB times. Vasopressor and inotropic agents such as vasopressin,
 norepinephrine, milrinone, and epinephrine are often used to maintain blood pressure and
 cardiac output. While some of these agents may increase systemic blood pressure by increasing
 the systemic vascular resistance, this may in fact result in a decrease in renal perfusion.
 The affect of these agents on the incidence of AKI is uncertain.

 Traditionally, the diagnosis of AKI is based on either a sustained fall in urine output or a
 rise in serum creatinine. The 2012 Kidney Disease Improving Global Outcomes (KDIGO)
 classification defines AKI as an increase in serum creatinine by 0.3 mg/dl or more in 48
 hours or a rise to at least 1.5 times baseline. Three stages of AKI are then defined based on
 increasing values of serum creatinine or duration of decreased urine output.

 The major limitation of creatinine and urine output as a marker of kidney function is the
 time lag between injury and diagnosis. It often takes 24-36 hours after renal injury for
 serum creatinine levels to rise. Peri-operative urine output is affected by volume status,
 anesthetic drugs, and the use of diuretics and AKI is not diagnosed until oliguria has
 occurred for at least 6-12 hrs. This renders serum creatinine and urinary output measurements
 insensitive to acute changes in renal function and relatively useless in the acute diagnosis
 of AKI during and after cardiac surgery.

 More recently, several early biomarkers have been developed to identify patients whom are at
 risk for developing AKI. Two of these biomarkers, TIMP-2 and IGFBP7, have been used for the
 early prediction of AKI in ICU and cardiac surgery patients. Nonetheless, "early detection"
 with these biomarkers is till limited to 3-4 hours (an in some studies 24 hours) after renal
 injury.

 One of major limitation in the efforts to reduce the incidence of AKI in cardiac surgery is
 the lack of a real-time monitor of renal perfusion. As mentioned above, urine output is well
 known to be a poor indicator of renal perfusion. While urinary flow rate may be linearly
 related to blood pressure while on CPB, this is likely related to a phenomenon called
 pressure diuresis and is unlikely to be a reflection of improved renal perfusion. Renal blood
 flow can be measured by cannulating the renal vein through a central venous catheter placed
 in the femoral vein. This, however, is a highly invasive technique and is not used routinely.

 As a result of the lack of real-time monitoring of the kidney during cardiac surgery,
 anesthesiologists are often left to make educated guesses as to what blood pressure and
 cardiac output are adequate for renal perfusion based on the patients baseline blood pressure
 and kidney function. In a patient with a long history of hypertension and/or chronic kidney
 disease the anesthesiologist's goal is often to try to maintain a higher mean arterial
 pressure (MAP) both on and off CPB than normal in order to "improve renal perfusion". There
 is very little data to support this practice, particularly if we need to use vasopressor
 agents to achieve these higher MAP goals, and the exact target MAP in these patients is
 unknown.

 This lack of real-time monitoring of renal perfusion is in stark contrast to the vigilant
 monitoring of the brain during cardiac surgery. Cerebral oxymeters that are routinely used to
 measure brain oxygen saturations, transcranial Doppler systems to measure cerebral blood
 flow, and EEG to measure brain activity. Often the argument is made to use the brain as an
 index organ for adequate perfusion to the rest of the body, but during periods of hemodynamic
 instability, brain perfusion is preserved at the cost of other organ. The lower limit of
 autoregulation of the brain (the BP below which blood flow becomes dependent on blood
 pressure) is thought to be a BP of 50-55 mmHg. [20, 21] Although the exact number in humans
 has not been determined and adequate BP for kidney perfusion is widely debated, the lower
 limit of autoregulation for the kidney is probably significantly higher than the brain. Brain
 desaturations, therefore, may be specific for poor perfusion to other organs such as the
 kidney and gut but they are likely not sensitive for these changes.

 Adequate renal perfusion is much more complicated than simply measuring renal blood flow or
 renal venous oxygenation. Grossly the kidney has three anatomical areas: the renal cortex
 where most of the filtration is done, the renal medulla where urine is actively concentrated,
 and the renal pelvis where urine is collected. Approximately ¼ of our cardiac output goes to
 our kidneys and most of that perfuses the cortex for filtration. In contrast, the medulla
 receives only a limited blood supply. This combined with the high metabolic activity of the
 renal medulla results in a relatively hypoxic medullary environment with a normal pO2 of
 10-20 mmHg and very little oxygen reserve. Medullary hypoxia may be a consequence of
 decreased oxygen delivery or increased oxygen consumption and is a major determinant of AKI
 and chronic kidney disease. The relatively hypoxic environment of the renal medulla and it's
 role in renal injury suggest that global measures of systemic venous oxygenation through a
 central venous catheter or even renal venous oxygenation through an invasive renal vein
 catheter may be poor monitors of adequate renal perfusion. The more ideal monitor of renal
 hypoxia and kidney injury would be a measure of medullary oxygenation.

 Due to the physical proximity of the vasa recta in the renal medulla with the urinary
 collecting ducts, medullary oxygen tension is more closely related to urinary oxygen tension
 than renal venous oxygenation. Medullary oxygen tension has been measured invasively in
 animal studies and correlates with both renal pelvic urine and bladder urine oxygenation. In
 pigs, bladder urinary oxygenation was shown to decrease with increasing degrees of hypoxemia
 and hemorrhage, then restored with resuscitation. These changes were found to proceed other
 global hemodynamic changes and increases in base deficit or lactic acidosis. In a sheep model
 of sepsis, both medullary and urinary oxygen was decreased and restoration of systemic blood
 pressure with norepinephrine further reduced oxygen tension in both the renal medulla and
 urine. Both medullary and pelvic urinary oxygen tension were found to decline significantly
 with the onset of CPB in pigs, gradually increasing after cessation of bypass but remaining
 lower than pre-CPB levels suggesting that the hemodynamics of CPB may be a significant
 contributor to the development of AKI in cardiac surgery.

 In 1996 Kainuma et al. placed an oxygen electrode inside the urinary catheter of 96 patients
 undergoing cardiac surgery with CPB. In their set up, there was 20 ml of deadspace between
 the tip of the catheter and the oxymeter. Samples were drawn from a stop-cock near the
 oxymeter every two hours for calibration. They found marked decreases in urine oxygen tension
 in all patients during CPB. Some patients recovered their urine oxygenation after CPB, but in
 34% of patients, urinary oxygen tension continued to decline after bypass and these patients
 had significantly higher incidence of AKI. They concluded that urinary oxygen monitoring may
 be superior to other more invasive measures of renal perfusion, but to date, no further work
 has been published on urine oxygen monitoring in humans during cardiac surgery

 Fiber-optic technology has been use in endoscopy for cancer detection. Continuous blood gas
 measurements has also been performed in patients undergoing cardiopulmonary bypass by
 implanting fiber optic oxygen sensing probes in the internal jugular vein through a central
 line catheter or in the radial artery though a radial artery catheter. Continuous blood gas
 measurements has also been performed in patients undergoing cardiopulmonary bypass by
 implanting fiber optic oxygen sensing probes in the internal jugular vein through a central
 line catheter or in the radial artery though a radial artery catheter.

 More recently Evans et al have placed a fiber optic oxygen sensing probe in the tip of a
 urinary catheter in 35 patients undergoing cardiac surgery with cardiopulmonary bypass. Their
 study design was very similar to ours in that they placed a fiber-optic oxygen sensing probe
 in the tip of a urinary catheter. The difference in our design is that we have created a flow
 through chamber with oxygen sensor in it as well.

 The later, we hope will correlate closely with that in the tip of the urinary catheter but
 will be a less invasive approach to urine oxygen monitoring. In our study, we plan to place
 two fiber optic oxygen tension probes in a standard urinary catheter. The first probe will be
 placed within the urinary catheter and threaded to the tip of the catheter (though still
 within the catheter and not in the body) in order to measure bladder urine oxygen tension.
 The second will be a flow through chamber with a fiber optic oxygen sensor and urinary flow
 rate sensor within it. This flow through chamber will be placed between the urinary catheter
 and the collecting tubing (see figure 1, attached under "other documents"). A one-way valve
 in the flow through chamber will allow passage of urine but prevent back flow of either urine
 or air.

 The hypothesis is that a the less invasive flow through chamber oxymeter will provide similar
 measurements to the more proximately placed fiber at the tip of the urinary catheter, that
 both will provide reliable measurement of urine oxygenation, and that these measurements will
 predict post-operative acute kidney injury in cardiac surgery patients.
Inclusion Criteria:

 -  Elective or semi-elective/urgent Cardiac surgery patients in whom CPB is a planned
 part of the procedure.

 -  18 years or older

 -  Urinary catheter is planned during the surgery

 Exclusion Criteria:

 -  Contra-indications to urinary catheter

 -  Pre-operative dialysis dependent end stage renal disease

 -  Emergency cases