Authors' Reply

We sincerely thank the Letter's authors for their scholarly comments about this case.1 The issues they raise are all highly clinically relevant and demand a comprehensive response. BACKGROUND Treatment of a cook's contusion included nonsteroidal anti-inflammatory drugs (NSAIDs): ibuprofen 2400 mg on days 1 to 19, and valdecoxib 10 mg on days 76 to 139. On day 10, she developed new hypertension, which became severe by day 19. Stage 5 kidney disease and small echogenic kidneys were first identified on day 38. Physicians treating her injury did not treat her hypertension or uremia. She died of renal failure and hypertensive cerebrovascular hemorrhage on day 149.1 HYPERTENSION Hypertension is clinically defined as repeatedly elevated pressure exceeding 140 mm Hg systolic or 90 mm Hg diastolic.2 We would not diagnose hypertension on day 1 (blood pressure 130/90 mm Hg). First, that lone elevation of diastolic pressure was not “repeated” elevation. Second, the recorded value was not even verified (eg, after the clinic visit, in the opposite arm, or in the seated, supine, and erect positions). Third, there was no record of preinjury hypertension; the patient rarely went to a doctor, and never previously sought treatment for hypertension or kidney disease. Her only preinjury record was of a single visit for an antibiotic prescription 5 months before day 0. Fourth, the measured blood pressure was probably higher than her preinjury baseline because of pain, which was so severe that it required the highest dose of ibuprofen. Pain augments the secretion of endogenous corticosteroids and catecholamines, which cause fluid retention and vasoconstriction. Pain-related increase in sympathetic activity has been documented by peroneal nerve electrodes.3 Fifth, the patient's blood pressure probably increased because of “white coat syndrome” wherein people exhibit hypertension in clinical settings but not elsewhere.4 Sixth, had the blood pressure been just 1 mm lower (130/89 mm Hg), hypertension would not have been diagnosed. PREHYPERTENSION Pre-hypertension is classically defined as systolic pressure of 120—139 mm or diastolic pressure of 80—89 mm.2 We would not diagnose pre-hypertension based on the single measurement of day 1, but would do so on day 6, the patient had prehypertension (130/80 mm Hg). However, that measurement did not reflect her preinjury state because of confounding by the 5-day ibuprofen treatment. The day-6 reading was slightly lower than day 1 probably because of relief of both pain and the white coat syndrome. Without the hypertensive effects of the triumvirate of ibuprofen, pain, and white coat syndrome, her blood pressure before day 1 probably was lower than 130/80 mm Hg. Besides, even if the patient had preinjury prehypertension, it did not necessarily indicate chronic kidney disease. In US adults, prevalence of prehypertension or hypertension is 60%, whereas that of chronic kidney disease is only 10%.5 Most cases of hypertension are idiopathic. NEPHROTOXICITY The crux of our article was the nephrotoxicity of NSAIDs. The diagnostic cutoff points for hypertension are not as important here as the specific numerical blood pressure values. We need to consider hypertension as a continuous variable, and not dichotomous (present or absent). The root issue would become crystal clear from the patient's sequential blood pressures: day 1, 130/90 mm Hg (start of ibuprofen 2400 mg daily); day 6, 130/80 mm Hg; day 10, 160/100 mm Hg; day 16, 170/100 mm Hg; day 19, 188/120 mm Hg (accelerated hypertension); day 22, 160/100 mm Hg; and day 139, 219/138 mm Hg (hypertensive crisis with cerebrovascular hemorrhage, while taking valdecoxib 10 mg daily). Although both values (130/90 and 188/120 mm Hg) represent hypertension, there is a day-and-night difference between their clinical significance. Moreover, even if the patient had been prehypertensive or even marginally hypertensive before the injury, it did not really matter. She had lived for 28 years without any known disability, and there was no reason to prognosticate that her life expectancy was going to be so short. It is only after the ibuprofen consumption that the patient's blood pressure rose exponentially to eventually reach dangerous levels. We admit that even severe hypertension can remain subclinical and suddenly cause hypertensive crisis. However, this patient did not have severe preinjury hypertension. In fact, there is a documentation of relatively benign blood pressures till day 6. NSAID nephrotoxicity is well-documented in the literature, especially in patients with impaired kidney function.1,6 NSAID prescribing information routinely contains admonitions about “renal disease” under Warnings and Adverse Reactions. Valdecoxib (selective COX-2 inhibitor NSAID) was withdrawn from the US market in 2005 because of an increased risk of cardiovascular events (including heart attack and stroke) and serious skin reactions. BODY WEIGHT The patient was indeed overweight and therefore at risk for hypertension. Nevertheless, she did not have hypertension till after day 6. So, her being overweight was inconsequential. In the United States, 36% adults are obese, and 69% obese or overweight.7 Not all overweight people are hypertensive. SMALL KIDNEYS Renal function does correlate with kidney size. The usual adult kidney size is as follows: length 11.5 to 12.0 cm, width 5.0 to 7.0 cm, and thickness 2.5 to 3.0 cm.8 There is no official definition of “small kidneys,” and there is significant interobserver variability. When developmental (renal hypoplasia), they are defined as smaller than the 95th percentile (2 standard deviations below the mean) for a given age; the usual standard deviation value is 0.9 to 1.0.9 The actual dimensions of this patient's kidneys were unavailable to us. The radiology report merely stated that both kidneys were small and echogenic; clearly, radiology reports should routinely provide details (eg, specific dimensions and reference normal values). Because of the patient's death and the disputed nature of her kidney claim, we could not obtain the actual ultrasonographic films. We know that people can survive with one kidney, and that kidneys shrink up to 30% with age. Therefore, the patient would have had a healthy life expectancy even if her kidneys were half the normal size. Even if she had preexisting small kidneys, they had been sufficiently functional for a productive life for 28 years. Besides the ibuprofen and valdecoxib, there was no reason for her small kidneys to suddenly fail so severely and so quickly. Let us not miss the forest for the trees. PROOF OF TAKING MEDICINES Sometimes, patients do not take medicines as prescribed because of doubts about need, cost, carelessness, polypharmacy, side effects, confusion, debility, senility, unavailability, postponement, job priorities, inconvenience, etc.10 However these negative factors usually affect chronic or subtle conditions, and do not apply in this case. In contrast, several affirmative reasons suggest that our patient took the medicines as prescribed. First, ibuprofen was dispensed without charge in the clinic itself—the patient did not have to obtain or buy it from a pharmacy elsewhere. Second, the clinic's dispensing log contained documentation (lot number, $27.70 charge) of dispensing 30 tablets of ibuprofen 800 mg on days 1 and 10. Third, ibuprofen prescriptions and dosing in physician's progress notes corroborated the dispensing logs. Fourth, the clinic dispensed the second bottle of ibuprofen on day 10, which indicated that the patient had finished the original 30 tablets by taking them as prescribed. Fifth, clinic notes documented significant acute pain, for which ibuprofen is normally prescribed in the community. Sixth, records verified that the patient's employer did not honor her work restrictions; this increased pain in the injured hand, and the need for ibuprofen. Seventh, an orthopedist recommended continuation of ibuprofen on day 29. Eighth, another orthopedist prescribed 30 tablets of valdecoxib 10 mg on days 76, 106, and 134; copies of the three separate prescriptions were in the patient's file. Ninth, valdecoxib was prescribed at roughly 30-day intervals, indicating that the patient had taken the previous 30 tablets as directed. Tenth, cost would not have been a factor. Valdecoxib was for the accepted hand injury claim for which the patient's employer had previously fully paid, and must have authorized a pharmacy to dispense valdecoxib without charge to the patient. Had there been a valdecoxib coverage issue, the prescriber would have changed the drug. Records contained no denials. Eleventh, the patient had a significant acute injury for which she sought relief and willingly went to the doctor; she therefore must have taken the medicines. Twelfth, there was nothing in the patient's records to indicate malingering or falsification. Thirteenth, the dangerous and progressive rise in blood pressure was tell-tale evidence of ibuprofen toxicity—the proof was in the pudding. Finally, there is nothing to suggest that this patient did not take medicines. With most other cases, we accept patients' word about medicine intake. Directly observed administration is not required as proof of taking ibuprofen or valdecoxib. Why a double standard here? PHYSICIANS' ERRORS We have no information about related professional negligence claim or peer review action. We are aware of other cases where no claim was filed despite frank negligence. The most serious errors were committed by the clinic and the emergency department physicians, and the second orthopedic surgeon. There is no established peer review process for such small outpatient settings. In isolation, the day 19 emergency encounter would normally not get flagged since the patient improved symptomatically. Errors during the patient's two hospitalizations were not dramatic enough to catch attention during a routine hurried quality review. We did file an Adverse Drug Event report with the Food and Drug Administration. CLAIM DETAILS As the commentators have astutely noted, this is an older workers' compensation claim from 2003. The patient's employer accepted her hand injury claim, but denied the amended claim for kidney failure and death. In multiple reports, the employer's toxicology physician incorrectly argued that the patient had died of natural progression of renal failure from preexisting small kidneys, diabetes (even though she was normoglycemic on days 37 to 40), and hypertension (even though she was normotensive on days 1 to 6). He opined that her death was unrelated to the injury's treatment because of ibuprofen's strong safety record and over-the-counter availability, lack of proof of actual ibuprofen consumption, omission of ibuprofen as a cause from the death certificate, and the lengthy interval between death and the last ibuprofen dose. He limited his toxicology research to the toxic effects listed on an ibuprofen (Advil) bottle, completely ignored valdecoxib, and did not correct his opinion even when contradictory evidence was presented. Clearly, as required by California's landmark workers' compensation reform legislation (Senate Bill 899), physicians should “base their opinion on evidence and science that is nationally recognized and peer-reviewed,” and not on their incorrect dogmas. The entire claim was settled in 2012 by “Compromise and Release,” wherein the parties buy their peace to avoid the risk and cost of extended litigation. Ghan-Shyam Lohiya, MD, MS, FACOEM Qualified Medical Evaluator, Occupational Medicine and Toxicology, Royal Medical Group, Santa Ana, Calif. Piyush Lohiya, MD Nephrologist, Tex. Sunita Lohiya, MD Occupational Medicine Physician, Royal Medical Group, Santa Ana, Calif. Vamsi Krishna, MD Fellow, Department of Cardiology, University of California, Irvine, Calif.

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