Not everything in life occurs as planned.
Ten days ago, a child was admitted to the Pediatric Research Ward at Queen Elizabeth Central Hospital (“Queens”) in Blantyre, Malawi. Her story was familiar. A previously healthy child, she woke up one morning with a high fever. Her family gave her fever reducing medicine and for the next few hours she felt a little better. The next morning, though, her fever was higher. Shortly thereafter, she had a short seizure and did not wake up afterwards.
Her family scooped her up in their arms and took her to the local health center. The health center referred the family onto a local hospital. The physicians at the local hospital contacted the Blantyre Malaria Project. Our physicians heard the story and arranged transportation for the child and her family to be brought to Queens. On arrival she was extremely ill. Her circulation was poor, and she was deeply comatose. When blood tests showed malaria infection, she was started on intravenous antimalarial medicines. Further testing showed other complications: her kidneys were failing and her effective circulation (the amount of blood being pumped out to her body) was poor, producing a build up of lactic acid in her blood.
The team approached her family to explain the research studies for which this young child was eligible. One of these is the Treating Brain Swelling clinical trial. In this study, eligible children, after they are medically stabilized, undergo brain MRI. Malaria can often cause a severe swelling in the brain and this is associated with a high risk of death. In this clinical trial, if an eligible child has severe brain swelling and the family consents, the child is randomly assigned to one of three treatments, added onto the high standard of care already in place at the Research Ward. The aim of the clinical trial is to decrease death from cerebral malaria, without increasing the severity of neurological abnormalities in those who survive. (Saving a life but leaving a child profoundly neurologically impaired didn’t seem like a great outcome when we were designing this clinical trial!)
Though patient safety must be the most important aspect of any physician-patient encounter (Do No Harm), this is especially true in clinical trials where the treatments are not yet proven to be helpful or harmful.
This young child received her brain MRI using our new portable Hyperfine machine. Two neuroradiologists viewed the images and agreed that her brain was severely swollen. Receiving this news, the team again approached her family and asked if they could randomly assign their child to be given one of these new treatments. They agreed. The girl was to be placed on a mechanical ventilator, a new technology in Malawi and unproven in severe cerebral malaria. The girl was transported across the street to the Mercy James Centre (thank you Madonna!) and one of our team’s intensive care unit doctors took over. The doctor sedated the child, put in an endotracheal tube, and started up the ventilator.
For the next two days things went well. The child’s repeat MRI scans showed that her brain was still severely swollen. The child remained deeply comatose, had a few more seizures, and these were treated. Bad but nothing out of the usual. But on her fourth day after arriving at the hospital, problems ensued. The girl began to have bronchospasm. Like asthma, her lungs were having difficulty emptying as she exhaled. Deep suctioning through her endotracheal tube showed no obstruction. The doctors decreased one of the ventilator’s pressures (the PEEP, positive end-expiratory pressure), the usual remedy to improve exhalation. It wasn’t working very well. The nurses tried more deep suctioning to see if mucus might be obstructing her airways farther down, causing her to be unable to effectively exhale. Nothing.
A few hours later, deep suctioning started to bring up old blood clots. Shortly afterwards, the child began coughing and bright red blood was in her endotracheal tube. She was hemorrhaging from somewhere in her breathing passages and it was not clear where or why this was happening. To stop bleeding, normally one applies pressure to a wound. Using a ventilator to stop bleeding, one increases the pressures, especially the PEEP. But, of course, increasing the PEEP would worsen the child’s ability to effectively exhale, something with which she was having trouble due to her bronchospasm. The intensive care unit doctors had to walk a tightrope. They needed to increase the PEEP to stop the bleeding but not so much that it would stop her exhaling and make the carbon dioxide in her blood rise to dangerous levels.
This tightrope walk lasted two days.
In the meantime, it was my job to let the many people overseeing the clinical trial know what was happening. Though patient safety must be the most important aspect of any physician-patient encounter (Do No Harm), this is especially true in clinical trials where the treatments are not yet proven to be helpful or harmful. Consequently, there are several layers of safety overview for these studies. First are the investigators, the people doing the study. Second are Independent Safety Monitors (ISMs), physicians familiar with the disease being studied, the new treatments, and the medical system in which the trial is conducted. (Medical care in Malawi and the USA is very different, so doing clinical trials in them is different as well.) Third are the two ethics boards that watch over the study, one in Malawi and the other in the USA. Fourth, atop this pile, is the NIH itself. Each clinical trial funded by the NIH has a Medical Monitor, a physician who reviews everything and makes sure that people being enrolled in the study are safe. Any of these four layers of safety oversight can stop a clinical trial if they think something unsafe is happening.
In medical care, as in life, not everything goes according to plan. In clinical trials, bad things that happen to patients are termed “Adverse Events.” These are graded from 1 to 3, three being the worst. If an adverse event fulfills certain criteria (among other possibilities it results in death or disability, prolongs or causes a hospitalization, or hurts an unborn fetus) it is called a Severe Adverse Event or SAE. SAEs must be reported to all four layers of safety oversight within 24 hours of their occurrence. The paperwork is complicated, and, in my opinion, it is best to assign one person to deal with all these safety oversight bodies. In the Treating Brain Swelling clinical trial, I am that person. None of it is difficult, but, when patient safety is at stake, it is important.
Fortunately, three days after the bronchospasm and bleeding started, the young girl’s severe brain swelling resolved. She was successfully taken off the ventilator. I was happy to inform each of the four layers of clinical trial oversight that this SAE was Resolved, the outcome we all aimed for. The child continues to recover, and we are all hoping that in a few days she will walk out of the Research Ward and return to her home village, back into the arms of her entire loving family.
